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[
"Fanconi Pancytopenia",
"Fanconi Pancytopenia",
"Breast cancer type 1 susceptibility protein",
"Breast cancer type 2 susceptibility protein",
"DNA repair endonuclease XPF",
"DNA repair protein RAD51 homolog 1",
"DNA repair protein RAD51 homolog 3",
"DNA repair protein XRCC2",
"E3 ubiquitin-protein ligase FANCL",
"E3 ubiquitin-protein ligase RFWD3",
"Fanconi anemia core complex-associated protein 100",
"Fanconi anemia group A protein",
"Fanconi anemia group B protein",
"Fanconi anemia group C protein",
"Fanconi anemia group D2 protein",
"Fanconi anemia group E protein",
"Fanconi anemia group F protein",
"Fanconi anemia group G protein",
"Fanconi anemia group I protein",
"Fanconi anemia group J protein",
"Fanconi anemia group M protein",
"Mitotic spindle assembly checkpoint protein MAD2B",
"Partner and localizer of BRCA2",
"Structure-specific endonuclease subunit SLX4",
"Ubiquitin-conjugating enzyme E2 T",
"BRCA1",
"BRCA2",
"BRIP1",
"ERCC4",
"FAAP100",
"FANCA",
"FANCB",
"FANCC",
"FANCD2",
"FANCE",
"FANCF",
"FANCG",
"FANCI",
"FANCL",
"FANCM",
"MAD2L2",
"PALB2",
"RAD51",
"RAD51C",
"RFWD3",
"SLX4",
"UBE2T",
"XRCC2",
"Fanconi Anemia"
] |
Fanconi Anemia
|
Parinda A Mehta, Christen Ebens
|
Summary Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA. The diagnosis of FA is established in a proband with increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC) and/or one of the following identified on molecular genetic testing: biallelic pathogenic variants in one of the 21 genes known to cause autosomal recessive FA; a heterozygous pathogenic variant in Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner ( Carrier testing for at-risk relatives (for autosomal recessive and X-linked FA) and prenatal and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known.
|
## Diagnosis
Recommendations for diagnosis were agreed upon at a 2013 consensus conference (see
Fanconi anemia (FA)
Prenatal and/or postnatal short stature
Abnormal skin pigmentation (e.g., café au lait macules, hypopigmentation)
Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)
Microcephaly
Ophthalmic anomalies
Genitourinary tract anomalies
Macrocytosis
Increased fetal hemoglobin (often precedes anemia)
Cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)
Progressive bone marrow failure
Adult-onset aplastic anemia
Myelodysplastic syndrome (MDS)
Acute myelogenous leukemia (AML)
Early-onset solid tumors (e.g., squamous cell carcinomas of the head and neck, esophagus, and vulva; cervical cancer; liver tumors)
Inordinate toxicities from chemotherapy or radiation
The diagnosis of FA
Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC).
Note: (1) The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers use DEB while other centers use both DEB and MMC. (2) If results of lymphocyte testing are normal or inconclusive and mosaicism is suspected, testing can be performed on an alternative cell type, such as skin fibroblasts. See
Identification of biallelic pathogenic (or likely pathogenic) variants in one of the 21 genes known to cause autosomal recessive FA, or a heterozygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fanconi Anemia
NA = not applicable
Genes are listed in alphabetic order.
See
Prior to identification of the genes, complementation groups were defined based on somatic cell-based methods. While complementation analysis testing has been supplanted by multigene panels; this terminology continues to be used in some contexts.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Author, personal communication
• Prenatal and/or postnatal short stature
• Abnormal skin pigmentation (e.g., café au lait macules, hypopigmentation)
• Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)
• Microcephaly
• Ophthalmic anomalies
• Genitourinary tract anomalies
• Macrocytosis
• Increased fetal hemoglobin (often precedes anemia)
• Cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)
• Progressive bone marrow failure
• Adult-onset aplastic anemia
• Myelodysplastic syndrome (MDS)
• Acute myelogenous leukemia (AML)
• Early-onset solid tumors (e.g., squamous cell carcinomas of the head and neck, esophagus, and vulva; cervical cancer; liver tumors)
• Inordinate toxicities from chemotherapy or radiation
• Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC).
• Note: (1) The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers use DEB while other centers use both DEB and MMC. (2) If results of lymphocyte testing are normal or inconclusive and mosaicism is suspected, testing can be performed on an alternative cell type, such as skin fibroblasts. See
• Identification of biallelic pathogenic (or likely pathogenic) variants in one of the 21 genes known to cause autosomal recessive FA, or a heterozygous pathogenic (or likely pathogenic) variant in
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Fanconi anemia (FA)
Prenatal and/or postnatal short stature
Abnormal skin pigmentation (e.g., café au lait macules, hypopigmentation)
Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)
Microcephaly
Ophthalmic anomalies
Genitourinary tract anomalies
Macrocytosis
Increased fetal hemoglobin (often precedes anemia)
Cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)
Progressive bone marrow failure
Adult-onset aplastic anemia
Myelodysplastic syndrome (MDS)
Acute myelogenous leukemia (AML)
Early-onset solid tumors (e.g., squamous cell carcinomas of the head and neck, esophagus, and vulva; cervical cancer; liver tumors)
Inordinate toxicities from chemotherapy or radiation
• Prenatal and/or postnatal short stature
• Abnormal skin pigmentation (e.g., café au lait macules, hypopigmentation)
• Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)
• Microcephaly
• Ophthalmic anomalies
• Genitourinary tract anomalies
• Macrocytosis
• Increased fetal hemoglobin (often precedes anemia)
• Cytopenia (especially thrombocytopenia, leukopenia, and neutropenia)
• Progressive bone marrow failure
• Adult-onset aplastic anemia
• Myelodysplastic syndrome (MDS)
• Acute myelogenous leukemia (AML)
• Early-onset solid tumors (e.g., squamous cell carcinomas of the head and neck, esophagus, and vulva; cervical cancer; liver tumors)
• Inordinate toxicities from chemotherapy or radiation
## Establishing the Diagnosis
The diagnosis of FA
Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC).
Note: (1) The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers use DEB while other centers use both DEB and MMC. (2) If results of lymphocyte testing are normal or inconclusive and mosaicism is suspected, testing can be performed on an alternative cell type, such as skin fibroblasts. See
Identification of biallelic pathogenic (or likely pathogenic) variants in one of the 21 genes known to cause autosomal recessive FA, or a heterozygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fanconi Anemia
NA = not applicable
Genes are listed in alphabetic order.
See
Prior to identification of the genes, complementation groups were defined based on somatic cell-based methods. While complementation analysis testing has been supplanted by multigene panels; this terminology continues to be used in some contexts.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Author, personal communication
• Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC).
• Note: (1) The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers use DEB while other centers use both DEB and MMC. (2) If results of lymphocyte testing are normal or inconclusive and mosaicism is suspected, testing can be performed on an alternative cell type, such as skin fibroblasts. See
• Identification of biallelic pathogenic (or likely pathogenic) variants in one of the 21 genes known to cause autosomal recessive FA, or a heterozygous pathogenic (or likely pathogenic) variant in
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
The primary clinical features of Fanconi anemia (FA) include physical features, progressive bone marrow failure manifest as pancytopenia, and cancer susceptibility; however, some individuals with FA have neither physical abnormalities nor bone marrow failure.
Physical features occur in approximately 75% of individuals with FA.
Growth deficiency. Prenatal and/or postnatal short stature, low birth weight
Abnormal skin pigmentation (40%). Generalized hyperpigmentation; café au lait macules, hypopigmentation
Skeletal malformations of upper limbs, unilateral or bilateral (35%):
Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
Ulnae (1%). Dysplastic, short
Skeletal malformations of lower limbs (5%):
Syndactyly, abnormal toes, club feet
Congenital hip dislocation
Microcephaly (20%)
Ophthalmic (20%). Microphthalmia, cataracts, astigmatism, strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosis
Genitourinary tract anomalies:
Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
Females (2%). Bicornuate or uterus malposition, small ovaries
Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
Endocrine disorders (50%-75%). Hypothyroidism (30%-60%), diabetes (8%-10%), hyperglycemia / impaired glucose tolerance (25%-70%), and insulin resistance [
Hearing loss (10%). Usually conductive secondary to middle-ear bony anomalies with or without additional ear anomalies (e.g., dysplastic auricle, narrow ear canal, abnormal pinna)
Congenital heart defect (6%). Patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus
Gastrointestinal (5%). Esophageal, duodenal, or jejunal atresia, imperforate anus, tracheoesophageal fistula, annular pancreas, malrotation
Central nervous system (3%). Small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventricles
Other:
Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
Note: Percentages are calculated from 2,000 individuals reported in the literature from 1927 to 2014. Frequencies are approximate, since many reports did not mention physical descriptions.
Developmental delay and/or intellectual disability is seen in 10%.
The age of onset of bone marrow failure is highly variable, even among sibs. An analysis of 754 individuals with pathogenic variants in
Thrombocytopenia or leukopenia usually precede anemia. These are commonly associated with macrocytosis and elevated fetal hemoglobin.
Pancytopenia generally worsens over time.
Sweet syndrome (neutrophilic skin infiltration) was associated with progression of hematologic disease in six of seven individuals with FA [
The severity of bone marrow failure can be classified by the degree of cytopenia(s) (
Severity of Bone Marrow Failure in Fanconi Anemia
An increased risk of developing myelodysplastic syndrome (MDS)/AML is associated with monosomy 7 and most 7q deletions. Clonal amplifications of chromosome 3q26-q29 were reported in association with an increased risk of progression to MDS/AML [
Head and neck squamous cell carcinomas (HNSCCs) are the most common solid tumor in individuals with FA. The incidence is 500- to 700-fold higher than in the general population. The HNSCCs in FA show distinct differences from HNSCCs seen in the general population. HNSCCs:
Occur at an earlier age (20-40 years) than in the general population;
Most commonly occur in the oral cavity (e.g., tongue);
Present at an advanced stage;
Respond poorly to therapy.
Individuals with FA are at increased risk for second primary cancers of the skin and genitourinary tract. The pattern of second primaries resembles that observed in HPV-associated HNSCCs in the general population [
Individuals with FA receiving androgen treatment for bone marrow failure are also at increased risk for liver tumors.
The clinical spectrum of FA remains heterogenous. There are no clear-cut genotype-phenotype correlations. In general, null variants lead to a more severe phenotype (e.g., congenital anomalies, early-onset bone marrow failure, and MDS/AML) than hypomorphic variants. A literature review of genotype-phenotype associations in Fanconi anemia was recently published [
Fanconi anemia (FA) is the most common genetic cause of aplastic anemia and one of the most common genetic causes of hematologic malignancy.
The ratio of males to females is 1.2:1 (p<0.001 vs expected 1.00).
• Growth deficiency. Prenatal and/or postnatal short stature, low birth weight
• Abnormal skin pigmentation (40%). Generalized hyperpigmentation; café au lait macules, hypopigmentation
• Skeletal malformations of upper limbs, unilateral or bilateral (35%):
• Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
• Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
• Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
• Ulnae (1%). Dysplastic, short
• Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
• Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
• Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
• Ulnae (1%). Dysplastic, short
• Skeletal malformations of lower limbs (5%):
• Syndactyly, abnormal toes, club feet
• Congenital hip dislocation
• Syndactyly, abnormal toes, club feet
• Congenital hip dislocation
• Microcephaly (20%)
• Ophthalmic (20%). Microphthalmia, cataracts, astigmatism, strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosis
• Genitourinary tract anomalies:
• Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
• Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
• Females (2%). Bicornuate or uterus malposition, small ovaries
• Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
• Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
• Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
• Females (2%). Bicornuate or uterus malposition, small ovaries
• Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
• Endocrine disorders (50%-75%). Hypothyroidism (30%-60%), diabetes (8%-10%), hyperglycemia / impaired glucose tolerance (25%-70%), and insulin resistance [
• Hearing loss (10%). Usually conductive secondary to middle-ear bony anomalies with or without additional ear anomalies (e.g., dysplastic auricle, narrow ear canal, abnormal pinna)
• Congenital heart defect (6%). Patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus
• Gastrointestinal (5%). Esophageal, duodenal, or jejunal atresia, imperforate anus, tracheoesophageal fistula, annular pancreas, malrotation
• Central nervous system (3%). Small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventricles
• Other:
• Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
• Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
• Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
• Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
• Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
• Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
• Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
• Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
• Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
• Ulnae (1%). Dysplastic, short
• Syndactyly, abnormal toes, club feet
• Congenital hip dislocation
• Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
• Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
• Females (2%). Bicornuate or uterus malposition, small ovaries
• Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
• Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
• Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
• Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
• Thrombocytopenia or leukopenia usually precede anemia. These are commonly associated with macrocytosis and elevated fetal hemoglobin.
• Pancytopenia generally worsens over time.
• Sweet syndrome (neutrophilic skin infiltration) was associated with progression of hematologic disease in six of seven individuals with FA [
• The severity of bone marrow failure can be classified by the degree of cytopenia(s) (
• Head and neck squamous cell carcinomas (HNSCCs) are the most common solid tumor in individuals with FA. The incidence is 500- to 700-fold higher than in the general population. The HNSCCs in FA show distinct differences from HNSCCs seen in the general population. HNSCCs:
• Occur at an earlier age (20-40 years) than in the general population;
• Most commonly occur in the oral cavity (e.g., tongue);
• Present at an advanced stage;
• Respond poorly to therapy.
• Occur at an earlier age (20-40 years) than in the general population;
• Most commonly occur in the oral cavity (e.g., tongue);
• Present at an advanced stage;
• Respond poorly to therapy.
• Individuals with FA are at increased risk for second primary cancers of the skin and genitourinary tract. The pattern of second primaries resembles that observed in HPV-associated HNSCCs in the general population [
• Individuals with FA receiving androgen treatment for bone marrow failure are also at increased risk for liver tumors.
• Occur at an earlier age (20-40 years) than in the general population;
• Most commonly occur in the oral cavity (e.g., tongue);
• Present at an advanced stage;
• Respond poorly to therapy.
## Clinical Description
The primary clinical features of Fanconi anemia (FA) include physical features, progressive bone marrow failure manifest as pancytopenia, and cancer susceptibility; however, some individuals with FA have neither physical abnormalities nor bone marrow failure.
Physical features occur in approximately 75% of individuals with FA.
Growth deficiency. Prenatal and/or postnatal short stature, low birth weight
Abnormal skin pigmentation (40%). Generalized hyperpigmentation; café au lait macules, hypopigmentation
Skeletal malformations of upper limbs, unilateral or bilateral (35%):
Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
Ulnae (1%). Dysplastic, short
Skeletal malformations of lower limbs (5%):
Syndactyly, abnormal toes, club feet
Congenital hip dislocation
Microcephaly (20%)
Ophthalmic (20%). Microphthalmia, cataracts, astigmatism, strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosis
Genitourinary tract anomalies:
Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
Females (2%). Bicornuate or uterus malposition, small ovaries
Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
Endocrine disorders (50%-75%). Hypothyroidism (30%-60%), diabetes (8%-10%), hyperglycemia / impaired glucose tolerance (25%-70%), and insulin resistance [
Hearing loss (10%). Usually conductive secondary to middle-ear bony anomalies with or without additional ear anomalies (e.g., dysplastic auricle, narrow ear canal, abnormal pinna)
Congenital heart defect (6%). Patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus
Gastrointestinal (5%). Esophageal, duodenal, or jejunal atresia, imperforate anus, tracheoesophageal fistula, annular pancreas, malrotation
Central nervous system (3%). Small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventricles
Other:
Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
Note: Percentages are calculated from 2,000 individuals reported in the literature from 1927 to 2014. Frequencies are approximate, since many reports did not mention physical descriptions.
Developmental delay and/or intellectual disability is seen in 10%.
The age of onset of bone marrow failure is highly variable, even among sibs. An analysis of 754 individuals with pathogenic variants in
Thrombocytopenia or leukopenia usually precede anemia. These are commonly associated with macrocytosis and elevated fetal hemoglobin.
Pancytopenia generally worsens over time.
Sweet syndrome (neutrophilic skin infiltration) was associated with progression of hematologic disease in six of seven individuals with FA [
The severity of bone marrow failure can be classified by the degree of cytopenia(s) (
Severity of Bone Marrow Failure in Fanconi Anemia
An increased risk of developing myelodysplastic syndrome (MDS)/AML is associated with monosomy 7 and most 7q deletions. Clonal amplifications of chromosome 3q26-q29 were reported in association with an increased risk of progression to MDS/AML [
Head and neck squamous cell carcinomas (HNSCCs) are the most common solid tumor in individuals with FA. The incidence is 500- to 700-fold higher than in the general population. The HNSCCs in FA show distinct differences from HNSCCs seen in the general population. HNSCCs:
Occur at an earlier age (20-40 years) than in the general population;
Most commonly occur in the oral cavity (e.g., tongue);
Present at an advanced stage;
Respond poorly to therapy.
Individuals with FA are at increased risk for second primary cancers of the skin and genitourinary tract. The pattern of second primaries resembles that observed in HPV-associated HNSCCs in the general population [
Individuals with FA receiving androgen treatment for bone marrow failure are also at increased risk for liver tumors.
• Growth deficiency. Prenatal and/or postnatal short stature, low birth weight
• Abnormal skin pigmentation (40%). Generalized hyperpigmentation; café au lait macules, hypopigmentation
• Skeletal malformations of upper limbs, unilateral or bilateral (35%):
• Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
• Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
• Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
• Ulnae (1%). Dysplastic, short
• Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
• Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
• Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
• Ulnae (1%). Dysplastic, short
• Skeletal malformations of lower limbs (5%):
• Syndactyly, abnormal toes, club feet
• Congenital hip dislocation
• Syndactyly, abnormal toes, club feet
• Congenital hip dislocation
• Microcephaly (20%)
• Ophthalmic (20%). Microphthalmia, cataracts, astigmatism, strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosis
• Genitourinary tract anomalies:
• Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
• Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
• Females (2%). Bicornuate or uterus malposition, small ovaries
• Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
• Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
• Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
• Females (2%). Bicornuate or uterus malposition, small ovaries
• Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
• Endocrine disorders (50%-75%). Hypothyroidism (30%-60%), diabetes (8%-10%), hyperglycemia / impaired glucose tolerance (25%-70%), and insulin resistance [
• Hearing loss (10%). Usually conductive secondary to middle-ear bony anomalies with or without additional ear anomalies (e.g., dysplastic auricle, narrow ear canal, abnormal pinna)
• Congenital heart defect (6%). Patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus
• Gastrointestinal (5%). Esophageal, duodenal, or jejunal atresia, imperforate anus, tracheoesophageal fistula, annular pancreas, malrotation
• Central nervous system (3%). Small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventricles
• Other:
• Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
• Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
• Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
• Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
• Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
• Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
• Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
• Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
• Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
• Ulnae (1%). Dysplastic, short
• Syndactyly, abnormal toes, club feet
• Congenital hip dislocation
• Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
• Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
• Females (2%). Bicornuate or uterus malposition, small ovaries
• Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
• Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
• Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
• Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
• Thrombocytopenia or leukopenia usually precede anemia. These are commonly associated with macrocytosis and elevated fetal hemoglobin.
• Pancytopenia generally worsens over time.
• Sweet syndrome (neutrophilic skin infiltration) was associated with progression of hematologic disease in six of seven individuals with FA [
• The severity of bone marrow failure can be classified by the degree of cytopenia(s) (
• Head and neck squamous cell carcinomas (HNSCCs) are the most common solid tumor in individuals with FA. The incidence is 500- to 700-fold higher than in the general population. The HNSCCs in FA show distinct differences from HNSCCs seen in the general population. HNSCCs:
• Occur at an earlier age (20-40 years) than in the general population;
• Most commonly occur in the oral cavity (e.g., tongue);
• Present at an advanced stage;
• Respond poorly to therapy.
• Occur at an earlier age (20-40 years) than in the general population;
• Most commonly occur in the oral cavity (e.g., tongue);
• Present at an advanced stage;
• Respond poorly to therapy.
• Individuals with FA are at increased risk for second primary cancers of the skin and genitourinary tract. The pattern of second primaries resembles that observed in HPV-associated HNSCCs in the general population [
• Individuals with FA receiving androgen treatment for bone marrow failure are also at increased risk for liver tumors.
• Occur at an earlier age (20-40 years) than in the general population;
• Most commonly occur in the oral cavity (e.g., tongue);
• Present at an advanced stage;
• Respond poorly to therapy.
## Physical Findings
Physical features occur in approximately 75% of individuals with FA.
Growth deficiency. Prenatal and/or postnatal short stature, low birth weight
Abnormal skin pigmentation (40%). Generalized hyperpigmentation; café au lait macules, hypopigmentation
Skeletal malformations of upper limbs, unilateral or bilateral (35%):
Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
Ulnae (1%). Dysplastic, short
Skeletal malformations of lower limbs (5%):
Syndactyly, abnormal toes, club feet
Congenital hip dislocation
Microcephaly (20%)
Ophthalmic (20%). Microphthalmia, cataracts, astigmatism, strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosis
Genitourinary tract anomalies:
Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
Females (2%). Bicornuate or uterus malposition, small ovaries
Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
Endocrine disorders (50%-75%). Hypothyroidism (30%-60%), diabetes (8%-10%), hyperglycemia / impaired glucose tolerance (25%-70%), and insulin resistance [
Hearing loss (10%). Usually conductive secondary to middle-ear bony anomalies with or without additional ear anomalies (e.g., dysplastic auricle, narrow ear canal, abnormal pinna)
Congenital heart defect (6%). Patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus
Gastrointestinal (5%). Esophageal, duodenal, or jejunal atresia, imperforate anus, tracheoesophageal fistula, annular pancreas, malrotation
Central nervous system (3%). Small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventricles
Other:
Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
Note: Percentages are calculated from 2,000 individuals reported in the literature from 1927 to 2014. Frequencies are approximate, since many reports did not mention physical descriptions.
• Growth deficiency. Prenatal and/or postnatal short stature, low birth weight
• Abnormal skin pigmentation (40%). Generalized hyperpigmentation; café au lait macules, hypopigmentation
• Skeletal malformations of upper limbs, unilateral or bilateral (35%):
• Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
• Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
• Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
• Ulnae (1%). Dysplastic, short
• Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
• Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
• Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
• Ulnae (1%). Dysplastic, short
• Skeletal malformations of lower limbs (5%):
• Syndactyly, abnormal toes, club feet
• Congenital hip dislocation
• Syndactyly, abnormal toes, club feet
• Congenital hip dislocation
• Microcephaly (20%)
• Ophthalmic (20%). Microphthalmia, cataracts, astigmatism, strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosis
• Genitourinary tract anomalies:
• Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
• Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
• Females (2%). Bicornuate or uterus malposition, small ovaries
• Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
• Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
• Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
• Females (2%). Bicornuate or uterus malposition, small ovaries
• Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
• Endocrine disorders (50%-75%). Hypothyroidism (30%-60%), diabetes (8%-10%), hyperglycemia / impaired glucose tolerance (25%-70%), and insulin resistance [
• Hearing loss (10%). Usually conductive secondary to middle-ear bony anomalies with or without additional ear anomalies (e.g., dysplastic auricle, narrow ear canal, abnormal pinna)
• Congenital heart defect (6%). Patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus
• Gastrointestinal (5%). Esophageal, duodenal, or jejunal atresia, imperforate anus, tracheoesophageal fistula, annular pancreas, malrotation
• Central nervous system (3%). Small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventricles
• Other:
• Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
• Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
• Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
• Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
• Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
• Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
• Thumbs (35%). Absent, hypoplastic, bifid, duplicated, triphalangeal, long, proximally placed
• Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse
• Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly
• Ulnae (1%). Dysplastic, short
• Syndactyly, abnormal toes, club feet
• Congenital hip dislocation
• Renal (20%). Horseshoe, ectopic, pelvic, hypoplastic, dysplastic, or absent kidney; hydronephrosis or hydroureter
• Males (25%). Hypospadias, micropenis, cryptorchidism, anorchia, hypo- or azoospermia, reduced fertility
• Females (2%). Bicornuate or uterus malposition, small ovaries
• Note: Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation (HSCT).
• Facial features (2%). Triangular face shape, micrognathia, mid-face hypoplasia
• Spine anomalies (2%). Spina bifida, scoliosis, hemivertebrae, rib anomalies, coccygeal aplasia
• Neck anomalies (1%). Sprengel deformity, Klippel-Feil anomaly, short or webbed neck, low hairline
## Developmental Delay / Intellectual Disability
Developmental delay and/or intellectual disability is seen in 10%.
## Bone Marrow Failure
The age of onset of bone marrow failure is highly variable, even among sibs. An analysis of 754 individuals with pathogenic variants in
Thrombocytopenia or leukopenia usually precede anemia. These are commonly associated with macrocytosis and elevated fetal hemoglobin.
Pancytopenia generally worsens over time.
Sweet syndrome (neutrophilic skin infiltration) was associated with progression of hematologic disease in six of seven individuals with FA [
The severity of bone marrow failure can be classified by the degree of cytopenia(s) (
Severity of Bone Marrow Failure in Fanconi Anemia
• Thrombocytopenia or leukopenia usually precede anemia. These are commonly associated with macrocytosis and elevated fetal hemoglobin.
• Pancytopenia generally worsens over time.
• Sweet syndrome (neutrophilic skin infiltration) was associated with progression of hematologic disease in six of seven individuals with FA [
• The severity of bone marrow failure can be classified by the degree of cytopenia(s) (
## Cancer Susceptibility
An increased risk of developing myelodysplastic syndrome (MDS)/AML is associated with monosomy 7 and most 7q deletions. Clonal amplifications of chromosome 3q26-q29 were reported in association with an increased risk of progression to MDS/AML [
Head and neck squamous cell carcinomas (HNSCCs) are the most common solid tumor in individuals with FA. The incidence is 500- to 700-fold higher than in the general population. The HNSCCs in FA show distinct differences from HNSCCs seen in the general population. HNSCCs:
Occur at an earlier age (20-40 years) than in the general population;
Most commonly occur in the oral cavity (e.g., tongue);
Present at an advanced stage;
Respond poorly to therapy.
Individuals with FA are at increased risk for second primary cancers of the skin and genitourinary tract. The pattern of second primaries resembles that observed in HPV-associated HNSCCs in the general population [
Individuals with FA receiving androgen treatment for bone marrow failure are also at increased risk for liver tumors.
• Head and neck squamous cell carcinomas (HNSCCs) are the most common solid tumor in individuals with FA. The incidence is 500- to 700-fold higher than in the general population. The HNSCCs in FA show distinct differences from HNSCCs seen in the general population. HNSCCs:
• Occur at an earlier age (20-40 years) than in the general population;
• Most commonly occur in the oral cavity (e.g., tongue);
• Present at an advanced stage;
• Respond poorly to therapy.
• Occur at an earlier age (20-40 years) than in the general population;
• Most commonly occur in the oral cavity (e.g., tongue);
• Present at an advanced stage;
• Respond poorly to therapy.
• Individuals with FA are at increased risk for second primary cancers of the skin and genitourinary tract. The pattern of second primaries resembles that observed in HPV-associated HNSCCs in the general population [
• Individuals with FA receiving androgen treatment for bone marrow failure are also at increased risk for liver tumors.
• Occur at an earlier age (20-40 years) than in the general population;
• Most commonly occur in the oral cavity (e.g., tongue);
• Present at an advanced stage;
• Respond poorly to therapy.
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
The clinical spectrum of FA remains heterogenous. There are no clear-cut genotype-phenotype correlations. In general, null variants lead to a more severe phenotype (e.g., congenital anomalies, early-onset bone marrow failure, and MDS/AML) than hypomorphic variants. A literature review of genotype-phenotype associations in Fanconi anemia was recently published [
## Prevalence
Fanconi anemia (FA) is the most common genetic cause of aplastic anemia and one of the most common genetic causes of hematologic malignancy.
The ratio of males to females is 1.2:1 (p<0.001 vs expected 1.00).
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
## Differential Diagnosis
Cells derived from individuals with other chromosome breakage syndromes may also exhibit high rates of spontaneous chromosome breakage; however, only cells derived from individuals with Fanconi anemia (FA) exhibit increased chromosome breakage in response to diepoxybutane (DEB). See
Genes and Disorders of Interest in the Differential Diagnosis of Fanconi Anemia
AD = autosomal dominant; AR = autosomal recessive; DEB = diepoxybutane; FA = Fanconi anemia; ID = intellectual disability; MMC = mitomycin C; MOI = mode of inheritance
The diagnosis of thrombocytopenia absent radius syndrome is confirmed by identification of a null heterozygous allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1, but in some cases a heterozygous
## Management
To establish the extent of disease and management requirements in an individual diagnosed with Fanconi anemia (FA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fanconi Anemia
Urgent eval w/gastroenterologist & surgery for those w/obstructive GI malformations (e.g., esophageal atresia, duodenal atresia, or imperforate or bifurcated anus) &/or tracheoesophageal fistula, intestinal malrotation, or annular pancreas
Nutrition/feeding eval as needed
Community or
Social work involvement for parental support;
Home nursing referral.
FA = Fanconi anemia; GI = gastrointestinal; HLA = human leukocyte antigen; MOI = mode of inheritance; MDS = myelodysplastic syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommendations for treatment were agreed upon at a 2014 consensus conference and updated in 2020 (
Treatment of Manifestations in Individuals with Fanconi Anemia
Mgmt per orthopedic surgeon
PT, OT
Supplemental feeding as needed by nasogastric tube or gastrostomy
Vitamin D supplementation
Liberal use of sunscreen & rash guards
Treatment per dermatologist
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
DD = developmental delay; OT = occupational therapy; PT = physical therapy
Oxymetholone, given orally at a starting dose of 2 mg/kg/day, may be increased up to 5 mg/kg/day.
Doses may be slowly tapered to the minimal effective dose with careful monitoring of the blood counts.
Other synthetic androgens used in FA include stanozolol in Asia, and oxandrolone and danazol in North America.
Side effects of androgen administration include virilization and liver toxicity (e.g., elevated liver enzymes, cholestasis, peliosis hepatis [vascular lesion with multiple blood-filled cysts], and hepatic tumors). Individuals taking androgens should be monitored for liver tumors and undergo regular liver function tests (LFTs) for abnormalities. Blood tests for LFTs should be performed every three to six months; liver ultrasound should be performed every six to twelve months. If no response is seen after three to four months, androgens should be discontinued [
A multi-institutional study reported a one-year probability of overall survival of 80% in 45 individuals with FA transplanted for marrow failure and/or MDS, using alternative donors (including mismatched related and unrelated donors) and chemotherapy-only preparative regimen. Survival for individuals younger than age ten years transplanted for marrow failure was even better, at 91.3% (±5.9%) [
Fludarabine reduced the incidence of graft failure and allowed for removal of radiation from the preparative regimens in a matched sib donor setting [
Human papilloma virus (HPV) vaccination should be initiated at age nine years in order to reduce the risk of gynecologic cancer in females, and possibly reduce the risk of oral cancer in all individuals.
Individuals with FA treated with HSCT who developed GVHD had a 28% incidence of head and neck cancers in the ten years following treatment (vs 0% in those without GVHD); this finding points to the importance of minimizing the risk of GVHD [
Individuals successfully treated with HSCT are at increased risk for solid tumors, in addition to the baseline increased risk [
See 2020 consensus guidelines (
Recommended Surveillance for Individuals with Fanconi Anemia
TSH & free T4
25-hydroxy vitamin D
2-hr oral glucose tolerance test, insulin levels
Bone marrow aspirate/biopsy to evaluate morphology & cellularity
FISH; & cytogenetics to evaluate for emergence of a malignant clone
At least annually (after age 2 yrs)
In persons on GCSF, bone marrow aspirate/biopsy every 6 mos, if possible
Prompt investigation for hematologic disease progression incl in those who develop Sweet syndrome
Every 6 mos beginning by age 9-10 yrs
Every 2-3 mos in those w/history of premalignant or malignant lesions
For example, hypothyroidism, vitamin D deficiency
Progressively changing blood counts without a potential cause (e.g., acute infection or suppression from medication) require immediate evaluation with a complete blood count and bone marrow examination with FISH and cytogenetics.
It is important to recognize that rising blood counts can be due to either the development of MDS/AML or, rarely, reversion of a germline pathogenic variant in a stem cell, which repopulates the marrow with normal cells (somatic stem cell mosaicism). These individuals may require immediate HSCT (for MDS/AML) or continued close monitoring with complete blood counts at least every one to two months and a bone marrow examination with cytogenetics every six months.
Neuroblastomas, brain tumors, kidney tumors
These cancer surveillance recommendations may be considered for persons with
It is appropriate to evaluate all sibs of an affected individual in order to identify as early as possible those who would benefit from appropriate monitoring for FA-related physical abnormalities, bone marrow failure, and related cancers. Evaluations include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC) for detection of increased chromosome breakage and radial forms.
See
Pregnancy is possible in females with FA, whether or not they have undergone HSCT [
Pregnancy needs to be managed by a high-risk maternal fetal obstetrician along with a hematologist.
Separately, the United States National Heart, Lung, and Blood Institute completed a Phase I trial of retroviral vector transduction of autologous CD34+ stem cells in individuals with
While some trials aim to correct CD34+ stem cells obtained from bone marrow harvest, others are exploring peripheral blood mobilization with combination of G-CSF and plerixafor, shown advantageous in pre-clinical models [
A Phase I/II trial will incorporate an anti-cKIT antibody into HSCT conditioning to aid in myeloablation and reduce chemotherapy/radiation toxicity. This will be given in combination with T-cell receptor alpha/beta depletion of the stem cell product to individuals older than age two years with bone marrow failure as the HSCT indication (Jasper Therapeutics sponsored at Stanford University in California).
Search
• Urgent eval w/gastroenterologist & surgery for those w/obstructive GI malformations (e.g., esophageal atresia, duodenal atresia, or imperforate or bifurcated anus) &/or tracheoesophageal fistula, intestinal malrotation, or annular pancreas
• Nutrition/feeding eval as needed
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Mgmt per orthopedic surgeon
• PT, OT
• Supplemental feeding as needed by nasogastric tube or gastrostomy
• Vitamin D supplementation
• Liberal use of sunscreen & rash guards
• Treatment per dermatologist
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• Oxymetholone, given orally at a starting dose of 2 mg/kg/day, may be increased up to 5 mg/kg/day.
• Doses may be slowly tapered to the minimal effective dose with careful monitoring of the blood counts.
• Other synthetic androgens used in FA include stanozolol in Asia, and oxandrolone and danazol in North America.
• TSH & free T4
• 25-hydroxy vitamin D
• 2-hr oral glucose tolerance test, insulin levels
• Bone marrow aspirate/biopsy to evaluate morphology & cellularity
• FISH; & cytogenetics to evaluate for emergence of a malignant clone
• At least annually (after age 2 yrs)
• In persons on GCSF, bone marrow aspirate/biopsy every 6 mos, if possible
• Prompt investigation for hematologic disease progression incl in those who develop Sweet syndrome
• Every 6 mos beginning by age 9-10 yrs
• Every 2-3 mos in those w/history of premalignant or malignant lesions
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC) for detection of increased chromosome breakage and radial forms.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and management requirements in an individual diagnosed with Fanconi anemia (FA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fanconi Anemia
Urgent eval w/gastroenterologist & surgery for those w/obstructive GI malformations (e.g., esophageal atresia, duodenal atresia, or imperforate or bifurcated anus) &/or tracheoesophageal fistula, intestinal malrotation, or annular pancreas
Nutrition/feeding eval as needed
Community or
Social work involvement for parental support;
Home nursing referral.
FA = Fanconi anemia; GI = gastrointestinal; HLA = human leukocyte antigen; MOI = mode of inheritance; MDS = myelodysplastic syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Urgent eval w/gastroenterologist & surgery for those w/obstructive GI malformations (e.g., esophageal atresia, duodenal atresia, or imperforate or bifurcated anus) &/or tracheoesophageal fistula, intestinal malrotation, or annular pancreas
• Nutrition/feeding eval as needed
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Recommendations for treatment were agreed upon at a 2014 consensus conference and updated in 2020 (
Treatment of Manifestations in Individuals with Fanconi Anemia
Mgmt per orthopedic surgeon
PT, OT
Supplemental feeding as needed by nasogastric tube or gastrostomy
Vitamin D supplementation
Liberal use of sunscreen & rash guards
Treatment per dermatologist
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
DD = developmental delay; OT = occupational therapy; PT = physical therapy
Oxymetholone, given orally at a starting dose of 2 mg/kg/day, may be increased up to 5 mg/kg/day.
Doses may be slowly tapered to the minimal effective dose with careful monitoring of the blood counts.
Other synthetic androgens used in FA include stanozolol in Asia, and oxandrolone and danazol in North America.
Side effects of androgen administration include virilization and liver toxicity (e.g., elevated liver enzymes, cholestasis, peliosis hepatis [vascular lesion with multiple blood-filled cysts], and hepatic tumors). Individuals taking androgens should be monitored for liver tumors and undergo regular liver function tests (LFTs) for abnormalities. Blood tests for LFTs should be performed every three to six months; liver ultrasound should be performed every six to twelve months. If no response is seen after three to four months, androgens should be discontinued [
A multi-institutional study reported a one-year probability of overall survival of 80% in 45 individuals with FA transplanted for marrow failure and/or MDS, using alternative donors (including mismatched related and unrelated donors) and chemotherapy-only preparative regimen. Survival for individuals younger than age ten years transplanted for marrow failure was even better, at 91.3% (±5.9%) [
Fludarabine reduced the incidence of graft failure and allowed for removal of radiation from the preparative regimens in a matched sib donor setting [
• Mgmt per orthopedic surgeon
• PT, OT
• Supplemental feeding as needed by nasogastric tube or gastrostomy
• Vitamin D supplementation
• Liberal use of sunscreen & rash guards
• Treatment per dermatologist
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• Oxymetholone, given orally at a starting dose of 2 mg/kg/day, may be increased up to 5 mg/kg/day.
• Doses may be slowly tapered to the minimal effective dose with careful monitoring of the blood counts.
• Other synthetic androgens used in FA include stanozolol in Asia, and oxandrolone and danazol in North America.
## Prevention of Primary Manifestations
Human papilloma virus (HPV) vaccination should be initiated at age nine years in order to reduce the risk of gynecologic cancer in females, and possibly reduce the risk of oral cancer in all individuals.
## Prevention of Secondary Complications
Individuals with FA treated with HSCT who developed GVHD had a 28% incidence of head and neck cancers in the ten years following treatment (vs 0% in those without GVHD); this finding points to the importance of minimizing the risk of GVHD [
Individuals successfully treated with HSCT are at increased risk for solid tumors, in addition to the baseline increased risk [
## Surveillance
See 2020 consensus guidelines (
Recommended Surveillance for Individuals with Fanconi Anemia
TSH & free T4
25-hydroxy vitamin D
2-hr oral glucose tolerance test, insulin levels
Bone marrow aspirate/biopsy to evaluate morphology & cellularity
FISH; & cytogenetics to evaluate for emergence of a malignant clone
At least annually (after age 2 yrs)
In persons on GCSF, bone marrow aspirate/biopsy every 6 mos, if possible
Prompt investigation for hematologic disease progression incl in those who develop Sweet syndrome
Every 6 mos beginning by age 9-10 yrs
Every 2-3 mos in those w/history of premalignant or malignant lesions
For example, hypothyroidism, vitamin D deficiency
Progressively changing blood counts without a potential cause (e.g., acute infection or suppression from medication) require immediate evaluation with a complete blood count and bone marrow examination with FISH and cytogenetics.
It is important to recognize that rising blood counts can be due to either the development of MDS/AML or, rarely, reversion of a germline pathogenic variant in a stem cell, which repopulates the marrow with normal cells (somatic stem cell mosaicism). These individuals may require immediate HSCT (for MDS/AML) or continued close monitoring with complete blood counts at least every one to two months and a bone marrow examination with cytogenetics every six months.
Neuroblastomas, brain tumors, kidney tumors
These cancer surveillance recommendations may be considered for persons with
• TSH & free T4
• 25-hydroxy vitamin D
• 2-hr oral glucose tolerance test, insulin levels
• Bone marrow aspirate/biopsy to evaluate morphology & cellularity
• FISH; & cytogenetics to evaluate for emergence of a malignant clone
• At least annually (after age 2 yrs)
• In persons on GCSF, bone marrow aspirate/biopsy every 6 mos, if possible
• Prompt investigation for hematologic disease progression incl in those who develop Sweet syndrome
• Every 6 mos beginning by age 9-10 yrs
• Every 2-3 mos in those w/history of premalignant or malignant lesions
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
It is appropriate to evaluate all sibs of an affected individual in order to identify as early as possible those who would benefit from appropriate monitoring for FA-related physical abnormalities, bone marrow failure, and related cancers. Evaluations include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC) for detection of increased chromosome breakage and radial forms.
See
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC) for detection of increased chromosome breakage and radial forms.
## Pregnancy Management
Pregnancy is possible in females with FA, whether or not they have undergone HSCT [
Pregnancy needs to be managed by a high-risk maternal fetal obstetrician along with a hematologist.
## Therapies Under Investigation
Separately, the United States National Heart, Lung, and Blood Institute completed a Phase I trial of retroviral vector transduction of autologous CD34+ stem cells in individuals with
While some trials aim to correct CD34+ stem cells obtained from bone marrow harvest, others are exploring peripheral blood mobilization with combination of G-CSF and plerixafor, shown advantageous in pre-clinical models [
A Phase I/II trial will incorporate an anti-cKIT antibody into HSCT conditioning to aid in myeloablation and reduce chemotherapy/radiation toxicity. This will be given in combination with T-cell receptor alpha/beta depletion of the stem cell product to individuals older than age two years with bone marrow failure as the HSCT indication (Jasper Therapeutics sponsored at Stanford University in California).
Search
## Genetic Counseling
Fanconi anemia (FA) is inherited in an autosomal recessive manner, an autosomal dominant manner (
The parents of a child with autosomal recessive FA are obligate heterozygotes (i.e., presumed to be carriers of one FA-related pathogenic variant based on family history).
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an FA-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent of a child with autosomal recessive FA, the following possibilities should be considered:
Heterozygotes are not at risk for autosomal recessive FA. However, heterozygous mutation of a subset of FA-related genes (e.g.,
If both parents are known to be heterozygous for an autosomal recessive FA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of inheriting neither of the familial FA-related pathogenic variants.
Heterozygotes are not at risk for FA. However, heterozygous mutation of a subset of FA-related genes (e.g.,
Individuals who are heterozygous for an autosomal recessive FA-related pathogenic variant cannot be detected by the DEB/MMC test.
All probands with
Molecular genetic testing is recommended for the parents of the proband evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the
The father of a male with X-linked FA will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Male sibs who inherit the pathogenic variant will be affected;
Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected [
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Affected males transmit the
To date, no male with
Note: Molecular genetic testing may be able to identify the family member in whom a
Individuals who are heterozygous for a
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers) or who are at increased risk of being heterozygotes.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of a child with autosomal recessive FA are obligate heterozygotes (i.e., presumed to be carriers of one FA-related pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an FA-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent of a child with autosomal recessive FA, the following possibilities should be considered:
• Heterozygotes are not at risk for autosomal recessive FA. However, heterozygous mutation of a subset of FA-related genes (e.g.,
• If both parents are known to be heterozygous for an autosomal recessive FA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of inheriting neither of the familial FA-related pathogenic variants.
• Heterozygotes are not at risk for FA. However, heterozygous mutation of a subset of FA-related genes (e.g.,
• All probands with
• Molecular genetic testing is recommended for the parents of the proband evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the
• The father of a male with X-linked FA will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected [
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected [
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected [
• Affected males transmit the
• To date, no male with
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers) or who are at increased risk of being heterozygotes.
## Mode of Inheritance
Fanconi anemia (FA) is inherited in an autosomal recessive manner, an autosomal dominant manner (
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with autosomal recessive FA are obligate heterozygotes (i.e., presumed to be carriers of one FA-related pathogenic variant based on family history).
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an FA-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent of a child with autosomal recessive FA, the following possibilities should be considered:
Heterozygotes are not at risk for autosomal recessive FA. However, heterozygous mutation of a subset of FA-related genes (e.g.,
If both parents are known to be heterozygous for an autosomal recessive FA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of inheriting neither of the familial FA-related pathogenic variants.
Heterozygotes are not at risk for FA. However, heterozygous mutation of a subset of FA-related genes (e.g.,
Individuals who are heterozygous for an autosomal recessive FA-related pathogenic variant cannot be detected by the DEB/MMC test.
• The parents of a child with autosomal recessive FA are obligate heterozygotes (i.e., presumed to be carriers of one FA-related pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an FA-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent of a child with autosomal recessive FA, the following possibilities should be considered:
• Heterozygotes are not at risk for autosomal recessive FA. However, heterozygous mutation of a subset of FA-related genes (e.g.,
• If both parents are known to be heterozygous for an autosomal recessive FA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a heterozygote, and a 25% chance of inheriting neither of the familial FA-related pathogenic variants.
• Heterozygotes are not at risk for FA. However, heterozygous mutation of a subset of FA-related genes (e.g.,
## Autosomal Dominant Inheritance – Risk to Family Members
All probands with
Molecular genetic testing is recommended for the parents of the proband evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the
• All probands with
• Molecular genetic testing is recommended for the parents of the proband evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the
## X-Linked Inheritance – Risk to Family Members
The father of a male with X-linked FA will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Male sibs who inherit the pathogenic variant will be affected;
Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected [
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Affected males transmit the
To date, no male with
Note: Molecular genetic testing may be able to identify the family member in whom a
Individuals who are heterozygous for a
• The father of a male with X-linked FA will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected [
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected [
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Male sibs who inherit the pathogenic variant will be affected;
• Female sibs who inherit the pathogenic variant will be heterozygotes and will usually not be affected [
• Affected males transmit the
• To date, no male with
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers) or who are at increased risk of being heterozygotes.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers) or who are at increased risk of being heterozygotes.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Department of Medical and Molecular Genetics
3181 Southwest Sam Jackson Park Road L103
Oregon Health & Science University
Portland OR 97201
1801 Williamette Street
Suite 200
Eugene OR 97401
The Rockefeller University
1230 York Avenue
New York NY 10065
•
• Department of Medical and Molecular Genetics
• 3181 Southwest Sam Jackson Park Road L103
• Oregon Health & Science University
• Portland OR 97201
•
• 1801 Williamette Street
• Suite 200
• Eugene OR 97401
•
•
• The Rockefeller University
• 1230 York Avenue
• New York NY 10065
•
•
•
## Molecular Genetics
Fanconi Anemia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Fanconi Anemia (
See
At least 23 genes that are involved in Fanconi anemia (FA) and also account for each of the phenotypic complementation groups have been identified. The proteins encoded by the FA-related genes are considered to work together in a common pathway/network called "the FA pathway" or "the FA-BRCA pathway/network," which regulates cellular resistance to DNA cross-linking agents [
Eight of the FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM), along with proteins FAAP24 [
Furthermore, the FA core complex forms a larger complex with BLM, RPA, and topoisomerase IIIα, called BRAFT (
Amelioration of FA pathology has been implicated in reports of downregulation of elements of the non-homologous end-joining pathway [
Fanconi Anemia: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes from
Variant designation that does not conform to current naming conventions
See
## Molecular Pathogenesis
At least 23 genes that are involved in Fanconi anemia (FA) and also account for each of the phenotypic complementation groups have been identified. The proteins encoded by the FA-related genes are considered to work together in a common pathway/network called "the FA pathway" or "the FA-BRCA pathway/network," which regulates cellular resistance to DNA cross-linking agents [
Eight of the FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM), along with proteins FAAP24 [
Furthermore, the FA core complex forms a larger complex with BLM, RPA, and topoisomerase IIIα, called BRAFT (
Amelioration of FA pathology has been implicated in reports of downregulation of elements of the non-homologous end-joining pathway [
Fanconi Anemia: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes from
Variant designation that does not conform to current naming conventions
See
## Chapter Notes
Blanche P Alter, MD, MPH, FAAP; National Cancer Institute (2011-2016)Alan D'Andrea, MD; Dana Farber Cancer Institute (2002-2007) Christen Ebens, MD, MPH (2021-present)Gary Kupfer, MD; Yale University School of Medicine (2011-2016)Parinda A Mehta, MD (2016-present)Lisa Moreau, MS; Dana Farber Cancer Institute (2002-2007) Akiko Shimamura, MD, PhD; Dana Farber Cancer Institute (2002-2007) Toshiyasu Taniguchi, MD, PhD; Fred Hutchinson Cancer Research Center (2007-2011)Jakub Tolar, MD, PhD; University of Minnesota (2016-2021)
3 June 2021 (sw) Comprehensive update posted live
22 September 2016 (sw) Comprehensive update posted live
10 February 2011 (me) Comprehensive update posted live
22 June 2007 (me) Comprehensive update posted live
13 September 2004 (me) Comprehensive update posted live
14 February 2002 (me) Review posted live
31 May 2001 (as) Original submission
• 3 June 2021 (sw) Comprehensive update posted live
• 22 September 2016 (sw) Comprehensive update posted live
• 10 February 2011 (me) Comprehensive update posted live
• 22 June 2007 (me) Comprehensive update posted live
• 13 September 2004 (me) Comprehensive update posted live
• 14 February 2002 (me) Review posted live
• 31 May 2001 (as) Original submission
## Author Notes
## Author History
Blanche P Alter, MD, MPH, FAAP; National Cancer Institute (2011-2016)Alan D'Andrea, MD; Dana Farber Cancer Institute (2002-2007) Christen Ebens, MD, MPH (2021-present)Gary Kupfer, MD; Yale University School of Medicine (2011-2016)Parinda A Mehta, MD (2016-present)Lisa Moreau, MS; Dana Farber Cancer Institute (2002-2007) Akiko Shimamura, MD, PhD; Dana Farber Cancer Institute (2002-2007) Toshiyasu Taniguchi, MD, PhD; Fred Hutchinson Cancer Research Center (2007-2011)Jakub Tolar, MD, PhD; University of Minnesota (2016-2021)
## Revision History
3 June 2021 (sw) Comprehensive update posted live
22 September 2016 (sw) Comprehensive update posted live
10 February 2011 (me) Comprehensive update posted live
22 June 2007 (me) Comprehensive update posted live
13 September 2004 (me) Comprehensive update posted live
14 February 2002 (me) Review posted live
31 May 2001 (as) Original submission
• 3 June 2021 (sw) Comprehensive update posted live
• 22 September 2016 (sw) Comprehensive update posted live
• 10 February 2011 (me) Comprehensive update posted live
• 22 June 2007 (me) Comprehensive update posted live
• 13 September 2004 (me) Comprehensive update posted live
• 14 February 2002 (me) Review posted live
• 31 May 2001 (as) Original submission
## References
## Literature Cited
|
[] |
14/2/2002
|
3/6/2021
|
8/3/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
fabry
|
fabry
|
[
"Alpha-Galactosidase A Deficiency",
"Anderson-Fabry Disease",
"Alpha-Galactosidase A Deficiency",
"Anderson-Fabry Disease",
"Classic Fabry Disease",
"Atypical and Late-Onset Variants of Fabry Disease",
"Alpha-galactosidase A",
"GLA",
"Fabry Disease"
] |
Fabry Disease
|
Atul Mehta, Derralynn A Hughes
|
Summary Fabry disease is the most common of the lysosomal storage disorders and results from deficient activity of the enzyme alpha-galactosidase A (α-Gal A), leading to progressive lysosomal deposition of globotriaosylceramide and its derivatives in cells throughout the body. The classic form, occurring in males with less than 1% α-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of kidney function to end-stage kidney disease (ESKD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESKD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, females may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. In contrast, late-onset forms occur in males with greater than 1% α-Gal A activity. Clinical manifestations include cardiac disease, which usually presents in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy, arrhythmia, and proteinuria; kidney failure, associated with ESKD but without the skin lesions or pain; or cerebrovascular disease presenting as stroke or transient ischemic attack. Identification of deficient α-Gal A enzyme activity in plasma, isolated leukocytes, and/or cultured cells is the most efficient and reliable method of diagnosing Fabry disease in males. Identification of a hemizygous Fabry disease is inherited in an X-linked manner: hemizygous males are affected; heterozygous females may be as severely affected as males or asymptomatic throughout a normal life span. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. If a male is the only affected family member, his mother is likely heterozygous for the
|
Classic Fabry disease
Atypical & late-onset variants of Fabry disease
• Classic Fabry disease
• Atypical & late-onset variants of Fabry disease
## Diagnosis
Fabry disease typically affects more than one organ system and
Vascular cutaneous lesions (angiokeratomas)
Periodic crises of severe pain in the extremities (acroparesthesia)
Sweating abnormalities (hypohidrosis, anhidrosis, or rarely hyperhidrosis)
Cornea verticillata (characteristic corneal opacity) and lenticular opacities
Unexplained left ventricular hypertrophy or cardiac arrhythmia
Unexplained stroke
Abdominal pain, nausea, and/or diarrhea of unknown etiology in young adulthood consistent with irritable bowel syndrome
Renal insufficiency of unknown etiology including unexplained proteinuria or microalbuminuria
Identification of deficient alpha-galactosidase A (α-Gal A) enzyme activity in plasma, isolated leukocytes, and/or cultured cells. The test is a fluorometric assay and uses the substrate 4-methylumbelliferyl-α-D-galactopyranoside.
Males with classic Fabry disease have <1% α-Gal A enzyme activity.
Males with atypical Fabry disease have >1% α-Gal A enzyme activity.
Note: Both plasma and leukocyte enzyme activity should be assayed, as some pathogenic variants (e.g.,
Identification of a hemizygous pathogenic (or likely pathogenic) variant in
(See also
Note: (1) Measurement of α-Gal A enzyme activity is unreliable for identification of heterozygous females. Although demonstration of markedly decreased α-Gal A enzyme activity in a female is diagnostic of the heterozygous state, some heterozygotes have α-Gal A activity in the normal range. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: Targeted analysis can be performed first in individuals from Nova Scotia or individuals of Chinese ancestry with atypical presentation (see
For an introduction to multigene panels click
When the diagnosis of Fabry disease has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fabry Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Have been reported to correlate with disease severity [
Are higher in affected males than females [
Can be used to distinguish between clinically relevant Fabry disease phenotypes (e.g., high risk versus low risk, classic versus late onset) [
Have been reported to correlate with treatment response [
Urinary levels of lyso-Gb3 derivatives also correlate with disease severity [
Note: There are no universally recognized biomarkers of Fabry disease.
• Vascular cutaneous lesions (angiokeratomas)
• Periodic crises of severe pain in the extremities (acroparesthesia)
• Sweating abnormalities (hypohidrosis, anhidrosis, or rarely hyperhidrosis)
• Cornea verticillata (characteristic corneal opacity) and lenticular opacities
• Unexplained left ventricular hypertrophy or cardiac arrhythmia
• Unexplained stroke
• Abdominal pain, nausea, and/or diarrhea of unknown etiology in young adulthood consistent with irritable bowel syndrome
• Renal insufficiency of unknown etiology including unexplained proteinuria or microalbuminuria
• Identification of deficient alpha-galactosidase A (α-Gal A) enzyme activity in plasma, isolated leukocytes, and/or cultured cells. The test is a fluorometric assay and uses the substrate 4-methylumbelliferyl-α-D-galactopyranoside.
• Males with classic Fabry disease have <1% α-Gal A enzyme activity.
• Males with atypical Fabry disease have >1% α-Gal A enzyme activity.
• Note: Both plasma and leukocyte enzyme activity should be assayed, as some pathogenic variants (e.g.,
• Males with classic Fabry disease have <1% α-Gal A enzyme activity.
• Males with atypical Fabry disease have >1% α-Gal A enzyme activity.
• Identification of a hemizygous pathogenic (or likely pathogenic) variant in
• Males with classic Fabry disease have <1% α-Gal A enzyme activity.
• Males with atypical Fabry disease have >1% α-Gal A enzyme activity.
• Note: Targeted analysis can be performed first in individuals from Nova Scotia or individuals of Chinese ancestry with atypical presentation (see
• For an introduction to multigene panels click
• Have been reported to correlate with disease severity [
• Are higher in affected males than females [
• Can be used to distinguish between clinically relevant Fabry disease phenotypes (e.g., high risk versus low risk, classic versus late onset) [
• Have been reported to correlate with treatment response [
## Suggestive Findings
Fabry disease typically affects more than one organ system and
Vascular cutaneous lesions (angiokeratomas)
Periodic crises of severe pain in the extremities (acroparesthesia)
Sweating abnormalities (hypohidrosis, anhidrosis, or rarely hyperhidrosis)
Cornea verticillata (characteristic corneal opacity) and lenticular opacities
Unexplained left ventricular hypertrophy or cardiac arrhythmia
Unexplained stroke
Abdominal pain, nausea, and/or diarrhea of unknown etiology in young adulthood consistent with irritable bowel syndrome
Renal insufficiency of unknown etiology including unexplained proteinuria or microalbuminuria
• Vascular cutaneous lesions (angiokeratomas)
• Periodic crises of severe pain in the extremities (acroparesthesia)
• Sweating abnormalities (hypohidrosis, anhidrosis, or rarely hyperhidrosis)
• Cornea verticillata (characteristic corneal opacity) and lenticular opacities
• Unexplained left ventricular hypertrophy or cardiac arrhythmia
• Unexplained stroke
• Abdominal pain, nausea, and/or diarrhea of unknown etiology in young adulthood consistent with irritable bowel syndrome
• Renal insufficiency of unknown etiology including unexplained proteinuria or microalbuminuria
## Establishing the Diagnosis
Identification of deficient alpha-galactosidase A (α-Gal A) enzyme activity in plasma, isolated leukocytes, and/or cultured cells. The test is a fluorometric assay and uses the substrate 4-methylumbelliferyl-α-D-galactopyranoside.
Males with classic Fabry disease have <1% α-Gal A enzyme activity.
Males with atypical Fabry disease have >1% α-Gal A enzyme activity.
Note: Both plasma and leukocyte enzyme activity should be assayed, as some pathogenic variants (e.g.,
Identification of a hemizygous pathogenic (or likely pathogenic) variant in
(See also
Note: (1) Measurement of α-Gal A enzyme activity is unreliable for identification of heterozygous females. Although demonstration of markedly decreased α-Gal A enzyme activity in a female is diagnostic of the heterozygous state, some heterozygotes have α-Gal A activity in the normal range. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: Targeted analysis can be performed first in individuals from Nova Scotia or individuals of Chinese ancestry with atypical presentation (see
For an introduction to multigene panels click
When the diagnosis of Fabry disease has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fabry Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Have been reported to correlate with disease severity [
Are higher in affected males than females [
Can be used to distinguish between clinically relevant Fabry disease phenotypes (e.g., high risk versus low risk, classic versus late onset) [
Have been reported to correlate with treatment response [
Urinary levels of lyso-Gb3 derivatives also correlate with disease severity [
Note: There are no universally recognized biomarkers of Fabry disease.
• Identification of deficient alpha-galactosidase A (α-Gal A) enzyme activity in plasma, isolated leukocytes, and/or cultured cells. The test is a fluorometric assay and uses the substrate 4-methylumbelliferyl-α-D-galactopyranoside.
• Males with classic Fabry disease have <1% α-Gal A enzyme activity.
• Males with atypical Fabry disease have >1% α-Gal A enzyme activity.
• Note: Both plasma and leukocyte enzyme activity should be assayed, as some pathogenic variants (e.g.,
• Males with classic Fabry disease have <1% α-Gal A enzyme activity.
• Males with atypical Fabry disease have >1% α-Gal A enzyme activity.
• Identification of a hemizygous pathogenic (or likely pathogenic) variant in
• Males with classic Fabry disease have <1% α-Gal A enzyme activity.
• Males with atypical Fabry disease have >1% α-Gal A enzyme activity.
• Note: Targeted analysis can be performed first in individuals from Nova Scotia or individuals of Chinese ancestry with atypical presentation (see
• For an introduction to multigene panels click
• Have been reported to correlate with disease severity [
• Are higher in affected males than females [
• Can be used to distinguish between clinically relevant Fabry disease phenotypes (e.g., high risk versus low risk, classic versus late onset) [
• Have been reported to correlate with treatment response [
## Molecular Testing
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: Targeted analysis can be performed first in individuals from Nova Scotia or individuals of Chinese ancestry with atypical presentation (see
For an introduction to multigene panels click
When the diagnosis of Fabry disease has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fabry Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Note: Targeted analysis can be performed first in individuals from Nova Scotia or individuals of Chinese ancestry with atypical presentation (see
• For an introduction to multigene panels click
##
Note: Targeted analysis can be performed first in individuals from Nova Scotia or individuals of Chinese ancestry with atypical presentation (see
For an introduction to multigene panels click
• Note: Targeted analysis can be performed first in individuals from Nova Scotia or individuals of Chinese ancestry with atypical presentation (see
• For an introduction to multigene panels click
##
When the diagnosis of Fabry disease has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fabry Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Additional Testing
Have been reported to correlate with disease severity [
Are higher in affected males than females [
Can be used to distinguish between clinically relevant Fabry disease phenotypes (e.g., high risk versus low risk, classic versus late onset) [
Have been reported to correlate with treatment response [
Urinary levels of lyso-Gb3 derivatives also correlate with disease severity [
Note: There are no universally recognized biomarkers of Fabry disease.
• Have been reported to correlate with disease severity [
• Are higher in affected males than females [
• Can be used to distinguish between clinically relevant Fabry disease phenotypes (e.g., high risk versus low risk, classic versus late onset) [
• Have been reported to correlate with treatment response [
## Clinical Characteristics
Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical late-onset forms. The late-onset forms are more common than the classic phenotype. However, in registries and publications individuals with the classic phenotype are overrepresented.
Individuals with atypical Fabry disease present later in life and are underdiagnosed [
The FOS and the Fabry Registry, multicenter international initiatives designed to examine the natural history of Fabry disease and the effects of enzyme replacement therapy (ERT), are an important source of long-term data on the disease [
Fabry Disease: Comparison of Phenotypes by Select Features
+ = present; – = absent; α-Gal A = alpha-galactosidase A; ESKD = end-stage kidney disease; LVH = left ventricular hypertrophy; TIA = transient ischemic attack
This is usually seen in hemizygous males with <1% alpha-galactosidase A (α-Gal A) enzyme activity but may occasionally be seen in heterozygous females. Onset of symptoms usually occurs in childhood or adolescence with the appearance of angiokeratomas, periodic crises of severe pain in the extremities (acroparesthesia), hypohidrosis, and the characteristic corneal and lenticular opacities. Although proteinuria may be detected early, renal insufficiency usually occurs in the third to fifth decade of life. Death occurs from complications of kidney disease, cardiac involvement, and/or cerebrovascular disease.
The clusters of lesions are most dense between the umbilicus and the knees; they most commonly involve the hips, back, thighs, buttocks, penis, and scrotum, and tend to be bilaterally symmetric. The oral mucosa, conjunctiva, and other mucosal areas are commonly involved. Wide variation in the distribution pattern and density of the lesions may occur. Examination of the skin, especially the scrotum and umbilicus, may reveal the presence of isolated lesions. Data from 714 affected individuals (345 males, 369 females) in the FOS [
The number and size of these cutaneous vascular lesions progressively increase with age. The presence of angiokeratomas correlated with the severity of the systemic disease manifestations [
The crises usually decrease in frequency and severity with increasing age; however, in some affected individuals, the frequency increases and the pain can be so excruciating and incapacitating that the individual may contemplate suicide.
Nerve conduction studies show evidence of a small fire neuropathy [
Mitral insufficiency may be present in childhood or adolescence. Left ventricular enlargement and conduction abnormalities are early findings. Left ventricular hypertrophy (LVH), often associated with hypertrophy of the interventricular septum and appearing similar to hypertrophic cardiomyopathy (HCM), is progressive and occurs earlier in males than females [
Among 714 predominantly adult individuals in the FOS [
During childhood and adolescence, protein, casts, red cells, and birefringent lipid globules with characteristic "Maltese crosses" can be observed in the urinary sediment. Proteinuria, isosthenuria, and a gradual deterioration of tubular reabsorption, secretion, and excretion occur with advancing age. Polyuria and a syndrome similar to vasopressin-resistant diabetes insipidus occasionally develop.
Gradual deterioration of renal function and the development of azotemia occur in the third to fifth decade of life in approximately 50% of males with classic Fabry disease [
Renal sinus and parapelvic cysts are seen in up to half of individuals with Fabry disease, compared to fewer than 10% of controls [
The clinical manifestations in heterozygous females range from asymptomatic throughout a normal life span to as severe as affected males. Variation in clinical manifestations is attributed to random X-chromosome inactivation [
Most heterozygous females from families in which affected males have the classic phenotype have a milder clinical course and better prognosis than affected males.
Mild manifestations include the characteristic cornea verticillata (70%-90%) and lenticular opacities that do not impair vision; acroparesthesia (50%-90%); angiokeratomas (10%-50%) that are usually isolated or sparse; hypohidrosis; and chronic abdominal pain.
With advancing age, heterozygotes may develop mild-to-moderate LVH and valvular disease. More serious manifestations include significant LVH, cardiomegaly, myocardial ischemia, infarction, and cardiac arrhythmias [
The occurrence of cerebrovascular disease including transient ischemic attacks and cerebrovascular accidents is consistent with the microvascular pathology of the disease [
Renal findings in heterozygotes include isosthenuria; the presence of erythrocytes, leukocytes, and granular and hyaline casts in the urinary sediment; and proteinuria. According to the United States and European dialysis and transplantation registries, approximately 10% of heterozygotes develop kidney failure requiring dialysis or transplantation.
Excessive guilt, fatigue, occupational difficulty, suicidal ideation, and depression have been noted in heterozygotes [
Individuals with the cardiac variant exhibit mild-to-moderate proteinuria with normal renal function for age. Renal pathology is limited to glycosphingolipid deposition in podocytes, which is presumably responsible for their proteinuria. They generally do not develop kidney failure except in the presence of an additional etiology or risk factor and kdiney biopsy should be considered for all individuals with a pathogenic variant predictive of late-onset cardiac disease who develop renal impairment.
Individuals with Fabry disease showed slower gait and transfer speed, poorer fine manual dexterity, and slower hand speed than controls.
Affected individuals had an increased incidence of depression, pain, and daytime sleepiness but did not exhibit extrapyramidal motor features or signs of significant cognitive impairment [
Movement disorders including Parkinson disease are reported [
Efforts to establish genotype-phenotype correlations have been limited because most families with Fabry disease have a private pathogenic variant, and significant phenotypic variability exists even among individuals with the same pathogenic variant.
Males with the classic phenotype have a variety of
Individuals with later-onset atypical Fabry disease (renal, cardiac, or cerebrovascular disease) have missense or splicing variants that express residual α-Gal A enzyme activity [
A number of pathogenic variants including
The
Individuals with the
Newborn screening in Taiwan has revealed a high prevalence (~1:1,600 males) of individuals with the
Fabry disease is found among all ethnic, racial, and demographic groups. The incidence of classic Fabry disease has been estimated at 1:50,000 to 1:117,000 males [
Targeted screening programs evaluating individuals on dialysis and those with HCM and newborn screening (NBS) of enzyme activity in dried blood spots suggests that atypical later-onset Fabry disease that primarily affects the cardiovascular, cerebrovascular, or renal system is more common than previously recognized [
NBS in northern Italy found an incidence of 1:7,879 newborns; all individuals had the later-onset or an unclassified variant of Fabry disease [
Enzyme-based NBS in the Taiwan Chinese population found a high prevalence (~1:1,600 males) of the cardiac-variant Fabry-causing pathogenic variant
In Japan the incidence of
• Individuals with Fabry disease showed slower gait and transfer speed, poorer fine manual dexterity, and slower hand speed than controls.
• Affected individuals had an increased incidence of depression, pain, and daytime sleepiness but did not exhibit extrapyramidal motor features or signs of significant cognitive impairment [
• Movement disorders including Parkinson disease are reported [
• Males with the classic phenotype have a variety of
• Individuals with later-onset atypical Fabry disease (renal, cardiac, or cerebrovascular disease) have missense or splicing variants that express residual α-Gal A enzyme activity [
• A number of pathogenic variants including
• The
• Individuals with the
• Newborn screening in Taiwan has revealed a high prevalence (~1:1,600 males) of individuals with the
## Clinical Description
Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical late-onset forms. The late-onset forms are more common than the classic phenotype. However, in registries and publications individuals with the classic phenotype are overrepresented.
Individuals with atypical Fabry disease present later in life and are underdiagnosed [
The FOS and the Fabry Registry, multicenter international initiatives designed to examine the natural history of Fabry disease and the effects of enzyme replacement therapy (ERT), are an important source of long-term data on the disease [
Fabry Disease: Comparison of Phenotypes by Select Features
+ = present; – = absent; α-Gal A = alpha-galactosidase A; ESKD = end-stage kidney disease; LVH = left ventricular hypertrophy; TIA = transient ischemic attack
This is usually seen in hemizygous males with <1% alpha-galactosidase A (α-Gal A) enzyme activity but may occasionally be seen in heterozygous females. Onset of symptoms usually occurs in childhood or adolescence with the appearance of angiokeratomas, periodic crises of severe pain in the extremities (acroparesthesia), hypohidrosis, and the characteristic corneal and lenticular opacities. Although proteinuria may be detected early, renal insufficiency usually occurs in the third to fifth decade of life. Death occurs from complications of kidney disease, cardiac involvement, and/or cerebrovascular disease.
The clusters of lesions are most dense between the umbilicus and the knees; they most commonly involve the hips, back, thighs, buttocks, penis, and scrotum, and tend to be bilaterally symmetric. The oral mucosa, conjunctiva, and other mucosal areas are commonly involved. Wide variation in the distribution pattern and density of the lesions may occur. Examination of the skin, especially the scrotum and umbilicus, may reveal the presence of isolated lesions. Data from 714 affected individuals (345 males, 369 females) in the FOS [
The number and size of these cutaneous vascular lesions progressively increase with age. The presence of angiokeratomas correlated with the severity of the systemic disease manifestations [
The crises usually decrease in frequency and severity with increasing age; however, in some affected individuals, the frequency increases and the pain can be so excruciating and incapacitating that the individual may contemplate suicide.
Nerve conduction studies show evidence of a small fire neuropathy [
Mitral insufficiency may be present in childhood or adolescence. Left ventricular enlargement and conduction abnormalities are early findings. Left ventricular hypertrophy (LVH), often associated with hypertrophy of the interventricular septum and appearing similar to hypertrophic cardiomyopathy (HCM), is progressive and occurs earlier in males than females [
Among 714 predominantly adult individuals in the FOS [
During childhood and adolescence, protein, casts, red cells, and birefringent lipid globules with characteristic "Maltese crosses" can be observed in the urinary sediment. Proteinuria, isosthenuria, and a gradual deterioration of tubular reabsorption, secretion, and excretion occur with advancing age. Polyuria and a syndrome similar to vasopressin-resistant diabetes insipidus occasionally develop.
Gradual deterioration of renal function and the development of azotemia occur in the third to fifth decade of life in approximately 50% of males with classic Fabry disease [
Renal sinus and parapelvic cysts are seen in up to half of individuals with Fabry disease, compared to fewer than 10% of controls [
The clinical manifestations in heterozygous females range from asymptomatic throughout a normal life span to as severe as affected males. Variation in clinical manifestations is attributed to random X-chromosome inactivation [
Most heterozygous females from families in which affected males have the classic phenotype have a milder clinical course and better prognosis than affected males.
Mild manifestations include the characteristic cornea verticillata (70%-90%) and lenticular opacities that do not impair vision; acroparesthesia (50%-90%); angiokeratomas (10%-50%) that are usually isolated or sparse; hypohidrosis; and chronic abdominal pain.
With advancing age, heterozygotes may develop mild-to-moderate LVH and valvular disease. More serious manifestations include significant LVH, cardiomegaly, myocardial ischemia, infarction, and cardiac arrhythmias [
The occurrence of cerebrovascular disease including transient ischemic attacks and cerebrovascular accidents is consistent with the microvascular pathology of the disease [
Renal findings in heterozygotes include isosthenuria; the presence of erythrocytes, leukocytes, and granular and hyaline casts in the urinary sediment; and proteinuria. According to the United States and European dialysis and transplantation registries, approximately 10% of heterozygotes develop kidney failure requiring dialysis or transplantation.
Excessive guilt, fatigue, occupational difficulty, suicidal ideation, and depression have been noted in heterozygotes [
Individuals with the cardiac variant exhibit mild-to-moderate proteinuria with normal renal function for age. Renal pathology is limited to glycosphingolipid deposition in podocytes, which is presumably responsible for their proteinuria. They generally do not develop kidney failure except in the presence of an additional etiology or risk factor and kdiney biopsy should be considered for all individuals with a pathogenic variant predictive of late-onset cardiac disease who develop renal impairment.
Individuals with Fabry disease showed slower gait and transfer speed, poorer fine manual dexterity, and slower hand speed than controls.
Affected individuals had an increased incidence of depression, pain, and daytime sleepiness but did not exhibit extrapyramidal motor features or signs of significant cognitive impairment [
Movement disorders including Parkinson disease are reported [
• Individuals with Fabry disease showed slower gait and transfer speed, poorer fine manual dexterity, and slower hand speed than controls.
• Affected individuals had an increased incidence of depression, pain, and daytime sleepiness but did not exhibit extrapyramidal motor features or signs of significant cognitive impairment [
• Movement disorders including Parkinson disease are reported [
## Classic Fabry Disease
This is usually seen in hemizygous males with <1% alpha-galactosidase A (α-Gal A) enzyme activity but may occasionally be seen in heterozygous females. Onset of symptoms usually occurs in childhood or adolescence with the appearance of angiokeratomas, periodic crises of severe pain in the extremities (acroparesthesia), hypohidrosis, and the characteristic corneal and lenticular opacities. Although proteinuria may be detected early, renal insufficiency usually occurs in the third to fifth decade of life. Death occurs from complications of kidney disease, cardiac involvement, and/or cerebrovascular disease.
The clusters of lesions are most dense between the umbilicus and the knees; they most commonly involve the hips, back, thighs, buttocks, penis, and scrotum, and tend to be bilaterally symmetric. The oral mucosa, conjunctiva, and other mucosal areas are commonly involved. Wide variation in the distribution pattern and density of the lesions may occur. Examination of the skin, especially the scrotum and umbilicus, may reveal the presence of isolated lesions. Data from 714 affected individuals (345 males, 369 females) in the FOS [
The number and size of these cutaneous vascular lesions progressively increase with age. The presence of angiokeratomas correlated with the severity of the systemic disease manifestations [
The crises usually decrease in frequency and severity with increasing age; however, in some affected individuals, the frequency increases and the pain can be so excruciating and incapacitating that the individual may contemplate suicide.
Nerve conduction studies show evidence of a small fire neuropathy [
Mitral insufficiency may be present in childhood or adolescence. Left ventricular enlargement and conduction abnormalities are early findings. Left ventricular hypertrophy (LVH), often associated with hypertrophy of the interventricular septum and appearing similar to hypertrophic cardiomyopathy (HCM), is progressive and occurs earlier in males than females [
Among 714 predominantly adult individuals in the FOS [
During childhood and adolescence, protein, casts, red cells, and birefringent lipid globules with characteristic "Maltese crosses" can be observed in the urinary sediment. Proteinuria, isosthenuria, and a gradual deterioration of tubular reabsorption, secretion, and excretion occur with advancing age. Polyuria and a syndrome similar to vasopressin-resistant diabetes insipidus occasionally develop.
Gradual deterioration of renal function and the development of azotemia occur in the third to fifth decade of life in approximately 50% of males with classic Fabry disease [
Renal sinus and parapelvic cysts are seen in up to half of individuals with Fabry disease, compared to fewer than 10% of controls [
## Heterozygous Females
The clinical manifestations in heterozygous females range from asymptomatic throughout a normal life span to as severe as affected males. Variation in clinical manifestations is attributed to random X-chromosome inactivation [
Most heterozygous females from families in which affected males have the classic phenotype have a milder clinical course and better prognosis than affected males.
Mild manifestations include the characteristic cornea verticillata (70%-90%) and lenticular opacities that do not impair vision; acroparesthesia (50%-90%); angiokeratomas (10%-50%) that are usually isolated or sparse; hypohidrosis; and chronic abdominal pain.
With advancing age, heterozygotes may develop mild-to-moderate LVH and valvular disease. More serious manifestations include significant LVH, cardiomegaly, myocardial ischemia, infarction, and cardiac arrhythmias [
The occurrence of cerebrovascular disease including transient ischemic attacks and cerebrovascular accidents is consistent with the microvascular pathology of the disease [
Renal findings in heterozygotes include isosthenuria; the presence of erythrocytes, leukocytes, and granular and hyaline casts in the urinary sediment; and proteinuria. According to the United States and European dialysis and transplantation registries, approximately 10% of heterozygotes develop kidney failure requiring dialysis or transplantation.
Excessive guilt, fatigue, occupational difficulty, suicidal ideation, and depression have been noted in heterozygotes [
## Late-Onset Variants of Fabry Disease
Individuals with the cardiac variant exhibit mild-to-moderate proteinuria with normal renal function for age. Renal pathology is limited to glycosphingolipid deposition in podocytes, which is presumably responsible for their proteinuria. They generally do not develop kidney failure except in the presence of an additional etiology or risk factor and kdiney biopsy should be considered for all individuals with a pathogenic variant predictive of late-onset cardiac disease who develop renal impairment.
## Classic and Late-Onset Fabry Disease
Individuals with Fabry disease showed slower gait and transfer speed, poorer fine manual dexterity, and slower hand speed than controls.
Affected individuals had an increased incidence of depression, pain, and daytime sleepiness but did not exhibit extrapyramidal motor features or signs of significant cognitive impairment [
Movement disorders including Parkinson disease are reported [
• Individuals with Fabry disease showed slower gait and transfer speed, poorer fine manual dexterity, and slower hand speed than controls.
• Affected individuals had an increased incidence of depression, pain, and daytime sleepiness but did not exhibit extrapyramidal motor features or signs of significant cognitive impairment [
• Movement disorders including Parkinson disease are reported [
## Genotype-Phenotype Correlations
Efforts to establish genotype-phenotype correlations have been limited because most families with Fabry disease have a private pathogenic variant, and significant phenotypic variability exists even among individuals with the same pathogenic variant.
Males with the classic phenotype have a variety of
Individuals with later-onset atypical Fabry disease (renal, cardiac, or cerebrovascular disease) have missense or splicing variants that express residual α-Gal A enzyme activity [
A number of pathogenic variants including
The
Individuals with the
Newborn screening in Taiwan has revealed a high prevalence (~1:1,600 males) of individuals with the
• Males with the classic phenotype have a variety of
• Individuals with later-onset atypical Fabry disease (renal, cardiac, or cerebrovascular disease) have missense or splicing variants that express residual α-Gal A enzyme activity [
• A number of pathogenic variants including
• The
• Individuals with the
• Newborn screening in Taiwan has revealed a high prevalence (~1:1,600 males) of individuals with the
## Prevalence
Fabry disease is found among all ethnic, racial, and demographic groups. The incidence of classic Fabry disease has been estimated at 1:50,000 to 1:117,000 males [
Targeted screening programs evaluating individuals on dialysis and those with HCM and newborn screening (NBS) of enzyme activity in dried blood spots suggests that atypical later-onset Fabry disease that primarily affects the cardiovascular, cerebrovascular, or renal system is more common than previously recognized [
NBS in northern Italy found an incidence of 1:7,879 newborns; all individuals had the later-onset or an unclassified variant of Fabry disease [
Enzyme-based NBS in the Taiwan Chinese population found a high prevalence (~1:1,600 males) of the cardiac-variant Fabry-causing pathogenic variant
In Japan the incidence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Common misdiagnoses in individuals with Fabry disease are summarized in
Common Misdiagnoses in Individuals with Fabry Disease
Differential diagnosis of the cutaneous lesions must exclude the angiokeratoma of Fordyce spots, angiokeratoma of Mibelli, and angiokeratoma circumscriptum (see
Differential Diagnosis of Cutaneous Lesions: Other Types of Angiokeratoma
Spots similar in appearance to those of Fabry disease but limited to scrotum
Usually appear after age 30 yrs
Warty lesions on extensor surfaces of extremities in young adults
Assoc w/erythematous subcutaneous swellings (chilblains)
Can occur anywhere on body
Clinically & histologically similar to angiokeratoma of Fordyce
Not assoc w/chilblains
Differential Diagnosis of Cutaneous Lesions: Angiokeratomas Associated with Autosomal Recessive Lysosomal Storage Disorders
• Spots similar in appearance to those of Fabry disease but limited to scrotum
• Usually appear after age 30 yrs
• Warty lesions on extensor surfaces of extremities in young adults
• Assoc w/erythematous subcutaneous swellings (chilblains)
• Can occur anywhere on body
• Clinically & histologically similar to angiokeratoma of Fordyce
• Not assoc w/chilblains
## Management
To establish the extent of disease and needs in an individual diagnosed with Fabry disease, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fabry Disease
Cardiac eval
EKG
Echocardiography
Cardiac MRI to evaluate for low T
BUN = blood urea nitrogen; GI = gastrointestinal; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
The two ERTs using recombinant or gene-activated human α-Gal A enzyme that have been evaluated in clinical trials are Fabrazyme
No differences were found with regard to the clinical efficacy of agalsidase alfa or agalsidase beta [
A Phase IV extension study showed that the risk of major clinical events (a combination of death, myocardial infarction, stroke, and development of ESKD or a 33% increase in serum creatinine concentration) was reduced by 53% with agalsidase beta treatment after adjustment for baseline proteinuria (P = 0.06) [
There is an emerging consensus that ERT has, at best, a limited effect on the long-term outcome of Fabry disease. Studies from individual centers suggest that cardiac, renal, and cerebrovascular outcomes are comparable among treated and untreated cohorts [
Despite these reservations, experts endorse the original recommendation that ERT be initiated as early as possible in all males with Fabry disease, including children and those with ESKD undergoing dialysis and kidney transplantation, and in heterozygous females with significant disease [
Chaperone therapy uses small molecules designed to enhance the residual enzyme activity by protecting the mutated enzyme from misfolding and degradation in the cell [
In a Phase III study, individuals previously treated with ERT were randomized to ongoing ERT or migalastat [
Criteria for assessment of safety and treatment response from migalastat in females have been established [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields.
Chronic hemodialysis and kidney transplantation have become lifesaving procedures. The engrafted kidney remains histologically free of glycosphingolipid deposition because the normal alpha-galactosidase A (α-Gal A) enzyme activity in the allograft catabolizes endogenous renal glycosphingolipid substrates. Therefore, successful kidney transplantation corrects renal dysfunction and is an option for end-stage kidney disease (ESKD) [
Note: (1) Immune function in males with Fabry disease is similar to that in other individuals with uremia, obviating any immunologic contraindication to transplantation. Autoimmune conditions have, however, been reported to occur at an increased frequency in individuals with Fabry disease [
The following are general guidelines, and the frequency of evaluations should be adjusted based on disease severity and needs of the affected individual. Individuals receiving ERT are typically evaluated more frequently (e.g., every 6 months).
Recommended Surveillance for Individuals with Fabry Disease
Cardiology eval
EKG
Echocardiogram
Annually in males beginning at age 18 yrs
Every 2 yrs in females from age 18 to ~35 yrs
Annually in males beginning at age 18 yrs
2x/yr in females from age 18 to 35 yrs (more frequently if symptomatic)
BUN = blood urea nitrogen
The obstructive lung disease that has been documented in older hemizygous males and heterozygous females is more severe in smokers; therefore, affected individuals should be discouraged from smoking.
Amiodarone has been reported to induce cellular and biochemical changes resulting in a phenocopy in particular of the keratopathy of Fabry disease [
It is appropriate to evaluate apparently asymptomatic older and younger at-risk male and female relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment (ERT) and preventive measures [
Molecular genetic testing capable of detecting the familial
If the
See
Search
• Cardiac eval
• EKG
• Echocardiography
• Cardiac MRI to evaluate for low T
• Cardiology eval
• EKG
• Echocardiogram
• Annually in males beginning at age 18 yrs
• Every 2 yrs in females from age 18 to ~35 yrs
• Annually in males beginning at age 18 yrs
• 2x/yr in females from age 18 to 35 yrs (more frequently if symptomatic)
• Molecular genetic testing capable of detecting the familial
• If the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Fabry disease, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fabry Disease
Cardiac eval
EKG
Echocardiography
Cardiac MRI to evaluate for low T
BUN = blood urea nitrogen; GI = gastrointestinal; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Cardiac eval
• EKG
• Echocardiography
• Cardiac MRI to evaluate for low T
## Treatment of Manifestations
The two ERTs using recombinant or gene-activated human α-Gal A enzyme that have been evaluated in clinical trials are Fabrazyme
No differences were found with regard to the clinical efficacy of agalsidase alfa or agalsidase beta [
A Phase IV extension study showed that the risk of major clinical events (a combination of death, myocardial infarction, stroke, and development of ESKD or a 33% increase in serum creatinine concentration) was reduced by 53% with agalsidase beta treatment after adjustment for baseline proteinuria (P = 0.06) [
There is an emerging consensus that ERT has, at best, a limited effect on the long-term outcome of Fabry disease. Studies from individual centers suggest that cardiac, renal, and cerebrovascular outcomes are comparable among treated and untreated cohorts [
Despite these reservations, experts endorse the original recommendation that ERT be initiated as early as possible in all males with Fabry disease, including children and those with ESKD undergoing dialysis and kidney transplantation, and in heterozygous females with significant disease [
Chaperone therapy uses small molecules designed to enhance the residual enzyme activity by protecting the mutated enzyme from misfolding and degradation in the cell [
In a Phase III study, individuals previously treated with ERT were randomized to ongoing ERT or migalastat [
Criteria for assessment of safety and treatment response from migalastat in females have been established [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields.
Chronic hemodialysis and kidney transplantation have become lifesaving procedures. The engrafted kidney remains histologically free of glycosphingolipid deposition because the normal alpha-galactosidase A (α-Gal A) enzyme activity in the allograft catabolizes endogenous renal glycosphingolipid substrates. Therefore, successful kidney transplantation corrects renal dysfunction and is an option for end-stage kidney disease (ESKD) [
Note: (1) Immune function in males with Fabry disease is similar to that in other individuals with uremia, obviating any immunologic contraindication to transplantation. Autoimmune conditions have, however, been reported to occur at an increased frequency in individuals with Fabry disease [
## Targeted Therapies
The two ERTs using recombinant or gene-activated human α-Gal A enzyme that have been evaluated in clinical trials are Fabrazyme
No differences were found with regard to the clinical efficacy of agalsidase alfa or agalsidase beta [
A Phase IV extension study showed that the risk of major clinical events (a combination of death, myocardial infarction, stroke, and development of ESKD or a 33% increase in serum creatinine concentration) was reduced by 53% with agalsidase beta treatment after adjustment for baseline proteinuria (P = 0.06) [
There is an emerging consensus that ERT has, at best, a limited effect on the long-term outcome of Fabry disease. Studies from individual centers suggest that cardiac, renal, and cerebrovascular outcomes are comparable among treated and untreated cohorts [
Despite these reservations, experts endorse the original recommendation that ERT be initiated as early as possible in all males with Fabry disease, including children and those with ESKD undergoing dialysis and kidney transplantation, and in heterozygous females with significant disease [
Chaperone therapy uses small molecules designed to enhance the residual enzyme activity by protecting the mutated enzyme from misfolding and degradation in the cell [
In a Phase III study, individuals previously treated with ERT were randomized to ongoing ERT or migalastat [
Criteria for assessment of safety and treatment response from migalastat in females have been established [
##
The two ERTs using recombinant or gene-activated human α-Gal A enzyme that have been evaluated in clinical trials are Fabrazyme
No differences were found with regard to the clinical efficacy of agalsidase alfa or agalsidase beta [
A Phase IV extension study showed that the risk of major clinical events (a combination of death, myocardial infarction, stroke, and development of ESKD or a 33% increase in serum creatinine concentration) was reduced by 53% with agalsidase beta treatment after adjustment for baseline proteinuria (P = 0.06) [
There is an emerging consensus that ERT has, at best, a limited effect on the long-term outcome of Fabry disease. Studies from individual centers suggest that cardiac, renal, and cerebrovascular outcomes are comparable among treated and untreated cohorts [
Despite these reservations, experts endorse the original recommendation that ERT be initiated as early as possible in all males with Fabry disease, including children and those with ESKD undergoing dialysis and kidney transplantation, and in heterozygous females with significant disease [
##
Chaperone therapy uses small molecules designed to enhance the residual enzyme activity by protecting the mutated enzyme from misfolding and degradation in the cell [
In a Phase III study, individuals previously treated with ERT were randomized to ongoing ERT or migalastat [
Criteria for assessment of safety and treatment response from migalastat in females have been established [
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields.
Chronic hemodialysis and kidney transplantation have become lifesaving procedures. The engrafted kidney remains histologically free of glycosphingolipid deposition because the normal alpha-galactosidase A (α-Gal A) enzyme activity in the allograft catabolizes endogenous renal glycosphingolipid substrates. Therefore, successful kidney transplantation corrects renal dysfunction and is an option for end-stage kidney disease (ESKD) [
Note: (1) Immune function in males with Fabry disease is similar to that in other individuals with uremia, obviating any immunologic contraindication to transplantation. Autoimmune conditions have, however, been reported to occur at an increased frequency in individuals with Fabry disease [
## Surveillance
The following are general guidelines, and the frequency of evaluations should be adjusted based on disease severity and needs of the affected individual. Individuals receiving ERT are typically evaluated more frequently (e.g., every 6 months).
Recommended Surveillance for Individuals with Fabry Disease
Cardiology eval
EKG
Echocardiogram
Annually in males beginning at age 18 yrs
Every 2 yrs in females from age 18 to ~35 yrs
Annually in males beginning at age 18 yrs
2x/yr in females from age 18 to 35 yrs (more frequently if symptomatic)
BUN = blood urea nitrogen
• Cardiology eval
• EKG
• Echocardiogram
• Annually in males beginning at age 18 yrs
• Every 2 yrs in females from age 18 to ~35 yrs
• Annually in males beginning at age 18 yrs
• 2x/yr in females from age 18 to 35 yrs (more frequently if symptomatic)
## Agents/Circumstances to Avoid
The obstructive lung disease that has been documented in older hemizygous males and heterozygous females is more severe in smokers; therefore, affected individuals should be discouraged from smoking.
Amiodarone has been reported to induce cellular and biochemical changes resulting in a phenocopy in particular of the keratopathy of Fabry disease [
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic older and younger at-risk male and female relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment (ERT) and preventive measures [
Molecular genetic testing capable of detecting the familial
If the
See
• Molecular genetic testing capable of detecting the familial
• If the
## Therapies Under Investigation
Search
## Genetic Counseling
Fabry disease is inherited in an X-linked manner: hemizygous males are affected; heterozygous females may be as severely affected as males or asymptomatic throughout a normal life span.
The father of a male proband will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and the
If a male is the only affected family member (i.e., a simplex case), the mother of the affected male is likely heterozygous for the
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected. Although the specific pathogenic variant segregating in a family and the manifestations of the disorder in other family members with the pathogenic variant can give some indication of likely clinical manifestations, accurate clinical prediction in a sib found to have a
Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females may be asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. See
If the proband represents a simplex case and if the
A heterozygous female may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish females with a
If the mother has a
If the father has a
If the heterozygous female represents a simplex case and if the
Fabry disease practice guidelines are available. See
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of a male proband will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and the
• If a male is the only affected family member (i.e., a simplex case), the mother of the affected male is likely heterozygous for the
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected. Although the specific pathogenic variant segregating in a family and the manifestations of the disorder in other family members with the pathogenic variant can give some indication of likely clinical manifestations, accurate clinical prediction in a sib found to have a
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females may be asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. See
• Males who inherit the pathogenic variant will be affected. Although the specific pathogenic variant segregating in a family and the manifestations of the disorder in other family members with the pathogenic variant can give some indication of likely clinical manifestations, accurate clinical prediction in a sib found to have a
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females may be asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. See
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected. Although the specific pathogenic variant segregating in a family and the manifestations of the disorder in other family members with the pathogenic variant can give some indication of likely clinical manifestations, accurate clinical prediction in a sib found to have a
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females may be asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. See
• A heterozygous female may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish females with a
• If the mother has a
• If the father has a
• If the heterozygous female represents a simplex case and if the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Mode of Inheritance
Fabry disease is inherited in an X-linked manner: hemizygous males are affected; heterozygous females may be as severely affected as males or asymptomatic throughout a normal life span.
## Risk to Family Members
The father of a male proband will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and the
If a male is the only affected family member (i.e., a simplex case), the mother of the affected male is likely heterozygous for the
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected. Although the specific pathogenic variant segregating in a family and the manifestations of the disorder in other family members with the pathogenic variant can give some indication of likely clinical manifestations, accurate clinical prediction in a sib found to have a
Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females may be asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. See
If the proband represents a simplex case and if the
A heterozygous female may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish females with a
If the mother has a
If the father has a
If the heterozygous female represents a simplex case and if the
• The father of a male proband will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and the
• If a male is the only affected family member (i.e., a simplex case), the mother of the affected male is likely heterozygous for the
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected. Although the specific pathogenic variant segregating in a family and the manifestations of the disorder in other family members with the pathogenic variant can give some indication of likely clinical manifestations, accurate clinical prediction in a sib found to have a
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females may be asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. See
• Males who inherit the pathogenic variant will be affected. Although the specific pathogenic variant segregating in a family and the manifestations of the disorder in other family members with the pathogenic variant can give some indication of likely clinical manifestations, accurate clinical prediction in a sib found to have a
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females may be asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. See
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected. Although the specific pathogenic variant segregating in a family and the manifestations of the disorder in other family members with the pathogenic variant can give some indication of likely clinical manifestations, accurate clinical prediction in a sib found to have a
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females may be asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. See
• A heterozygous female may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish females with a
• If the mother has a
• If the father has a
• If the heterozygous female represents a simplex case and if the
## Heterozygote Detection
## Related Genetic Counseling Issues
Fabry disease practice guidelines are available. See
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
108 NE 2nd Street
Suite C
PO Box 510
Concordia MO 64020
4301 Connecticut Avenue Northwest
Suite 404
Washington DC 20008-2369
Canada
United Kingdom
•
• 108 NE 2nd Street
• Suite C
• PO Box 510
• Concordia MO 64020
•
•
•
•
•
•
• 4301 Connecticut Avenue Northwest
• Suite 404
• Washington DC 20008-2369
•
•
• Canada
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
Fabry Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Fabry Disease (
Pathogenic mechanisms have been extensively reviewed [
Impaired mitochondrial function and energy metabolism may not only contribute to cardiomyopathy and kidney disease but also disturb the autophagy-lysosomal pathway. Substrate accumulation also promotes endothelial dysfunction and structural changes in the vasculature, which contribute to cerebrovascular and cardiovascular complications.
Notable
LVH = left ventricular hypertrophy; VUS = variant of uncertain significance
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
## Molecular Pathogenesis
Pathogenic mechanisms have been extensively reviewed [
Impaired mitochondrial function and energy metabolism may not only contribute to cardiomyopathy and kidney disease but also disturb the autophagy-lysosomal pathway. Substrate accumulation also promotes endothelial dysfunction and structural changes in the vasculature, which contribute to cerebrovascular and cardiovascular complications.
Notable
LVH = left ventricular hypertrophy; VUS = variant of uncertain significance
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
## Chapter Notes
Kenneth H Astrin, PhD; Mount Sinai School of Medicine (2001-2008) Robert J Desnick, PhD, MD; Mount Sinai School of Medicine (2001-2008) Derralynn A Hughes, MA, DPhil, FRCP, FRCPath (2008-present) Atul Mehta, MA, MD, FRCP, FRCPath (2008-present)
11 April 2024 (aa) Revision:
9 March 2023 (aa) Revision:
27 January 2022 (sw) Comprehensive update posted live
5 January 2017 (sw) Comprehensive update posted live
17 October 2013 (me) Comprehensive update posted live
10 March 2011 (me) Comprehensive update posted live
26 February 2008 (me) Comprehensive update posted live
27 August 2004 (me) Comprehensive update posted live
5 August 2002 (me) Review posted live
17 September 2001 (rd) Original submission
• 11 April 2024 (aa) Revision:
• 9 March 2023 (aa) Revision:
• 27 January 2022 (sw) Comprehensive update posted live
• 5 January 2017 (sw) Comprehensive update posted live
• 17 October 2013 (me) Comprehensive update posted live
• 10 March 2011 (me) Comprehensive update posted live
• 26 February 2008 (me) Comprehensive update posted live
• 27 August 2004 (me) Comprehensive update posted live
• 5 August 2002 (me) Review posted live
• 17 September 2001 (rd) Original submission
## Author History
Kenneth H Astrin, PhD; Mount Sinai School of Medicine (2001-2008) Robert J Desnick, PhD, MD; Mount Sinai School of Medicine (2001-2008) Derralynn A Hughes, MA, DPhil, FRCP, FRCPath (2008-present) Atul Mehta, MA, MD, FRCP, FRCPath (2008-present)
## Revision History
11 April 2024 (aa) Revision:
9 March 2023 (aa) Revision:
27 January 2022 (sw) Comprehensive update posted live
5 January 2017 (sw) Comprehensive update posted live
17 October 2013 (me) Comprehensive update posted live
10 March 2011 (me) Comprehensive update posted live
26 February 2008 (me) Comprehensive update posted live
27 August 2004 (me) Comprehensive update posted live
5 August 2002 (me) Review posted live
17 September 2001 (rd) Original submission
• 11 April 2024 (aa) Revision:
• 9 March 2023 (aa) Revision:
• 27 January 2022 (sw) Comprehensive update posted live
• 5 January 2017 (sw) Comprehensive update posted live
• 17 October 2013 (me) Comprehensive update posted live
• 10 March 2011 (me) Comprehensive update posted live
• 26 February 2008 (me) Comprehensive update posted live
• 27 August 2004 (me) Comprehensive update posted live
• 5 August 2002 (me) Review posted live
• 17 September 2001 (rd) Original submission
## Key Sections in this
## References
Bennett RL, Hart KA, O Rourke E, Barranger JA, Johnson J, MacDermot KD, Pastores GM, Steiner RD, Thadhani R. Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors (pdf). Available
Germain DP, Fouilhoux A, Decramer S, Tardieu M, Pillet P, Fila M, Rivera S, Deschênes G, Lacombe D. Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients. Clin Genet. 2019;96:107-17. [
Henderson N, Berry L, Laney DA. Fabry disease practice resource: focused revision. J Genet Couns. 2020;29:715-7. [
Laney DA, Bennett RL, Clarke V, Fox A, Hopkin RJ, Johnson J, O'Rourke E, Sims K, Walter G. Fabry Disease Practice Guidelines: Recommendations of the National Society of Genetic Counselors. Available
Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123:416-27. [
• Bennett RL, Hart KA, O Rourke E, Barranger JA, Johnson J, MacDermot KD, Pastores GM, Steiner RD, Thadhani R. Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors (pdf). Available
• Germain DP, Fouilhoux A, Decramer S, Tardieu M, Pillet P, Fila M, Rivera S, Deschênes G, Lacombe D. Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients. Clin Genet. 2019;96:107-17. [
• Henderson N, Berry L, Laney DA. Fabry disease practice resource: focused revision. J Genet Couns. 2020;29:715-7. [
• Laney DA, Bennett RL, Clarke V, Fox A, Hopkin RJ, Johnson J, O'Rourke E, Sims K, Walter G. Fabry Disease Practice Guidelines: Recommendations of the National Society of Genetic Counselors. Available
• Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123:416-27. [
## Published Guidelines / Consensus Statements
Bennett RL, Hart KA, O Rourke E, Barranger JA, Johnson J, MacDermot KD, Pastores GM, Steiner RD, Thadhani R. Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors (pdf). Available
Germain DP, Fouilhoux A, Decramer S, Tardieu M, Pillet P, Fila M, Rivera S, Deschênes G, Lacombe D. Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients. Clin Genet. 2019;96:107-17. [
Henderson N, Berry L, Laney DA. Fabry disease practice resource: focused revision. J Genet Couns. 2020;29:715-7. [
Laney DA, Bennett RL, Clarke V, Fox A, Hopkin RJ, Johnson J, O'Rourke E, Sims K, Walter G. Fabry Disease Practice Guidelines: Recommendations of the National Society of Genetic Counselors. Available
Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123:416-27. [
• Bennett RL, Hart KA, O Rourke E, Barranger JA, Johnson J, MacDermot KD, Pastores GM, Steiner RD, Thadhani R. Fabry disease in genetic counseling practice: recommendations of the National Society of Genetic Counselors (pdf). Available
• Germain DP, Fouilhoux A, Decramer S, Tardieu M, Pillet P, Fila M, Rivera S, Deschênes G, Lacombe D. Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients. Clin Genet. 2019;96:107-17. [
• Henderson N, Berry L, Laney DA. Fabry disease practice resource: focused revision. J Genet Couns. 2020;29:715-7. [
• Laney DA, Bennett RL, Clarke V, Fox A, Hopkin RJ, Johnson J, O'Rourke E, Sims K, Walter G. Fabry Disease Practice Guidelines: Recommendations of the National Society of Genetic Counselors. Available
• Ortiz A, Germain DP, Desnick RJ, Politei J, Mauer M, Burlina A, Eng C, Hopkin RJ, Laney D, Linhart A, Waldek S, Wallace E, Weidemann F, Wilcox WR. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123:416-27. [
## Literature Cited
|
[] |
5/8/2002
|
27/1/2022
|
11/4/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
factor-v-leiden
|
factor-v-leiden
|
[
"Hereditary Resistance to Activated Protein C",
"Hereditary Resistance to Activated Protein C",
"Coagulation factor V",
"F5",
"Factor V Leiden Thrombophilia"
] |
Factor V Leiden Thrombophilia
|
Daniele Pastori, Danilo Menichelli, Emanuele Valeriani, Pasquale Pignatelli
|
Summary Factor V Leiden thrombophilia is characterized by venous thromboembolism (VTE) manifesting most commonly in adults as deep vein thrombosis (DVT) in the legs or pulmonary embolism. Thrombosis in unusual locations is less common. Factors that predispose to VTE in factor V Leiden thrombophilia include: the number of factor V Leiden variant alleles (homozygotes have a much greater thrombotic risk); family history of VTE; presence of coexisting genetic thrombophilic disorders; acquired thrombophilic disorders (e.g., antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders); and circumstantial risk factors (e.g., pregnancy, malignancy, central venous catheters, travel, combined oral contraceptive use and other combined contraceptives, oral hormone replacement therapy [HRT], obesity, leg injury, and advancing age). The diagnosis of factor V Leiden thrombophilia is established in a proband by identification of a heterozygous or homozygous c.1601G>A (p.Arg534Gln) variant in Factor V Leiden thrombophilia is inherited in an autosomal dominant manner. Individuals who are heterozygous for the factor V Leiden variant have a slightly increased risk for VTE; individuals who are homozygous for the factor V Leiden variant have a much greater thrombotic risk. Many individuals with the factor V Leiden variant never develop thrombosis. Most individuals with factor V Leiden thrombophilia are heterozygous for the factor V Leiden variant, which they inherited from a parent who is also heterozygous for the factor V Leiden variant. Each child of a heterozygous proband has a 50% chance of inheriting the factor V Leiden variant from the proband; if the proband's reproductive partner is also heterozygous for the factor V Leiden variant, each of their children has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.
|
## Diagnosis
Factor V Leiden thrombophilia
Note: The assay is (1) cost effective with high sensitivity and specificity; (2) can detect pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another
Low APC resistance assay values to confirm the diagnosis and to distinguish factor V Leiden variant heterozygotes from homozygotes and pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another
Borderline APC resistance assay values to confirm the diagnosis;
Received direct thrombin inhibitors or direct factor Xa inhibitors, which may interfere with the results of the APC resistance assay [
Positive lupus anticoagulant and prolonged baseline activated partial thromboplastin time (aPTT);
VTE provoked by pregnancy or occurring post partum;
VTE associated with the use of combined oral contraceptives;
VTE at age ≤40 years, either spontaneous or associated with weak environmental risk factors and family history of at least one first-degree relative with VTE.
Persons with a first unprovoked VTE who are planning to stop anticoagulation;
Female relatives of persons with VTE or hereditary thrombophilia considering estrogen contraception or hormone replacement therapy (HRT);
Female relatives of persons with VTE or hereditary thrombophilia contemplating prophylactic anticoagulation during pregnancy.
Adults with VTE provoked by major transient risk factors;
Persons with arterial thrombosis;
Women with unexplained pregnancy loss;
Neonates and children with asymptomatic central venous catheter-related thrombosis;
Asymptomatic adult family members of individuals known to have a factor V Leiden variant;
Routine testing in unaffected individuals (e.g., during pregnancy or prior to use of oral contraceptives, HRT, or selective estrogen receptor modulators), in asymptomatic children, prenatal testing of the fetus, or newborn testing.
The diagnosis of factor V Leiden thrombophilia
Molecular genetic testing approaches can include
Molecular Genetic Testing Used in Factor V Leiden Thrombophilia
See
See
• Note: The assay is (1) cost effective with high sensitivity and specificity; (2) can detect pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another
• Low APC resistance assay values to confirm the diagnosis and to distinguish factor V Leiden variant heterozygotes from homozygotes and pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another
• Borderline APC resistance assay values to confirm the diagnosis;
• Received direct thrombin inhibitors or direct factor Xa inhibitors, which may interfere with the results of the APC resistance assay [
• Positive lupus anticoagulant and prolonged baseline activated partial thromboplastin time (aPTT);
• VTE provoked by pregnancy or occurring post partum;
• VTE associated with the use of combined oral contraceptives;
• VTE at age ≤40 years, either spontaneous or associated with weak environmental risk factors and family history of at least one first-degree relative with VTE.
• Persons with a first unprovoked VTE who are planning to stop anticoagulation;
• Female relatives of persons with VTE or hereditary thrombophilia considering estrogen contraception or hormone replacement therapy (HRT);
• Female relatives of persons with VTE or hereditary thrombophilia contemplating prophylactic anticoagulation during pregnancy.
• Adults with VTE provoked by major transient risk factors;
• Persons with arterial thrombosis;
• Women with unexplained pregnancy loss;
• Neonates and children with asymptomatic central venous catheter-related thrombosis;
• Asymptomatic adult family members of individuals known to have a factor V Leiden variant;
• Routine testing in unaffected individuals (e.g., during pregnancy or prior to use of oral contraceptives, HRT, or selective estrogen receptor modulators), in asymptomatic children, prenatal testing of the fetus, or newborn testing.
## Suggestive Findings
Factor V Leiden thrombophilia
Note: The assay is (1) cost effective with high sensitivity and specificity; (2) can detect pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another
Low APC resistance assay values to confirm the diagnosis and to distinguish factor V Leiden variant heterozygotes from homozygotes and pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another
Borderline APC resistance assay values to confirm the diagnosis;
Received direct thrombin inhibitors or direct factor Xa inhibitors, which may interfere with the results of the APC resistance assay [
Positive lupus anticoagulant and prolonged baseline activated partial thromboplastin time (aPTT);
VTE provoked by pregnancy or occurring post partum;
VTE associated with the use of combined oral contraceptives;
VTE at age ≤40 years, either spontaneous or associated with weak environmental risk factors and family history of at least one first-degree relative with VTE.
Persons with a first unprovoked VTE who are planning to stop anticoagulation;
Female relatives of persons with VTE or hereditary thrombophilia considering estrogen contraception or hormone replacement therapy (HRT);
Female relatives of persons with VTE or hereditary thrombophilia contemplating prophylactic anticoagulation during pregnancy.
Adults with VTE provoked by major transient risk factors;
Persons with arterial thrombosis;
Women with unexplained pregnancy loss;
Neonates and children with asymptomatic central venous catheter-related thrombosis;
Asymptomatic adult family members of individuals known to have a factor V Leiden variant;
Routine testing in unaffected individuals (e.g., during pregnancy or prior to use of oral contraceptives, HRT, or selective estrogen receptor modulators), in asymptomatic children, prenatal testing of the fetus, or newborn testing.
• Note: The assay is (1) cost effective with high sensitivity and specificity; (2) can detect pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another
• Low APC resistance assay values to confirm the diagnosis and to distinguish factor V Leiden variant heterozygotes from homozygotes and pseudohomozygotes (compound heterozygotes for factor V Leiden variant and another
• Borderline APC resistance assay values to confirm the diagnosis;
• Received direct thrombin inhibitors or direct factor Xa inhibitors, which may interfere with the results of the APC resistance assay [
• Positive lupus anticoagulant and prolonged baseline activated partial thromboplastin time (aPTT);
• VTE provoked by pregnancy or occurring post partum;
• VTE associated with the use of combined oral contraceptives;
• VTE at age ≤40 years, either spontaneous or associated with weak environmental risk factors and family history of at least one first-degree relative with VTE.
• Persons with a first unprovoked VTE who are planning to stop anticoagulation;
• Female relatives of persons with VTE or hereditary thrombophilia considering estrogen contraception or hormone replacement therapy (HRT);
• Female relatives of persons with VTE or hereditary thrombophilia contemplating prophylactic anticoagulation during pregnancy.
• Adults with VTE provoked by major transient risk factors;
• Persons with arterial thrombosis;
• Women with unexplained pregnancy loss;
• Neonates and children with asymptomatic central venous catheter-related thrombosis;
• Asymptomatic adult family members of individuals known to have a factor V Leiden variant;
• Routine testing in unaffected individuals (e.g., during pregnancy or prior to use of oral contraceptives, HRT, or selective estrogen receptor modulators), in asymptomatic children, prenatal testing of the fetus, or newborn testing.
## Establishing the Diagnosis
The diagnosis of factor V Leiden thrombophilia
Molecular genetic testing approaches can include
Molecular Genetic Testing Used in Factor V Leiden Thrombophilia
See
See
## Clinical Characteristics
The relative risk for VTE is increased approximately three- to eightfold in factor V Leiden variant heterozygotes [
Individuals heterozygous for the factor V Leiden variant have a sixfold increased risk for primary upper-extremity thrombosis (not related to malignancy or a venous catheter) [
There is an increased risk of VTE at unusual sites. Increased prevalence of the factor V Leiden variant was reported in individuals with cerebral venous thrombosis in a meta-analysis including 1,822 affected individuals and 7,795 controls (odds ratio [OR] 2.70, 95% CI 2.16-3.38) [
The VTE recurrence risk may be higher in individuals from families prone to thrombosis than in unselected individuals. In a prospective study of families with a strong history of thrombosis, the incidence of recurrent VTE was 3.5 in 100 person-years in persons with the factor V Leiden variant [
The most important clinical risk factor for thrombosis in children is a central venous catheter (CVC). A factor V Leiden variant was associated with CVC-related VTE in some [
A factor V Leiden variant was reported to increase the risk of neonatal cerebral vein thrombosis [
In a prospective study, asymptomatic children heterozygous for a factor V Leiden variant had no thrombotic complications during follow up that averaged five years [
While heterozygosity for the factor V Leiden variant increases the relative risk for pregnancy-associated VTE, the absolute risk is low in the absence of other predisposing factors. VTE is estimated to occur in 1% of pregnancies in women who are factor V Leiden variant heterozygotes. The absolute risk increases to 3% in those with a positive family history of VTE [
Women with a prior unprovoked VTE and factor V Leiden thrombophilia had the highest recurrence rate during pregnancy (20% of pregnancies). A factor V Leiden variant was associated with an increased risk of antepartum recurrence (OR 10) [
A systematic review focused on prospective cohort studies found no significant association of preeclampsia or placental abruption with factor V Leiden thrombophilia [
In addition to the number of factor V Leiden variant alleles, the clinical expression of factor V Leiden thrombophilia is influenced by family history, coexisting genetic abnormalities, acquired thrombophilic disorders, and circumstantial risk factors.
The risk was increased to fivefold in those with a relative with a VTE before age 50 years and to 18-fold with two or more affected relatives. The family history had additional value in predicting risk even in those with a factor V Leiden variant, suggesting the presence of unknown genetic risk factors.
Factor V Leiden variant heterozygotes with factor VIII levels greater than 150% of normal had a two- to threefold increased incidence of VTE than factor V Leiden variant heterozygotes alone [
A factor V Leiden variant was reported to contribute to increased risk for thrombotic complications in persons with polycythemia vera and essential thrombocytosis [
Additional acquired risk factors for VTE in factor V Leiden variant heterozygotes or homozygotes are summarized in
Increased Risk of Thrombosis in Persons with the Factor V Leiden Variant and Additional Acquired Risk Factors
O blood group: OR 5.6
(95% CI 2.4-12.9)
Non-O blood group: OR 16.3
(95% CI 7.5-35.4)
O blood group: OR 13.6
(95% CI 3.1-60.9)
Non-O blood group: OR 21.7
(95% CI 10.0-47.1)
O blood group: OR 9.2
(95% CI 2.0-42.2)
Non-O blood group: OR 37.5
(95% CI 10.5-133)
≤1 yr COC use: OR 62.2
(95% CI 29.8-129.6)
>1 yr COC use: OR 25.4
(95% CI 16.5-39.2)
Gestodene: OR 22.1
(95% CI 11.3-43.3)
Desogestrel: OR 26.3
(95% CI 15.2-45.5)
Levonorgestrel: OR 17.4
(95% CI 11.4-26.6)
Cyproterone: OR 31.8
(95% CI 17.2-59.0)
≤2 yrs COC use: HR 5.73
(95% CI 5.31-6.17)
>2 yrs COC use: HR 2
(95% CI 1.86-2.16)
O blood group: OR 5.6
(95% CI 3.0-10.4)
Non-O blood group: OR 15.7
(95% CI 9.4-25.9)
O blood group: OR 4.4
(95% CI 2.9-6.6)
Non-O blood group: OR 10.7
(95% CI 7.7-14.8)
BMI = body mass index; COCs = combined oral contraceptives; CVC = central venous catheter; HR = hazard ratio; HRT = hormone replacement therapy; OR = odds ratio; RR = relative risk; VTE = venous thromboembolism
See text that follows table for more details.
The supra-additive effect of both a factor V Leiden variant and use of COCs was confirmed in multiple studies in which the OR for VTE ranged from 11 to 41 [
The thrombotic risk in COC users with the factor V Leiden variant is at least as high in women older than age 50 years as in younger users [
Recent evidence from a large meta-analysis suggested a role for factor V thrombophilia in arterial thrombotic disease [
Factor V Leiden thrombophilia is the most common inherited form of thrombophilia. The prevalence varies by population.
Heterozygosity for the factor V Leiden variant occurs in 3%-8% of the general United States and European populations. The highest heterozygosity rate is found in Europe. Within Europe, prevalence varies from 10%-15% in southern Sweden and Greece to 2%-3% in Italy and Spain [
The frequency of homozygosity for the factor V Leiden variant is approximately 1:5,000.
The factor V Leiden variant is present in approximately 15%-20% of individuals with a first deep vein thrombosis and up to 50% of individuals with recurrent VTE or an estrogen-related thrombosis.
• Factor V Leiden variant heterozygotes with factor VIII levels greater than 150% of normal had a two- to threefold increased incidence of VTE than factor V Leiden variant heterozygotes alone [
• A factor V Leiden variant was reported to contribute to increased risk for thrombotic complications in persons with polycythemia vera and essential thrombocytosis [
• O blood group: OR 5.6
• (95% CI 2.4-12.9)
• Non-O blood group: OR 16.3
• (95% CI 7.5-35.4)
• O blood group: OR 13.6
• (95% CI 3.1-60.9)
• Non-O blood group: OR 21.7
• (95% CI 10.0-47.1)
• O blood group: OR 9.2
• (95% CI 2.0-42.2)
• Non-O blood group: OR 37.5
• (95% CI 10.5-133)
• ≤1 yr COC use: OR 62.2
• (95% CI 29.8-129.6)
• >1 yr COC use: OR 25.4
• (95% CI 16.5-39.2)
• Gestodene: OR 22.1
• (95% CI 11.3-43.3)
• Desogestrel: OR 26.3
• (95% CI 15.2-45.5)
• Levonorgestrel: OR 17.4
• (95% CI 11.4-26.6)
• Cyproterone: OR 31.8
• (95% CI 17.2-59.0)
• ≤2 yrs COC use: HR 5.73
• (95% CI 5.31-6.17)
• >2 yrs COC use: HR 2
• (95% CI 1.86-2.16)
• O blood group: OR 5.6
• (95% CI 3.0-10.4)
• Non-O blood group: OR 15.7
• (95% CI 9.4-25.9)
• O blood group: OR 4.4
• (95% CI 2.9-6.6)
• Non-O blood group: OR 10.7
• (95% CI 7.7-14.8)
## Clinical Description
The relative risk for VTE is increased approximately three- to eightfold in factor V Leiden variant heterozygotes [
Individuals heterozygous for the factor V Leiden variant have a sixfold increased risk for primary upper-extremity thrombosis (not related to malignancy or a venous catheter) [
There is an increased risk of VTE at unusual sites. Increased prevalence of the factor V Leiden variant was reported in individuals with cerebral venous thrombosis in a meta-analysis including 1,822 affected individuals and 7,795 controls (odds ratio [OR] 2.70, 95% CI 2.16-3.38) [
The VTE recurrence risk may be higher in individuals from families prone to thrombosis than in unselected individuals. In a prospective study of families with a strong history of thrombosis, the incidence of recurrent VTE was 3.5 in 100 person-years in persons with the factor V Leiden variant [
The most important clinical risk factor for thrombosis in children is a central venous catheter (CVC). A factor V Leiden variant was associated with CVC-related VTE in some [
A factor V Leiden variant was reported to increase the risk of neonatal cerebral vein thrombosis [
In a prospective study, asymptomatic children heterozygous for a factor V Leiden variant had no thrombotic complications during follow up that averaged five years [
While heterozygosity for the factor V Leiden variant increases the relative risk for pregnancy-associated VTE, the absolute risk is low in the absence of other predisposing factors. VTE is estimated to occur in 1% of pregnancies in women who are factor V Leiden variant heterozygotes. The absolute risk increases to 3% in those with a positive family history of VTE [
Women with a prior unprovoked VTE and factor V Leiden thrombophilia had the highest recurrence rate during pregnancy (20% of pregnancies). A factor V Leiden variant was associated with an increased risk of antepartum recurrence (OR 10) [
A systematic review focused on prospective cohort studies found no significant association of preeclampsia or placental abruption with factor V Leiden thrombophilia [
In addition to the number of factor V Leiden variant alleles, the clinical expression of factor V Leiden thrombophilia is influenced by family history, coexisting genetic abnormalities, acquired thrombophilic disorders, and circumstantial risk factors.
The risk was increased to fivefold in those with a relative with a VTE before age 50 years and to 18-fold with two or more affected relatives. The family history had additional value in predicting risk even in those with a factor V Leiden variant, suggesting the presence of unknown genetic risk factors.
Factor V Leiden variant heterozygotes with factor VIII levels greater than 150% of normal had a two- to threefold increased incidence of VTE than factor V Leiden variant heterozygotes alone [
A factor V Leiden variant was reported to contribute to increased risk for thrombotic complications in persons with polycythemia vera and essential thrombocytosis [
Additional acquired risk factors for VTE in factor V Leiden variant heterozygotes or homozygotes are summarized in
Increased Risk of Thrombosis in Persons with the Factor V Leiden Variant and Additional Acquired Risk Factors
O blood group: OR 5.6
(95% CI 2.4-12.9)
Non-O blood group: OR 16.3
(95% CI 7.5-35.4)
O blood group: OR 13.6
(95% CI 3.1-60.9)
Non-O blood group: OR 21.7
(95% CI 10.0-47.1)
O blood group: OR 9.2
(95% CI 2.0-42.2)
Non-O blood group: OR 37.5
(95% CI 10.5-133)
≤1 yr COC use: OR 62.2
(95% CI 29.8-129.6)
>1 yr COC use: OR 25.4
(95% CI 16.5-39.2)
Gestodene: OR 22.1
(95% CI 11.3-43.3)
Desogestrel: OR 26.3
(95% CI 15.2-45.5)
Levonorgestrel: OR 17.4
(95% CI 11.4-26.6)
Cyproterone: OR 31.8
(95% CI 17.2-59.0)
≤2 yrs COC use: HR 5.73
(95% CI 5.31-6.17)
>2 yrs COC use: HR 2
(95% CI 1.86-2.16)
O blood group: OR 5.6
(95% CI 3.0-10.4)
Non-O blood group: OR 15.7
(95% CI 9.4-25.9)
O blood group: OR 4.4
(95% CI 2.9-6.6)
Non-O blood group: OR 10.7
(95% CI 7.7-14.8)
BMI = body mass index; COCs = combined oral contraceptives; CVC = central venous catheter; HR = hazard ratio; HRT = hormone replacement therapy; OR = odds ratio; RR = relative risk; VTE = venous thromboembolism
See text that follows table for more details.
The supra-additive effect of both a factor V Leiden variant and use of COCs was confirmed in multiple studies in which the OR for VTE ranged from 11 to 41 [
The thrombotic risk in COC users with the factor V Leiden variant is at least as high in women older than age 50 years as in younger users [
Recent evidence from a large meta-analysis suggested a role for factor V thrombophilia in arterial thrombotic disease [
• Factor V Leiden variant heterozygotes with factor VIII levels greater than 150% of normal had a two- to threefold increased incidence of VTE than factor V Leiden variant heterozygotes alone [
• A factor V Leiden variant was reported to contribute to increased risk for thrombotic complications in persons with polycythemia vera and essential thrombocytosis [
• O blood group: OR 5.6
• (95% CI 2.4-12.9)
• Non-O blood group: OR 16.3
• (95% CI 7.5-35.4)
• O blood group: OR 13.6
• (95% CI 3.1-60.9)
• Non-O blood group: OR 21.7
• (95% CI 10.0-47.1)
• O blood group: OR 9.2
• (95% CI 2.0-42.2)
• Non-O blood group: OR 37.5
• (95% CI 10.5-133)
• ≤1 yr COC use: OR 62.2
• (95% CI 29.8-129.6)
• >1 yr COC use: OR 25.4
• (95% CI 16.5-39.2)
• Gestodene: OR 22.1
• (95% CI 11.3-43.3)
• Desogestrel: OR 26.3
• (95% CI 15.2-45.5)
• Levonorgestrel: OR 17.4
• (95% CI 11.4-26.6)
• Cyproterone: OR 31.8
• (95% CI 17.2-59.0)
• ≤2 yrs COC use: HR 5.73
• (95% CI 5.31-6.17)
• >2 yrs COC use: HR 2
• (95% CI 1.86-2.16)
• O blood group: OR 5.6
• (95% CI 3.0-10.4)
• Non-O blood group: OR 15.7
• (95% CI 9.4-25.9)
• O blood group: OR 4.4
• (95% CI 2.9-6.6)
• Non-O blood group: OR 10.7
• (95% CI 7.7-14.8)
## Heterozygosity for the Factor V Leiden Variant
The relative risk for VTE is increased approximately three- to eightfold in factor V Leiden variant heterozygotes [
Individuals heterozygous for the factor V Leiden variant have a sixfold increased risk for primary upper-extremity thrombosis (not related to malignancy or a venous catheter) [
There is an increased risk of VTE at unusual sites. Increased prevalence of the factor V Leiden variant was reported in individuals with cerebral venous thrombosis in a meta-analysis including 1,822 affected individuals and 7,795 controls (odds ratio [OR] 2.70, 95% CI 2.16-3.38) [
The VTE recurrence risk may be higher in individuals from families prone to thrombosis than in unselected individuals. In a prospective study of families with a strong history of thrombosis, the incidence of recurrent VTE was 3.5 in 100 person-years in persons with the factor V Leiden variant [
The most important clinical risk factor for thrombosis in children is a central venous catheter (CVC). A factor V Leiden variant was associated with CVC-related VTE in some [
A factor V Leiden variant was reported to increase the risk of neonatal cerebral vein thrombosis [
In a prospective study, asymptomatic children heterozygous for a factor V Leiden variant had no thrombotic complications during follow up that averaged five years [
While heterozygosity for the factor V Leiden variant increases the relative risk for pregnancy-associated VTE, the absolute risk is low in the absence of other predisposing factors. VTE is estimated to occur in 1% of pregnancies in women who are factor V Leiden variant heterozygotes. The absolute risk increases to 3% in those with a positive family history of VTE [
Women with a prior unprovoked VTE and factor V Leiden thrombophilia had the highest recurrence rate during pregnancy (20% of pregnancies). A factor V Leiden variant was associated with an increased risk of antepartum recurrence (OR 10) [
A systematic review focused on prospective cohort studies found no significant association of preeclampsia or placental abruption with factor V Leiden thrombophilia [
## Homozygosity for the Factor V Leiden Variant
## Additional Factors that Predispose to Thrombosis
In addition to the number of factor V Leiden variant alleles, the clinical expression of factor V Leiden thrombophilia is influenced by family history, coexisting genetic abnormalities, acquired thrombophilic disorders, and circumstantial risk factors.
The risk was increased to fivefold in those with a relative with a VTE before age 50 years and to 18-fold with two or more affected relatives. The family history had additional value in predicting risk even in those with a factor V Leiden variant, suggesting the presence of unknown genetic risk factors.
Factor V Leiden variant heterozygotes with factor VIII levels greater than 150% of normal had a two- to threefold increased incidence of VTE than factor V Leiden variant heterozygotes alone [
A factor V Leiden variant was reported to contribute to increased risk for thrombotic complications in persons with polycythemia vera and essential thrombocytosis [
• Factor V Leiden variant heterozygotes with factor VIII levels greater than 150% of normal had a two- to threefold increased incidence of VTE than factor V Leiden variant heterozygotes alone [
• A factor V Leiden variant was reported to contribute to increased risk for thrombotic complications in persons with polycythemia vera and essential thrombocytosis [
## Additional Acquired Risk Factors for VTE
Additional acquired risk factors for VTE in factor V Leiden variant heterozygotes or homozygotes are summarized in
Increased Risk of Thrombosis in Persons with the Factor V Leiden Variant and Additional Acquired Risk Factors
O blood group: OR 5.6
(95% CI 2.4-12.9)
Non-O blood group: OR 16.3
(95% CI 7.5-35.4)
O blood group: OR 13.6
(95% CI 3.1-60.9)
Non-O blood group: OR 21.7
(95% CI 10.0-47.1)
O blood group: OR 9.2
(95% CI 2.0-42.2)
Non-O blood group: OR 37.5
(95% CI 10.5-133)
≤1 yr COC use: OR 62.2
(95% CI 29.8-129.6)
>1 yr COC use: OR 25.4
(95% CI 16.5-39.2)
Gestodene: OR 22.1
(95% CI 11.3-43.3)
Desogestrel: OR 26.3
(95% CI 15.2-45.5)
Levonorgestrel: OR 17.4
(95% CI 11.4-26.6)
Cyproterone: OR 31.8
(95% CI 17.2-59.0)
≤2 yrs COC use: HR 5.73
(95% CI 5.31-6.17)
>2 yrs COC use: HR 2
(95% CI 1.86-2.16)
O blood group: OR 5.6
(95% CI 3.0-10.4)
Non-O blood group: OR 15.7
(95% CI 9.4-25.9)
O blood group: OR 4.4
(95% CI 2.9-6.6)
Non-O blood group: OR 10.7
(95% CI 7.7-14.8)
BMI = body mass index; COCs = combined oral contraceptives; CVC = central venous catheter; HR = hazard ratio; HRT = hormone replacement therapy; OR = odds ratio; RR = relative risk; VTE = venous thromboembolism
See text that follows table for more details.
The supra-additive effect of both a factor V Leiden variant and use of COCs was confirmed in multiple studies in which the OR for VTE ranged from 11 to 41 [
The thrombotic risk in COC users with the factor V Leiden variant is at least as high in women older than age 50 years as in younger users [
• O blood group: OR 5.6
• (95% CI 2.4-12.9)
• Non-O blood group: OR 16.3
• (95% CI 7.5-35.4)
• O blood group: OR 13.6
• (95% CI 3.1-60.9)
• Non-O blood group: OR 21.7
• (95% CI 10.0-47.1)
• O blood group: OR 9.2
• (95% CI 2.0-42.2)
• Non-O blood group: OR 37.5
• (95% CI 10.5-133)
• ≤1 yr COC use: OR 62.2
• (95% CI 29.8-129.6)
• >1 yr COC use: OR 25.4
• (95% CI 16.5-39.2)
• Gestodene: OR 22.1
• (95% CI 11.3-43.3)
• Desogestrel: OR 26.3
• (95% CI 15.2-45.5)
• Levonorgestrel: OR 17.4
• (95% CI 11.4-26.6)
• Cyproterone: OR 31.8
• (95% CI 17.2-59.0)
• ≤2 yrs COC use: HR 5.73
• (95% CI 5.31-6.17)
• >2 yrs COC use: HR 2
• (95% CI 1.86-2.16)
• O blood group: OR 5.6
• (95% CI 3.0-10.4)
• Non-O blood group: OR 15.7
• (95% CI 9.4-25.9)
• O blood group: OR 4.4
• (95% CI 2.9-6.6)
• Non-O blood group: OR 10.7
• (95% CI 7.7-14.8)
## Arterial Thrombosis
Recent evidence from a large meta-analysis suggested a role for factor V thrombophilia in arterial thrombotic disease [
## Prevalence
Factor V Leiden thrombophilia is the most common inherited form of thrombophilia. The prevalence varies by population.
Heterozygosity for the factor V Leiden variant occurs in 3%-8% of the general United States and European populations. The highest heterozygosity rate is found in Europe. Within Europe, prevalence varies from 10%-15% in southern Sweden and Greece to 2%-3% in Italy and Spain [
The frequency of homozygosity for the factor V Leiden variant is approximately 1:5,000.
The factor V Leiden variant is present in approximately 15%-20% of individuals with a first deep vein thrombosis and up to 50% of individuals with recurrent VTE or an estrogen-related thrombosis.
## Differential Diagnosis
The differential diagnosis of venous thromboembolism (VTE) includes several other inherited thrombophilic disorders, including those caused by other variants in
See
## Management
To assess the risk for venous thromboembolism (VTE) in an individual found to have a factor V Leiden variant, the following are recommended:
DNA analysis for prothrombin thrombophilia (
Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
Serologic assays for anticardiolipin antibodies and anti-beta-2-glycoprotein 1 antibodies
For high-risk individuals (i.e., those with a history of recurrent VTE, especially at a young age, or those with strong family history of VTE at a young age), evaluation should also include assays of:
Protein C activity
Antithrombin activity
Protein S activity or free protein S antigen
Note: Measurement of the following is NOT recommended:
Plasma concentration of homocysteine, as no data support a change in duration of anticoagulation or the use of vitamin supplementation in individuals with hyperhomocysteinemia and a history of VTE
Factor VIII and other clotting factor levels [
The management of individuals with factor V Leiden thrombophilia depends on the clinical circumstances.
For individuals not treated with one of the direct oral anticoagulants, administration of warfarin is started concurrently with low-molecular-weight heparin (LMWH) or fondaparinux (except during pregnancy), and monitored with the international normalized ratio (INR). A target INR of 2.5 (therapeutic range 2.0-3.0) provides effective anticoagulation, even in individuals homozygous for the factor V Leiden variant [
Note: LMWH and warfarin are both safe in women who are breastfeeding (see
Heterozygosity for the factor V Leiden variant alone is not an indication for long-term anticoagulation in the absence of other risk factors, according to the American College of Chest Physicians guidelines on antithrombotic therapy [
Anticoagulation for at least three months is recommended for persons with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) associated with a transient (reversible) risk factor [
Several scores were developed to help clinicians estimate the risk of recurrence of DVT or PE after a first episode [
Treatment recommendations for children with VTE were largely adapted from studies in adults, but recently, studies on VTE recurrence and treatment in children have been performed [
The treatment of acute VTE is not influenced by identification of a factor V Leiden variant. Children with a first VTE should receive initial treatment with either unfractionated heparin or LMWH for at least five days. ASH guidelines suggest using either LMWH or warfarin in children with symptomatic DVT or PE [
In children with a factor V Leiden variant, the duration of anticoagulation following VTE may include indefinite anticoagulation or intermittent anticoagulation in high-risk situations after considering the risk of side effects of anticoagulation (e.g., major bleeding), the risk of recurrent VTE, and the preference of the affected individual. To date, outcomes from these treatment strategies have not been studied in children [
For at least three months following a VTE provoked by a clinical risk factor that has resolved;
At least three months and until the risk factor has resolved in children with an ongoing but potentially reversible risk factor;
For six to 12 months after a first unprovoked VTE.
Consensus guidelines and expert opinion emphasize the importance of a careful risk vs benefit assessment in each individual.
In the absence of a history of thrombosis, long-term anticoagulation is not routinely recommended for asymptomatic individuals who are heterozygous for the factor V Leiden variant because the 1%-3% per year risk for major bleeding from warfarin is greater than the estimated less than 1% per year risk for thrombosis.
Because the initial thrombosis in 50% of factor V Leiden variant heterozygotes occurs in association with other circumstantial risk factors (see
Selected factor V Leiden variant heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in consensus guidelines [
Individuals receiving long-term anticoagulation require periodic reevaluation of their clinical course to confirm that the benefits of anticoagulation continue to outweigh the risk of bleeding.
Factor V Leiden heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy.
Women with a history of VTE who are heterozygous for the factor V Leiden variant should avoid estrogen-containing contraception and hormone replacement therapy (HRT).
Women homozygous for the factor V Leiden variant with or without prior VTE should avoid estrogen-containing contraception and HRT.
Asymptomatic women heterozygous for the factor V Leiden variant:
Should be counseled on the risks of estrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms;
Electing to use oral contraceptives should avoid third-generation and other progestins with a higher thrombotic risk;
Electing short-term HRT for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations and is not associated with higher thrombotic risk in healthy women [
The genetic status of apparently asymptomatic at-risk family members can be established using molecular genetic testing for the
Note: The indications for family testing are sustained by low clinical evidence.
In the absence of evidence that early identification of the factor V Leiden variant leads to interventions that can reduce morbidity or mortality, decisions regarding testing should be made on an individual basis. In particular, individuals with a first-degree relative with a factor V Leiden variant, no (or only minor) risk factors, and no history of VTE should not tested [
At-risk females (family history of recurrent VTE at a young age and/or known factor V Leiden thrombophilia) should avoid estrogen-containing contraception and HRT [
See
Guidelines from ASH state all women with inherited thrombophilia should undergo individualized risk assessment [
For pregnant women with a prior VTE, including those heterozygous for the factor V Leiden variant, who are not already receiving anticoagulation for a prior VTE:
Provoked by a hormonal risk factor or unprovoked, antepartum prophylactic anticoagulation is recommended [
Provoked by a transient risk factor not related either to pregnancy or to the use of estrogen, antepartum prophylactic anticoagulation is not suggested [
In women heterozygous for the factor V Leiden variant, antepartum prophylactic anticoagulation is not suggested for first VTE prevention, regardless of family history of VTE [
In women homozygous for the factor V Leiden variant, antepartum prophylactic anticoagulation is suggested to prevent a first VTE, regardless of family history of VTE [
In double heterozygous women for the factor V Leiden and
Standard-dose LMWH is suggested for antepartum prophylaxis, while standard- or intermediate-dose LMWH is suggested for postpartum prophylaxis [
The oral direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) are not recommended during pregnancy and breastfeeding because of (1) absence of data on fetal and neonatal safety and (2) animal studies that showed reproductive toxicity [
For pregnant women with a prior VTE, including those heterozygous for the factor V Leiden variant, not already receiving anticoagulation, postpartum prophylactic anticoagulation is recommended [
In
With a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE;
Without a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE.
In
In
In breastfeeding women using unfractionated heparin, LMWH, fondaparinux, or danaparoid are recommended for prophylaxis [
Although an increased risk of VTE may persist for 12 weeks post partum [
Search
• DNA analysis for prothrombin thrombophilia (
• Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
• Serologic assays for anticardiolipin antibodies and anti-beta-2-glycoprotein 1 antibodies
• Protein C activity
• Antithrombin activity
• Protein S activity or free protein S antigen
• Plasma concentration of homocysteine, as no data support a change in duration of anticoagulation or the use of vitamin supplementation in individuals with hyperhomocysteinemia and a history of VTE
• Factor VIII and other clotting factor levels [
• Heterozygosity for the factor V Leiden variant alone is not an indication for long-term anticoagulation in the absence of other risk factors, according to the American College of Chest Physicians guidelines on antithrombotic therapy [
• Anticoagulation for at least three months is recommended for persons with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) associated with a transient (reversible) risk factor [
• For at least three months following a VTE provoked by a clinical risk factor that has resolved;
• At least three months and until the risk factor has resolved in children with an ongoing but potentially reversible risk factor;
• For six to 12 months after a first unprovoked VTE.
• Should be counseled on the risks of estrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms;
• Electing to use oral contraceptives should avoid third-generation and other progestins with a higher thrombotic risk;
• Electing short-term HRT for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations and is not associated with higher thrombotic risk in healthy women [
• Provoked by a hormonal risk factor or unprovoked, antepartum prophylactic anticoagulation is recommended [
• Provoked by a transient risk factor not related either to pregnancy or to the use of estrogen, antepartum prophylactic anticoagulation is not suggested [
• With a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE;
• Without a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE.
## Evaluations Following Initial Diagnosis
To assess the risk for venous thromboembolism (VTE) in an individual found to have a factor V Leiden variant, the following are recommended:
DNA analysis for prothrombin thrombophilia (
Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
Serologic assays for anticardiolipin antibodies and anti-beta-2-glycoprotein 1 antibodies
For high-risk individuals (i.e., those with a history of recurrent VTE, especially at a young age, or those with strong family history of VTE at a young age), evaluation should also include assays of:
Protein C activity
Antithrombin activity
Protein S activity or free protein S antigen
Note: Measurement of the following is NOT recommended:
Plasma concentration of homocysteine, as no data support a change in duration of anticoagulation or the use of vitamin supplementation in individuals with hyperhomocysteinemia and a history of VTE
Factor VIII and other clotting factor levels [
• DNA analysis for prothrombin thrombophilia (
• Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
• Serologic assays for anticardiolipin antibodies and anti-beta-2-glycoprotein 1 antibodies
• Protein C activity
• Antithrombin activity
• Protein S activity or free protein S antigen
• Plasma concentration of homocysteine, as no data support a change in duration of anticoagulation or the use of vitamin supplementation in individuals with hyperhomocysteinemia and a history of VTE
• Factor VIII and other clotting factor levels [
## Treatment of Manifestations
The management of individuals with factor V Leiden thrombophilia depends on the clinical circumstances.
For individuals not treated with one of the direct oral anticoagulants, administration of warfarin is started concurrently with low-molecular-weight heparin (LMWH) or fondaparinux (except during pregnancy), and monitored with the international normalized ratio (INR). A target INR of 2.5 (therapeutic range 2.0-3.0) provides effective anticoagulation, even in individuals homozygous for the factor V Leiden variant [
Note: LMWH and warfarin are both safe in women who are breastfeeding (see
Heterozygosity for the factor V Leiden variant alone is not an indication for long-term anticoagulation in the absence of other risk factors, according to the American College of Chest Physicians guidelines on antithrombotic therapy [
Anticoagulation for at least three months is recommended for persons with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) associated with a transient (reversible) risk factor [
Several scores were developed to help clinicians estimate the risk of recurrence of DVT or PE after a first episode [
Treatment recommendations for children with VTE were largely adapted from studies in adults, but recently, studies on VTE recurrence and treatment in children have been performed [
The treatment of acute VTE is not influenced by identification of a factor V Leiden variant. Children with a first VTE should receive initial treatment with either unfractionated heparin or LMWH for at least five days. ASH guidelines suggest using either LMWH or warfarin in children with symptomatic DVT or PE [
In children with a factor V Leiden variant, the duration of anticoagulation following VTE may include indefinite anticoagulation or intermittent anticoagulation in high-risk situations after considering the risk of side effects of anticoagulation (e.g., major bleeding), the risk of recurrent VTE, and the preference of the affected individual. To date, outcomes from these treatment strategies have not been studied in children [
For at least three months following a VTE provoked by a clinical risk factor that has resolved;
At least three months and until the risk factor has resolved in children with an ongoing but potentially reversible risk factor;
For six to 12 months after a first unprovoked VTE.
Consensus guidelines and expert opinion emphasize the importance of a careful risk vs benefit assessment in each individual.
• Heterozygosity for the factor V Leiden variant alone is not an indication for long-term anticoagulation in the absence of other risk factors, according to the American College of Chest Physicians guidelines on antithrombotic therapy [
• Anticoagulation for at least three months is recommended for persons with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) associated with a transient (reversible) risk factor [
• For at least three months following a VTE provoked by a clinical risk factor that has resolved;
• At least three months and until the risk factor has resolved in children with an ongoing but potentially reversible risk factor;
• For six to 12 months after a first unprovoked VTE.
## Treatment of VTE in Adults
The management of individuals with factor V Leiden thrombophilia depends on the clinical circumstances.
For individuals not treated with one of the direct oral anticoagulants, administration of warfarin is started concurrently with low-molecular-weight heparin (LMWH) or fondaparinux (except during pregnancy), and monitored with the international normalized ratio (INR). A target INR of 2.5 (therapeutic range 2.0-3.0) provides effective anticoagulation, even in individuals homozygous for the factor V Leiden variant [
Note: LMWH and warfarin are both safe in women who are breastfeeding (see
Heterozygosity for the factor V Leiden variant alone is not an indication for long-term anticoagulation in the absence of other risk factors, according to the American College of Chest Physicians guidelines on antithrombotic therapy [
Anticoagulation for at least three months is recommended for persons with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) associated with a transient (reversible) risk factor [
Several scores were developed to help clinicians estimate the risk of recurrence of DVT or PE after a first episode [
• Heterozygosity for the factor V Leiden variant alone is not an indication for long-term anticoagulation in the absence of other risk factors, according to the American College of Chest Physicians guidelines on antithrombotic therapy [
• Anticoagulation for at least three months is recommended for persons with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) associated with a transient (reversible) risk factor [
## Treatment of VTE in Children
Treatment recommendations for children with VTE were largely adapted from studies in adults, but recently, studies on VTE recurrence and treatment in children have been performed [
The treatment of acute VTE is not influenced by identification of a factor V Leiden variant. Children with a first VTE should receive initial treatment with either unfractionated heparin or LMWH for at least five days. ASH guidelines suggest using either LMWH or warfarin in children with symptomatic DVT or PE [
In children with a factor V Leiden variant, the duration of anticoagulation following VTE may include indefinite anticoagulation or intermittent anticoagulation in high-risk situations after considering the risk of side effects of anticoagulation (e.g., major bleeding), the risk of recurrent VTE, and the preference of the affected individual. To date, outcomes from these treatment strategies have not been studied in children [
For at least three months following a VTE provoked by a clinical risk factor that has resolved;
At least three months and until the risk factor has resolved in children with an ongoing but potentially reversible risk factor;
For six to 12 months after a first unprovoked VTE.
Consensus guidelines and expert opinion emphasize the importance of a careful risk vs benefit assessment in each individual.
• For at least three months following a VTE provoked by a clinical risk factor that has resolved;
• At least three months and until the risk factor has resolved in children with an ongoing but potentially reversible risk factor;
• For six to 12 months after a first unprovoked VTE.
## Prevention of Primary Manifestations
In the absence of a history of thrombosis, long-term anticoagulation is not routinely recommended for asymptomatic individuals who are heterozygous for the factor V Leiden variant because the 1%-3% per year risk for major bleeding from warfarin is greater than the estimated less than 1% per year risk for thrombosis.
Because the initial thrombosis in 50% of factor V Leiden variant heterozygotes occurs in association with other circumstantial risk factors (see
Selected factor V Leiden variant heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in consensus guidelines [
## Surveillance
Individuals receiving long-term anticoagulation require periodic reevaluation of their clinical course to confirm that the benefits of anticoagulation continue to outweigh the risk of bleeding.
Factor V Leiden heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy.
## Agents/Circumstances to Avoid
Women with a history of VTE who are heterozygous for the factor V Leiden variant should avoid estrogen-containing contraception and hormone replacement therapy (HRT).
Women homozygous for the factor V Leiden variant with or without prior VTE should avoid estrogen-containing contraception and HRT.
Asymptomatic women heterozygous for the factor V Leiden variant:
Should be counseled on the risks of estrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms;
Electing to use oral contraceptives should avoid third-generation and other progestins with a higher thrombotic risk;
Electing short-term HRT for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations and is not associated with higher thrombotic risk in healthy women [
• Should be counseled on the risks of estrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms;
• Electing to use oral contraceptives should avoid third-generation and other progestins with a higher thrombotic risk;
• Electing short-term HRT for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations and is not associated with higher thrombotic risk in healthy women [
## Evaluation of Relatives at Risk
The genetic status of apparently asymptomatic at-risk family members can be established using molecular genetic testing for the
Note: The indications for family testing are sustained by low clinical evidence.
In the absence of evidence that early identification of the factor V Leiden variant leads to interventions that can reduce morbidity or mortality, decisions regarding testing should be made on an individual basis. In particular, individuals with a first-degree relative with a factor V Leiden variant, no (or only minor) risk factors, and no history of VTE should not tested [
At-risk females (family history of recurrent VTE at a young age and/or known factor V Leiden thrombophilia) should avoid estrogen-containing contraception and HRT [
See
## Pregnancy Management
Guidelines from ASH state all women with inherited thrombophilia should undergo individualized risk assessment [
For pregnant women with a prior VTE, including those heterozygous for the factor V Leiden variant, who are not already receiving anticoagulation for a prior VTE:
Provoked by a hormonal risk factor or unprovoked, antepartum prophylactic anticoagulation is recommended [
Provoked by a transient risk factor not related either to pregnancy or to the use of estrogen, antepartum prophylactic anticoagulation is not suggested [
In women heterozygous for the factor V Leiden variant, antepartum prophylactic anticoagulation is not suggested for first VTE prevention, regardless of family history of VTE [
In women homozygous for the factor V Leiden variant, antepartum prophylactic anticoagulation is suggested to prevent a first VTE, regardless of family history of VTE [
In double heterozygous women for the factor V Leiden and
Standard-dose LMWH is suggested for antepartum prophylaxis, while standard- or intermediate-dose LMWH is suggested for postpartum prophylaxis [
The oral direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) are not recommended during pregnancy and breastfeeding because of (1) absence of data on fetal and neonatal safety and (2) animal studies that showed reproductive toxicity [
For pregnant women with a prior VTE, including those heterozygous for the factor V Leiden variant, not already receiving anticoagulation, postpartum prophylactic anticoagulation is recommended [
In
With a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE;
Without a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE.
In
In
In breastfeeding women using unfractionated heparin, LMWH, fondaparinux, or danaparoid are recommended for prophylaxis [
Although an increased risk of VTE may persist for 12 weeks post partum [
• Provoked by a hormonal risk factor or unprovoked, antepartum prophylactic anticoagulation is recommended [
• Provoked by a transient risk factor not related either to pregnancy or to the use of estrogen, antepartum prophylactic anticoagulation is not suggested [
• With a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE;
• Without a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE.
## Prevention of Thrombosis During Pregnancy
Guidelines from ASH state all women with inherited thrombophilia should undergo individualized risk assessment [
For pregnant women with a prior VTE, including those heterozygous for the factor V Leiden variant, who are not already receiving anticoagulation for a prior VTE:
Provoked by a hormonal risk factor or unprovoked, antepartum prophylactic anticoagulation is recommended [
Provoked by a transient risk factor not related either to pregnancy or to the use of estrogen, antepartum prophylactic anticoagulation is not suggested [
In women heterozygous for the factor V Leiden variant, antepartum prophylactic anticoagulation is not suggested for first VTE prevention, regardless of family history of VTE [
In women homozygous for the factor V Leiden variant, antepartum prophylactic anticoagulation is suggested to prevent a first VTE, regardless of family history of VTE [
In double heterozygous women for the factor V Leiden and
Standard-dose LMWH is suggested for antepartum prophylaxis, while standard- or intermediate-dose LMWH is suggested for postpartum prophylaxis [
The oral direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) are not recommended during pregnancy and breastfeeding because of (1) absence of data on fetal and neonatal safety and (2) animal studies that showed reproductive toxicity [
• Provoked by a hormonal risk factor or unprovoked, antepartum prophylactic anticoagulation is recommended [
• Provoked by a transient risk factor not related either to pregnancy or to the use of estrogen, antepartum prophylactic anticoagulation is not suggested [
## Prevention of Thrombosis During the Postpartum Period
For pregnant women with a prior VTE, including those heterozygous for the factor V Leiden variant, not already receiving anticoagulation, postpartum prophylactic anticoagulation is recommended [
In
With a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE;
Without a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE.
In
In
In breastfeeding women using unfractionated heparin, LMWH, fondaparinux, or danaparoid are recommended for prophylaxis [
Although an increased risk of VTE may persist for 12 weeks post partum [
• With a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE;
• Without a family history of VTE, postpartum prophylactic anticoagulation is not suggested to prevent a first VTE.
## Other
## Therapies Under Investigation
Search
## Genetic Counseling
Factor V Leiden thrombophilia (i.e., predisposition to the development of venous thrombosis) is inherited in an autosomal dominant manner.
Individuals who are heterozygous for the factor V Leiden variant (
Most individuals with factor V Leiden thrombophilia are heterozygous for the factor V Leiden variant, which they inherited from a parent who is also heterozygous for the factor V Leiden variant.
More rarely, individuals with factor V Leiden thrombophilia are homozygous for the factor V Leiden variant, having inherited one factor V Leiden variant from each parent.
Occasionally – because of the relatively high frequency of the factor V Leiden variant in the general population – one parent is homozygous for the factor V Leiden variant or both parents are heterozygous for the factor V Leiden variant.
The family history of some individuals diagnosed with factor V Leiden thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize factor V Leiden thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous (or homozygous) for the factor V Leiden variant.
If one parent is heterozygous for the factor V Leiden variant, each sib of the proband is at a 50% risk of being heterozygous for the factor V Leiden variant.
If one parent is homozygous for the factor V Leiden variant, each sib of the proband has a 100% chance of being heterozygous for the factor V Leiden variant.
If both parents are heterozygous for the factor V Leiden variant, each sib of the proband has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.
Each child of a heterozygous proband has a 50% chance of inheriting the factor V Leiden variant from the proband. If the proband's reproductive partner is also heterozygous for the factor V Leiden variant, each of their children has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.
All children of an individual who is homozygous for the factor V Leiden variant will inherit the factor V Leiden variant from the proband. If the proband's reproductive partner is heterozygous for the factor V Leiden variant, each of their children has a 50% chance of being homozygous and a 50% chance of being heterozygous for the factor V Leiden variant.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with factor V Leiden thrombophilia.
See
Once the factor V Leiden variant has been identified in a family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly in regard to testing for the factor V Leiden variant, which is common in the general population and is predisposing to, but not predictive of, thrombosis.
• Most individuals with factor V Leiden thrombophilia are heterozygous for the factor V Leiden variant, which they inherited from a parent who is also heterozygous for the factor V Leiden variant.
• More rarely, individuals with factor V Leiden thrombophilia are homozygous for the factor V Leiden variant, having inherited one factor V Leiden variant from each parent.
• Occasionally – because of the relatively high frequency of the factor V Leiden variant in the general population – one parent is homozygous for the factor V Leiden variant or both parents are heterozygous for the factor V Leiden variant.
• The family history of some individuals diagnosed with factor V Leiden thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize factor V Leiden thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous (or homozygous) for the factor V Leiden variant.
• If one parent is heterozygous for the factor V Leiden variant, each sib of the proband is at a 50% risk of being heterozygous for the factor V Leiden variant.
• If one parent is homozygous for the factor V Leiden variant, each sib of the proband has a 100% chance of being heterozygous for the factor V Leiden variant.
• If both parents are heterozygous for the factor V Leiden variant, each sib of the proband has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.
• Each child of a heterozygous proband has a 50% chance of inheriting the factor V Leiden variant from the proband. If the proband's reproductive partner is also heterozygous for the factor V Leiden variant, each of their children has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.
• All children of an individual who is homozygous for the factor V Leiden variant will inherit the factor V Leiden variant from the proband. If the proband's reproductive partner is heterozygous for the factor V Leiden variant, each of their children has a 50% chance of being homozygous and a 50% chance of being heterozygous for the factor V Leiden variant.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with factor V Leiden thrombophilia.
• See
## Mode of Inheritance
Factor V Leiden thrombophilia (i.e., predisposition to the development of venous thrombosis) is inherited in an autosomal dominant manner.
Individuals who are heterozygous for the factor V Leiden variant (
## Risk to Family Members
Most individuals with factor V Leiden thrombophilia are heterozygous for the factor V Leiden variant, which they inherited from a parent who is also heterozygous for the factor V Leiden variant.
More rarely, individuals with factor V Leiden thrombophilia are homozygous for the factor V Leiden variant, having inherited one factor V Leiden variant from each parent.
Occasionally – because of the relatively high frequency of the factor V Leiden variant in the general population – one parent is homozygous for the factor V Leiden variant or both parents are heterozygous for the factor V Leiden variant.
The family history of some individuals diagnosed with factor V Leiden thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize factor V Leiden thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous (or homozygous) for the factor V Leiden variant.
If one parent is heterozygous for the factor V Leiden variant, each sib of the proband is at a 50% risk of being heterozygous for the factor V Leiden variant.
If one parent is homozygous for the factor V Leiden variant, each sib of the proband has a 100% chance of being heterozygous for the factor V Leiden variant.
If both parents are heterozygous for the factor V Leiden variant, each sib of the proband has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.
Each child of a heterozygous proband has a 50% chance of inheriting the factor V Leiden variant from the proband. If the proband's reproductive partner is also heterozygous for the factor V Leiden variant, each of their children has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.
All children of an individual who is homozygous for the factor V Leiden variant will inherit the factor V Leiden variant from the proband. If the proband's reproductive partner is heterozygous for the factor V Leiden variant, each of their children has a 50% chance of being homozygous and a 50% chance of being heterozygous for the factor V Leiden variant.
• Most individuals with factor V Leiden thrombophilia are heterozygous for the factor V Leiden variant, which they inherited from a parent who is also heterozygous for the factor V Leiden variant.
• More rarely, individuals with factor V Leiden thrombophilia are homozygous for the factor V Leiden variant, having inherited one factor V Leiden variant from each parent.
• Occasionally – because of the relatively high frequency of the factor V Leiden variant in the general population – one parent is homozygous for the factor V Leiden variant or both parents are heterozygous for the factor V Leiden variant.
• The family history of some individuals diagnosed with factor V Leiden thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize factor V Leiden thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous (or homozygous) for the factor V Leiden variant.
• If one parent is heterozygous for the factor V Leiden variant, each sib of the proband is at a 50% risk of being heterozygous for the factor V Leiden variant.
• If one parent is homozygous for the factor V Leiden variant, each sib of the proband has a 100% chance of being heterozygous for the factor V Leiden variant.
• If both parents are heterozygous for the factor V Leiden variant, each sib of the proband has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.
• Each child of a heterozygous proband has a 50% chance of inheriting the factor V Leiden variant from the proband. If the proband's reproductive partner is also heterozygous for the factor V Leiden variant, each of their children has a 25% chance of being homozygous for the factor V Leiden variant, a 50% chance of being heterozygous, and a 25% chance of being neither heterozygous nor homozygous for the factor V Leiden variant.
• All children of an individual who is homozygous for the factor V Leiden variant will inherit the factor V Leiden variant from the proband. If the proband's reproductive partner is heterozygous for the factor V Leiden variant, each of their children has a 50% chance of being homozygous and a 50% chance of being heterozygous for the factor V Leiden variant.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with factor V Leiden thrombophilia.
See
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with factor V Leiden thrombophilia.
• See
## Prenatal Testing and Preimplantation Genetic Testing
Once the factor V Leiden variant has been identified in a family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly in regard to testing for the factor V Leiden variant, which is common in the general population and is predisposing to, but not predictive of, thrombosis.
## Resources
United Kingdom
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Factor V Leiden Thrombophilia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Factor V Leiden Thrombophilia (
Factor V Leiden variant refers to missense variant c.1601G>A in
Factor V with the Leiden variant is inactivated at an approximately tenfold slower rate than normal due to this amino acid change, resulting in less efficient APC cleavage. Factor V with the Leiden variant persists longer in the circulation, resulting in increased thrombin generation and a mild hypercoagulable state, reflected by elevated levels of D-dimer, prothrombin fragment F1+2, and other activated coagulation markers [
The factor V Leiden variant is frequent in the population (see
Other
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions. Using legacy nomenclature amino acid numbering begins 28 amino acids after the ATG transcription start site.
## Molecular Pathogenesis
Factor V Leiden variant refers to missense variant c.1601G>A in
Factor V with the Leiden variant is inactivated at an approximately tenfold slower rate than normal due to this amino acid change, resulting in less efficient APC cleavage. Factor V with the Leiden variant persists longer in the circulation, resulting in increased thrombin generation and a mild hypercoagulable state, reflected by elevated levels of D-dimer, prothrombin fragment F1+2, and other activated coagulation markers [
The factor V Leiden variant is frequent in the population (see
Other
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions. Using legacy nomenclature amino acid numbering begins 28 amino acids after the ATG transcription start site.
## Chapter Notes
Prof Daniele Pastori, MD, PhD, FESC; Sapienza University of RomeEmail:
Dr Danilo Menichelli, MD; Sapienza University of RomeEmail:
Dr Emanuele Valeriani, MD; Sapienza University of RomeEmail:
Prof Pasquale Pignatelli, MD, PhD; Sapienza University of RomeEmail:
Contact Prof Daniele Pastori to inquire about review of
Scott H Goodnight, MD; Oregon Health & Science University (1998-2004)Jody L Kujovich, MD; Oregon Health and Science University (1998-2024)Danilo Menichelli, MD (2024-present)Daniele Pastori, MD, PhD, FESC (2024-present)Pasquale Pignatelli, MD, PhD (2024-present)Emanuele Valeriani, MD (2024-present)
16 May 2024 (sw) Comprehensive update posted live
4 January 2018 (bp) Comprehensive update posted live
9 March 2010 (me) Comprehensive update posted live
12 February 2007 (me) Comprehensive update posted live
20 May 2004 (me) Comprehensive update posted live
18 June 2002 (me) Comprehensive update posted live
14 May 1999 (pb) Review posted live
29 December 1998 (jk) Original submission
• 16 May 2024 (sw) Comprehensive update posted live
• 4 January 2018 (bp) Comprehensive update posted live
• 9 March 2010 (me) Comprehensive update posted live
• 12 February 2007 (me) Comprehensive update posted live
• 20 May 2004 (me) Comprehensive update posted live
• 18 June 2002 (me) Comprehensive update posted live
• 14 May 1999 (pb) Review posted live
• 29 December 1998 (jk) Original submission
## Author Notes
Prof Daniele Pastori, MD, PhD, FESC; Sapienza University of RomeEmail:
Dr Danilo Menichelli, MD; Sapienza University of RomeEmail:
Dr Emanuele Valeriani, MD; Sapienza University of RomeEmail:
Prof Pasquale Pignatelli, MD, PhD; Sapienza University of RomeEmail:
Contact Prof Daniele Pastori to inquire about review of
## Author History
Scott H Goodnight, MD; Oregon Health & Science University (1998-2004)Jody L Kujovich, MD; Oregon Health and Science University (1998-2024)Danilo Menichelli, MD (2024-present)Daniele Pastori, MD, PhD, FESC (2024-present)Pasquale Pignatelli, MD, PhD (2024-present)Emanuele Valeriani, MD (2024-present)
## Revision History
16 May 2024 (sw) Comprehensive update posted live
4 January 2018 (bp) Comprehensive update posted live
9 March 2010 (me) Comprehensive update posted live
12 February 2007 (me) Comprehensive update posted live
20 May 2004 (me) Comprehensive update posted live
18 June 2002 (me) Comprehensive update posted live
14 May 1999 (pb) Review posted live
29 December 1998 (jk) Original submission
• 16 May 2024 (sw) Comprehensive update posted live
• 4 January 2018 (bp) Comprehensive update posted live
• 9 March 2010 (me) Comprehensive update posted live
• 12 February 2007 (me) Comprehensive update posted live
• 20 May 2004 (me) Comprehensive update posted live
• 18 June 2002 (me) Comprehensive update posted live
• 14 May 1999 (pb) Review posted live
• 29 December 1998 (jk) Original submission
## References
## Literature Cited
|
[] |
14/5/1999
|
16/5/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
fahn
|
fahn
|
[
"Spastic Paraplegia 35 (SPG35)",
"Spastic Paraplegia 35 (SPG35)",
"Fatty acid 2-hydroxylase",
"FA2H",
"Fatty Acid Hydroxylase-Associated Neurodegeneration"
] |
Fatty Acid Hydroxylase-Associated Neurodegeneration
|
Allison Gregory, Sunita Venkateswaran, Susan J Hayflick
|
Summary Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), and eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence. Life expectancy is variable. FAHN is considered to be a subtype of neurodegeneration with brain iron accumulation (NBIA). The diagnosis of FAHN is established in a proband with suggestive findings and typically by identification of biallelic Independence should be encouraged when possible through use of adaptive aids (e.g., walker or wheelchair for gait abnormalities, augmentative communication devices) and appropriate community resources (e.g., financial services, programs for the visually impaired, special education). Genetic counseling for fatty acid hydroxylase-associated neurodegeneration (FAHN) depends on the causative genetic mechanism: FAHN caused by transmission of one pathogenic variant from each parent is inherited in an autosomal recessive manner; FAHN caused by transmission of two pathogenic variants from one parent (as the result of uniparental disomy [UPD] for chromosome 16) is a Autosomal recessive inheritance: At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
|
## Diagnosis
Fatty acid hydroxylase-associated neurodegeneration (FAHN)
Onset within the first or second decade of life
Corticospinal tract involvement:
Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
Movement disorder including one or both of the following:
Dystonia
Ataxia
Dysarthria
Dysphagia
Eye findings:
Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
Epilepsy
Cognitive decline
On T
Progressive atrophy of the cerebellar hemispheres, vermis, pons, medulla and spinal cord
Thinning of the corpus callosum
Optic atrophy
T
Note: T
The diagnosis of FAHN
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and imaging findings suggest the diagnosis of FAHN or a similar type of neurodegeneration with brain iron accumulation (see
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited neurodegenerative disorders with pyramidal and extrapyramidal involvement,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One reported to date [
Various methods can detect UPD in an apparent
Four probands from nonconsanguineous families had uniparental disomy (UPD, maternal or paternal) [
• Onset within the first or second decade of life
• Corticospinal tract involvement:
• Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
• Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
• Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
• Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
• Movement disorder including one or both of the following:
• Dystonia
• Ataxia
• Dystonia
• Ataxia
• Dysarthria
• Dysphagia
• Eye findings:
• Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
• In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
• Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
• In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
• Epilepsy
• Cognitive decline
• Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
• Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
• Dystonia
• Ataxia
• Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
• In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
• On T
• Progressive atrophy of the cerebellar hemispheres, vermis, pons, medulla and spinal cord
• Thinning of the corpus callosum
• Optic atrophy
• T
• Note: T
## Suggestive Findings
Fatty acid hydroxylase-associated neurodegeneration (FAHN)
Onset within the first or second decade of life
Corticospinal tract involvement:
Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
Movement disorder including one or both of the following:
Dystonia
Ataxia
Dysarthria
Dysphagia
Eye findings:
Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
Epilepsy
Cognitive decline
On T
Progressive atrophy of the cerebellar hemispheres, vermis, pons, medulla and spinal cord
Thinning of the corpus callosum
Optic atrophy
T
Note: T
• Onset within the first or second decade of life
• Corticospinal tract involvement:
• Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
• Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
• Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
• Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
• Movement disorder including one or both of the following:
• Dystonia
• Ataxia
• Dystonia
• Ataxia
• Dysarthria
• Dysphagia
• Eye findings:
• Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
• In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
• Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
• In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
• Epilepsy
• Cognitive decline
• Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
• Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
• Dystonia
• Ataxia
• Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
• In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
• On T
• Progressive atrophy of the cerebellar hemispheres, vermis, pons, medulla and spinal cord
• Thinning of the corpus callosum
• Optic atrophy
• T
• Note: T
## Establishing the Diagnosis
The diagnosis of FAHN
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic and imaging findings suggest the diagnosis of FAHN or a similar type of neurodegeneration with brain iron accumulation (see
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited neurodegenerative disorders with pyramidal and extrapyramidal involvement,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One reported to date [
Various methods can detect UPD in an apparent
Four probands from nonconsanguineous families had uniparental disomy (UPD, maternal or paternal) [
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of FAHN or a similar type of neurodegeneration with brain iron accumulation (see
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited neurodegenerative disorders with pyramidal and extrapyramidal involvement,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One reported to date [
Various methods can detect UPD in an apparent
Four probands from nonconsanguineous families had uniparental disomy (UPD, maternal or paternal) [
## Clinical Characteristics
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. FAHN is a subtype of
Of note, leukodystrophy and hereditary spastic paraplegia 35 (HSP35), two phenotypes previously considered distinct disorders based on clinical findings [
The most frequent presenting finding is a subtle change in gait that may lead to increasingly frequent falls. This typically occurs in childhood or adolescence and may be the result of focal dystonia and/or corticospinal tract involvement.
The degree of spasticity resulting from corticospinal tract involvement can vary among persons with FAHN. Individuals affected to a lesser degree may develop spastic paraparesis but retain the ability to walk, while individuals with more severe disease may demonstrate a spastic quadriplegic pattern of disability and lose their ability to ambulate, instead relying on a wheelchair.
Dystonia may begin focally (e.g., affecting one foot) but typically spreads to assume a generalized pattern. The degree of dystonia seen in FAHN is generally milder than that in other forms of NBIA, such as PKAN, in which status dystonicus occurs.
Ataxia typically begins in childhood or adolescence and may emerge along with dystonia and/or spasticity. The ataxia that occurs in FAHN may affect both axial and appendicular function and, along with both dystonia and spasticity, can markedly impair gait.
Dysarthria may be prominent in FAHN. In some individuals, expressive speech can be impaired to the point of anarthria. Dysphagia, potentially necessitating gastrostomy tube placement, can also occur.
Optic atrophy in FAHN may begin as a subtle loss of visual acuity in childhood, but may progress to the point of functional blindness. The oculomotor abnormalities seen in FAHN may impair functional vision as well.
A few individuals with FAHN and peripheral neuropathy have been reported [
Seizures are not typically seen in the early stages of disease, but may occur later in the disease course. When present, seizures (which tend to be complex partial or generalized) are typically infrequent and respond relatively well to anticonvulsants.
While progressive intellectual impairment occurs in most persons with FAHN, more information on the cognitive phenotype and natural history are needed. Serial assessments have documented cognitive decline in two individuals [
Although the neurodegeneration in FAHN is progressive, declines may be intermittent and punctuated by periods of relative clinical stability. However, lost skills are not usually regained. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence.
No genotype-phenotype correlations have been observed for pathogenic variants in
Historically, the
The authors prefer to refer to the
No reliable prevalence data are available. However, the prevalence is estimated to be lower than one in 1,000,000.
## Clinical Description
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. FAHN is a subtype of
Of note, leukodystrophy and hereditary spastic paraplegia 35 (HSP35), two phenotypes previously considered distinct disorders based on clinical findings [
The most frequent presenting finding is a subtle change in gait that may lead to increasingly frequent falls. This typically occurs in childhood or adolescence and may be the result of focal dystonia and/or corticospinal tract involvement.
The degree of spasticity resulting from corticospinal tract involvement can vary among persons with FAHN. Individuals affected to a lesser degree may develop spastic paraparesis but retain the ability to walk, while individuals with more severe disease may demonstrate a spastic quadriplegic pattern of disability and lose their ability to ambulate, instead relying on a wheelchair.
Dystonia may begin focally (e.g., affecting one foot) but typically spreads to assume a generalized pattern. The degree of dystonia seen in FAHN is generally milder than that in other forms of NBIA, such as PKAN, in which status dystonicus occurs.
Ataxia typically begins in childhood or adolescence and may emerge along with dystonia and/or spasticity. The ataxia that occurs in FAHN may affect both axial and appendicular function and, along with both dystonia and spasticity, can markedly impair gait.
Dysarthria may be prominent in FAHN. In some individuals, expressive speech can be impaired to the point of anarthria. Dysphagia, potentially necessitating gastrostomy tube placement, can also occur.
Optic atrophy in FAHN may begin as a subtle loss of visual acuity in childhood, but may progress to the point of functional blindness. The oculomotor abnormalities seen in FAHN may impair functional vision as well.
A few individuals with FAHN and peripheral neuropathy have been reported [
Seizures are not typically seen in the early stages of disease, but may occur later in the disease course. When present, seizures (which tend to be complex partial or generalized) are typically infrequent and respond relatively well to anticonvulsants.
While progressive intellectual impairment occurs in most persons with FAHN, more information on the cognitive phenotype and natural history are needed. Serial assessments have documented cognitive decline in two individuals [
Although the neurodegeneration in FAHN is progressive, declines may be intermittent and punctuated by periods of relative clinical stability. However, lost skills are not usually regained. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been observed for pathogenic variants in
## Nomenclature
Historically, the
The authors prefer to refer to the
## Prevalence
No reliable prevalence data are available. However, the prevalence is estimated to be lower than one in 1,000,000.
## Genetically Related (Allelic) Disorders
No other phenotypes are known to be associated with biallelic
## Differential Diagnosis
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a neurodegenerative disorder that shows clinical overlap with other early-onset neurodegenerative disorders. Disorders that may exhibit clinical and neuroimaging features similar to those seen in FAHN are summarized in
Disorders to Consider in the Differential Diagnosis of FAHN
Cognitive decline
Progressive spasticity & dystonia
Optic atrophy
Hyperintense streaking of medial medullary lamina often observed on T
Parkinsonism developing in later disease
"Eye of the tiger" sign
More severe dystonia
Progressive spasticity & dystonia
Optic atrophy
Cognitive decline
Cerebellar atrophy
Fewer cerebellar findings
Apparent claval hypertrophy
More prominent extrapyramidal signs
Pallidal iron
Gait disturbance
Spasticity
Dystonia
T
Kayser-Fleischer rings
Liver disease (most common 1st manifestation of Wilson disease in children)
Spastic paraplegia
Dysarthria
Optic atrophy
Peripheral neuropathy
Cerebellar atrophy
More prominent early gait ataxia (cerebellar & proprioceptive)
Absence of early spasticity
Cardiomyopathy
Diabetes mellitus in later stages
Prominent cervical cord atrophy & only later-onset cerebellar atrophy on MRI
Early childhood spastic ataxia
Oculomotor abnormalities
Teenage-onset of seizures
Unsteady at onset of gait
Hypermyelinated retinal fibers
Polyneuropathy
Childhood-onset spasticity ± ataxia
Nystagmus
Preserved cognition
Milder course
Spasticity
Hyperreflexia
Intention tremor
Preservation of basal ganglia & no cerebellar atrophy
Diffuse hypomyelination on MRI
Spastic paraparesis
Mild cognitive delay
Cerebellar & bulbar involvement
Periventricular white matter abnormalities & thin corpus callosum on MRI
Early childhood motor regression
Spasticity
Dysarthria
Behavior & cognitive ability decline first
More frequent peripheral neuropathy
Periventricular demyelination on MRI
Variable-onset motor regression w/spasticity
Dystonia
Bulbar & cerebellar dysfunction
Cerebellar atrophy on MRI
More prominent extrapyramidal features
Diffuse hypomyelination, atrophy of caudate & putamen, preservation of globus pallidus on MRI
Spasticity
Tremor
Extrapyramidal symptoms
MRI: thin corpus callosum w/cerebellar atrophy.
Cerebellar features predominate
Abnormal dentition
Endocrine abnormalities
± myopia
Hypomyelination pattern on MRI
Childhood or later onset spasticity, ataxia, & seizures
± optic atrophy
± cerebellar atrophy
± retinitis pigmentosa
Juvenile form more aggressive
Diurinal fluctuation
Improvement w/low-dose levodopa
MRI: normal
AD = autosomal dominant; AR = autosomal recessive; ARSACS = autosomal recessive spastic ataxia of Charlevoix Saguenay; DiffDx = differential diagnosis; MOI = mode of inheritance; NBIA = neurodegeneration with brain iron accumulation; XL = X-linked
• Cognitive decline
• Progressive spasticity & dystonia
• Optic atrophy
• Hyperintense streaking of medial medullary lamina often observed on T
• Parkinsonism developing in later disease
• "Eye of the tiger" sign
• More severe dystonia
• Progressive spasticity & dystonia
• Optic atrophy
• Cognitive decline
• Cerebellar atrophy
• Fewer cerebellar findings
• Apparent claval hypertrophy
• More prominent extrapyramidal signs
• Pallidal iron
• Gait disturbance
• Spasticity
• Dystonia
• T
• Kayser-Fleischer rings
• Liver disease (most common 1st manifestation of Wilson disease in children)
• Spastic paraplegia
• Dysarthria
• Optic atrophy
• Peripheral neuropathy
• Cerebellar atrophy
• More prominent early gait ataxia (cerebellar & proprioceptive)
• Absence of early spasticity
• Cardiomyopathy
• Diabetes mellitus in later stages
• Prominent cervical cord atrophy & only later-onset cerebellar atrophy on MRI
• Early childhood spastic ataxia
• Oculomotor abnormalities
• Teenage-onset of seizures
• Unsteady at onset of gait
• Hypermyelinated retinal fibers
• Polyneuropathy
• Childhood-onset spasticity ± ataxia
• Nystagmus
• Preserved cognition
• Milder course
• Spasticity
• Hyperreflexia
• Intention tremor
• Preservation of basal ganglia & no cerebellar atrophy
• Diffuse hypomyelination on MRI
• Spastic paraparesis
• Mild cognitive delay
• Cerebellar & bulbar involvement
• Periventricular white matter abnormalities & thin corpus callosum on MRI
• Early childhood motor regression
• Spasticity
• Dysarthria
• Behavior & cognitive ability decline first
• More frequent peripheral neuropathy
• Periventricular demyelination on MRI
• Variable-onset motor regression w/spasticity
• Dystonia
• Bulbar & cerebellar dysfunction
• Cerebellar atrophy on MRI
• More prominent extrapyramidal features
• Diffuse hypomyelination, atrophy of caudate & putamen, preservation of globus pallidus on MRI
• Spasticity
• Tremor
• Extrapyramidal symptoms
• MRI: thin corpus callosum w/cerebellar atrophy.
• Cerebellar features predominate
• Abnormal dentition
• Endocrine abnormalities
• ± myopia
• Hypomyelination pattern on MRI
• Childhood or later onset spasticity, ataxia, & seizures
• ± optic atrophy
• ± cerebellar atrophy
• ± retinitis pigmentosa
• Juvenile form more aggressive
• Diurinal fluctuation
• Improvement w/low-dose levodopa
• MRI: normal
## Management
To establish the extent of disease in an individual diagnosed with fatty acid hydroxylase-associated neurodegeneration (FAHN), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)
OT = occupational therapy; PT = physical therapy
Refer those with visual impairment to appropriate community resources.
Once swallowing evaluation and nutrition assessments indicate that the individual cannot maintain adequate nutrition and/or avoid the risk of aspiration with oral feeding, gastrostomy tube placement is indicated.
Pharmacologic and surgical interventions are focused on palliation of symptoms.
Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene. Of note, while levodopa could potentially provide benefit, it often does not; thus, a trial is reasonable, but should only be continued if there is clear benefit.
Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups
Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US and Canada, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
The following should be performed on a regular basis:
Swallowing evaluation, nutrition assessment, and monitoring of height and weight to screen for evidence of worsening nutritional status
Ophthalmologic assessment with particular attention to visual acuity.
Assessment of mobility, self-help skills, and activities of daily living and need for adaptive devices
Assessment of speech and communication needs
See
Search
• Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene. Of note, while levodopa could potentially provide benefit, it often does not; thus, a trial is reasonable, but should only be continued if there is clear benefit.
• Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups
• Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• In the US and Canada, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Swallowing evaluation, nutrition assessment, and monitoring of height and weight to screen for evidence of worsening nutritional status
• Ophthalmologic assessment with particular attention to visual acuity.
• Assessment of mobility, self-help skills, and activities of daily living and need for adaptive devices
• Assessment of speech and communication needs
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with fatty acid hydroxylase-associated neurodegeneration (FAHN), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN)
OT = occupational therapy; PT = physical therapy
## Treatment of Manifestations
Refer those with visual impairment to appropriate community resources.
Once swallowing evaluation and nutrition assessments indicate that the individual cannot maintain adequate nutrition and/or avoid the risk of aspiration with oral feeding, gastrostomy tube placement is indicated.
Pharmacologic and surgical interventions are focused on palliation of symptoms.
Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene. Of note, while levodopa could potentially provide benefit, it often does not; thus, a trial is reasonable, but should only be continued if there is clear benefit.
Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups
Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US and Canada, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene. Of note, while levodopa could potentially provide benefit, it often does not; thus, a trial is reasonable, but should only be continued if there is clear benefit.
• Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups
• Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• In the US and Canada, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Eyes
Refer those with visual impairment to appropriate community resources.
## Feeding
Once swallowing evaluation and nutrition assessments indicate that the individual cannot maintain adequate nutrition and/or avoid the risk of aspiration with oral feeding, gastrostomy tube placement is indicated.
## Neurologic
Pharmacologic and surgical interventions are focused on palliation of symptoms.
Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene. Of note, while levodopa could potentially provide benefit, it often does not; thus, a trial is reasonable, but should only be continued if there is clear benefit.
Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups
Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
• Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene. Of note, while levodopa could potentially provide benefit, it often does not; thus, a trial is reasonable, but should only be continued if there is clear benefit.
• Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups
• Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US and Canada, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• In the US and Canada, an IEP based on the individual’s level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Surveillance
The following should be performed on a regular basis:
Swallowing evaluation, nutrition assessment, and monitoring of height and weight to screen for evidence of worsening nutritional status
Ophthalmologic assessment with particular attention to visual acuity.
Assessment of mobility, self-help skills, and activities of daily living and need for adaptive devices
Assessment of speech and communication needs
• Swallowing evaluation, nutrition assessment, and monitoring of height and weight to screen for evidence of worsening nutritional status
• Ophthalmologic assessment with particular attention to visual acuity.
• Assessment of mobility, self-help skills, and activities of daily living and need for adaptive devices
• Assessment of speech and communication needs
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Genetic counseling for fatty acid hydroxylase-associated neurodegeneration (FAHN) depends on the causative genetic mechanism:
FAHN caused by transmission of one pathogenic variant from each parent is inherited in an autosomal recessive manner.
FAHN caused by transmission of two pathogenic variants from one parent (as the result of uniparental disomy [UPD] for chromosome 16) is a
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
The risk to parents, sibs, and offspring of an individual with FAHN caused by UPD16 is unlikely to be higher than the risk to the general population, as UPD16 is a
If the proband has a chromosome abnormality in addition to UPD16, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband.
Note: UPD for chromosome 16 has led to four published cases of FAHN [
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
• FAHN caused by transmission of one pathogenic variant from each parent is inherited in an autosomal recessive manner.
• FAHN caused by transmission of two pathogenic variants from one parent (as the result of uniparental disomy [UPD] for chromosome 16) is a
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The risk to parents, sibs, and offspring of an individual with FAHN caused by UPD16 is unlikely to be higher than the risk to the general population, as UPD16 is a
• If the proband has a chromosome abnormality in addition to UPD16, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband.
• Note: UPD for chromosome 16 has led to four published cases of FAHN [
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Genetic counseling for fatty acid hydroxylase-associated neurodegeneration (FAHN) depends on the causative genetic mechanism:
FAHN caused by transmission of one pathogenic variant from each parent is inherited in an autosomal recessive manner.
FAHN caused by transmission of two pathogenic variants from one parent (as the result of uniparental disomy [UPD] for chromosome 16) is a
• FAHN caused by transmission of one pathogenic variant from each parent is inherited in an autosomal recessive manner.
• FAHN caused by transmission of two pathogenic variants from one parent (as the result of uniparental disomy [UPD] for chromosome 16) is a
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Uniparental Disomy of Chromosome 16 (UPD16) – Risk to Family Members
The risk to parents, sibs, and offspring of an individual with FAHN caused by UPD16 is unlikely to be higher than the risk to the general population, as UPD16 is a
If the proband has a chromosome abnormality in addition to UPD16, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband.
Note: UPD for chromosome 16 has led to four published cases of FAHN [
• The risk to parents, sibs, and offspring of an individual with FAHN caused by UPD16 is unlikely to be higher than the risk to the general population, as UPD16 is a
• If the proband has a chromosome abnormality in addition to UPD16, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband.
• Note: UPD for chromosome 16 has led to four published cases of FAHN [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
## Resources
PO Box 29
South River Newfoundland and Labrador A0A 3W0
Canada
Center of Excellence for NBIA Clinical Care and Research
International Registry for NBIA and Related Disorders
Oregon Health & Science University
Germany
•
•
•
• PO Box 29
• South River Newfoundland and Labrador A0A 3W0
• Canada
•
•
•
•
•
•
•
•
• Center of Excellence for NBIA Clinical Care and Research
• International Registry for NBIA and Related Disorders
• Oregon Health & Science University
•
•
• Germany
•
## Molecular Genetics
Fatty Acid Hydroxylase-Associated Neurodegeneration: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Fatty Acid Hydroxylase-Associated Neurodegeneration (
Human
In the peripheral nervous system, there is evidence that a second fatty acid-hydroxylating enzyme (perhaps phytanoyl coA 2-hydroxylase) may compensate for loss of FA2H activity [
## Molecular Pathogenesis
Human
In the peripheral nervous system, there is evidence that a second fatty acid-hydroxylating enzyme (perhaps phytanoyl coA 2-hydroxylase) may compensate for loss of FA2H activity [
## Chapter Notes
Allison Gregory, MS (2011-present)Susan J Hayflick, MD (2011-present)Michael C Kruer, MD, University of South Dakota Sanford School of Medicine (2011-2018)Sunita Venkateswaran, MD (2018-present)
27 September 2018 (bp) Comprehensive update posted live
20 September 2012 (cd) Revision: deletion/duplication analysis available clinically
28 June 2011 (me) Review posted live
3 January 2011 (mk) Original submission
• 27 September 2018 (bp) Comprehensive update posted live
• 20 September 2012 (cd) Revision: deletion/duplication analysis available clinically
• 28 June 2011 (me) Review posted live
• 3 January 2011 (mk) Original submission
## Author History
Allison Gregory, MS (2011-present)Susan J Hayflick, MD (2011-present)Michael C Kruer, MD, University of South Dakota Sanford School of Medicine (2011-2018)Sunita Venkateswaran, MD (2018-present)
## Revision History
27 September 2018 (bp) Comprehensive update posted live
20 September 2012 (cd) Revision: deletion/duplication analysis available clinically
28 June 2011 (me) Review posted live
3 January 2011 (mk) Original submission
• 27 September 2018 (bp) Comprehensive update posted live
• 20 September 2012 (cd) Revision: deletion/duplication analysis available clinically
• 28 June 2011 (me) Review posted live
• 3 January 2011 (mk) Original submission
## References
## Literature Cited
Neuroimaging features of FAHN (A) vs PKAN (B)
The two forms of NBIA share T
|
[
"NL Alderson, H Hama. Fatty acid 2-hydroxylase regulates cAMP-induced cell cycle exit in D6P2T schwannoma cells.. J Lipid Res. 2009;50:1203-8",
"NL Alderson, BM Rembiesa, MD Walla, A Bielawska, J Bielawski, H Hama. The human FA2H gene encodes a fatty acid 2-hydroxylase.. J Biol Chem. 2004;279:48562-8",
"N Boddaert, KH Le Quan Sang, A Rötig, A Leroy-Willig, S Gallet, F Brunelle, D Sidi, JC Thalabard, A Munnich, ZI Cabantchik. Selective iron chelation in Friedreich ataxia: biologic and clinical implications.. Blood. 2007;110:401-8",
"KJ Dick, R Al-Mjeni, W Baskir, R Koul, MA Simpson, MA Patton, S Raeburn, AH Crosby. A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23.. Neurology. 2008;71:248-52",
"KJ Dick, M Eckhardt, C Paisán-Ruiz, AA Alshehhi, C Proukakis, NA Sibtain, H Maier, R Sharifi, MA Patton, W Bashir, R Koul, S Raeburn, V Gieselmann, H Houlden, AH Crosby. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35).. Hum Mutat. 2010;31:E1251-60",
"S Donkervoort, J Dastgir, Y Hu, WM Zein, H Marks, C Blackstone, CG Bönnemann. Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia.. Clin Genet. 2014;85:393-5",
"M Eckhardt, A Yaghootfam, SN Fewou, I Zöller, V Gieselmann. A mammalian fatty acid hydroxylase responsible for the formation of alpha-hydroxylated galactosylceramide in myelin.. Biochem J. 2005;388:245-54",
"S Edvardson, H Hama, A Shaag, JM Gomori, I Berger, D Soffer, SH Korman, I Taustein, A Saada, O Elpeleg. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia.. Am J Hum Genet. 2008;83:643-8",
"L Guo, D Zhou, KM Pryse, AL Okunade, X Su. Fatty acid 2-hydroxylase mediates diffusional mobility of Raft-associated lipids, GLUT4 level, and lipogenesis in 3T3-L1 adipocytes.. J Biol Chem. 2010;285:25438-47",
"CR Justesen, RD Penn, JS Kroin, RT Egel. Stereotactic pallidotomy in a child with Hallervorden-Spatz disease. Case report.. J Neurosurg. 1999;90:551-4",
"MC Kruer, C Paisán-Ruiz, N Boddaert, MY Yoon, H Hama, A Gregory, A Malandrini, RL Woltjer, A Munnich, S Gobin, BJ Polster, S Palmeri, S Edvardson, J Hardy, H Houlden, SJ Hayflick. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA).. Ann Neurol. 2010;68:611-8",
"M Levy, RH Llinas. Deferiprone reduces hemosiderin deposits in the brain of a patient with superficial siderosis.. AJNR Am J Neuroradiol. 2011;32:E1-2",
"A Magariello, C Russo, L Citrigno, S Zuchner, A Patitucci, R Mazzei, FL Conforti, E Ferlazzo, U Aguglia, M Muglia. Exome sequencing reveals two. J Neurol Sci. 2017;372:347-9",
"TM Pierson, DR Simeonov, M Sincan, DA Adams, T Markello, G Golas, K Fuentes-Fajardo, NF Hansen, PF Cherukuri, P Cruz, JC Mullikin, C Blackstone, C Tifft, CF Boerkoel, WA Gahl. Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration.. Eur J Hum Genet. 2012;20:476-9",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"G Ristori, S Romano, A Visconti, S Cannoni, M Spadaro, M Frontali, FE Pontieri, N Vanacore, M Salvetti. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial.. Neurology. 2010;74:839-45",
"AS Soehn, TW Rattay, S Beck-Wödl, K Schäferhoff, D Monk, M Döbler-Neumann, K Hörtnagel, A Schlüter, M Ruiz, A Pujol, S Züchner, O Riess, R Schüle, P Bauer, L Schöls. Uniparental disomy of chromosome 16 unmasks recessive mutations of. Neurology. 2016;87:186-91",
"A Tonelli, MG D’Angelo, F Arrigoni, E Brighina, A Arnoldi, A Citterio, N Bresolin, MT Bassi. Atypical adult onset complicated spastic paraparesis with thin corpus callosum in two patients carrying a novel. Eur J Neurol. 2012;19:e127-9",
"A Vanderver, M Prust, D Tonduti, F Mochel, HM Hussey, G Helman, J Garbern, F Eichler, P Labauge, P Aubourg, D Rodriguez, MC Patterson, JL Van Hove, J Schmidt, NI Wolf, O Boespflug-Tanguy, R Schiffmann, MS van der Knaap. Case definition and classification of leukodystrophies and leukoencephalopathies.. Mol Genet Metab. 2015;114:494-500",
"MS Zaki, L Selim, L Mansour, IG Mahmoud, AG Fenstermaker, SB Gabriel, JG Gleeson. Mutations in FA2H in three Arab families with a clinical spectrum of neurodegeneration and hereditary spastic paraparesis.. Clin Genet. 2015;88:95-7"
] |
28/6/2011
|
27/9/2018
|
20/9/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
fam111a-dysp
|
fam111a-dysp
|
[
"Osteocraniostenosis (Gracile Bone Dysplasia)",
"Kenny-Caffey Syndrome",
"Serine protease FAM111A",
"FAM111A",
"FAM111A-Related Skeletal Dysplasias"
] |
Shirley Cheng, Ivan FM Lo, Ho-Ming Luk
|
Summary The diagnosis of a Once the
|
Kenny-Caffey syndrome
Osteocraniostenosis (gracile bone dysplasia)
For synonyms and outdated names, see
For other genetic causes of these phenotypes, see
• Kenny-Caffey syndrome
• Osteocraniostenosis (gracile bone dysplasia)
## Diagnosis
No consensus clinical diagnostic criteria for
Proportionate short stature, most often postnatal onset
Dysmorphic facial features such as frontal bossing or prominent forehead with relative macrocephaly, triangular face, short palpebral fissures, deeply set eyes, midface retrusion, short nose, narrow nasal ridge, and micrognathia or microretrognathia (See
Ocular manifestations including microphthalmia, aniridia, hyperopia or myopia, astigmatism, cataract, corneal and retinal calcification, and pseudopapilledema
Dental manifestations including oligodontia, enamel hypoplasia, retention of primary dentition, delayed eruption of secondary dentition, increased dental caries, and loss of secondary dentition due to dental caries
Other features including small testes and infertility have been described.
Skeletal radiographs show delayed anterior fontanelle closure and short long bones with cortical thickening and stenosis of the medullary cavity (see
Brain imaging shows calcification (typically of the basal ganglia but also reported in dentate nuclei and parts of the cerebrum and cerebellum).
Other imaging findings including wormian bones, prominent odontoid process, craniosynostosis (coronal and/or basal sutures), and coxa valga have also been reported.
Intrauterine growth deficiency with micromelia and disproportionately small hands and feet
Craniofacial features such as ear anomalies, short nose, and narrow mouth
Micropenis and small testes
Respiratory insufficiency secondary to pulmonary hypoplasia
Splenic aplasia or hypoplasia
Extramedullary hematopoiesis
Cloverleaf-shaped skull (can be detected antenatally)
Decreased skull ossification (can be detected antenatally)
Slender long bones with cortical thickening, stenosis of the medullary cavity, and flared metaphyses
Thin ribs and thoracic hypoplasia
Bone fractures in some individuals, typically affecting long bones (e.g., femur, radius, ulna) and occasionally rib fractures
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
• Proportionate short stature, most often postnatal onset
• Dysmorphic facial features such as frontal bossing or prominent forehead with relative macrocephaly, triangular face, short palpebral fissures, deeply set eyes, midface retrusion, short nose, narrow nasal ridge, and micrognathia or microretrognathia (See
• Ocular manifestations including microphthalmia, aniridia, hyperopia or myopia, astigmatism, cataract, corneal and retinal calcification, and pseudopapilledema
• Dental manifestations including oligodontia, enamel hypoplasia, retention of primary dentition, delayed eruption of secondary dentition, increased dental caries, and loss of secondary dentition due to dental caries
• Other features including small testes and infertility have been described.
• Skeletal radiographs show delayed anterior fontanelle closure and short long bones with cortical thickening and stenosis of the medullary cavity (see
• Brain imaging shows calcification (typically of the basal ganglia but also reported in dentate nuclei and parts of the cerebrum and cerebellum).
• Other imaging findings including wormian bones, prominent odontoid process, craniosynostosis (coronal and/or basal sutures), and coxa valga have also been reported.
• Intrauterine growth deficiency with micromelia and disproportionately small hands and feet
• Craniofacial features such as ear anomalies, short nose, and narrow mouth
• Micropenis and small testes
• Respiratory insufficiency secondary to pulmonary hypoplasia
• Splenic aplasia or hypoplasia
• Extramedullary hematopoiesis
• Cloverleaf-shaped skull (can be detected antenatally)
• Decreased skull ossification (can be detected antenatally)
• Slender long bones with cortical thickening, stenosis of the medullary cavity, and flared metaphyses
• Thin ribs and thoracic hypoplasia
• Bone fractures in some individuals, typically affecting long bones (e.g., femur, radius, ulna) and occasionally rib fractures
## Suggestive Findings
Proportionate short stature, most often postnatal onset
Dysmorphic facial features such as frontal bossing or prominent forehead with relative macrocephaly, triangular face, short palpebral fissures, deeply set eyes, midface retrusion, short nose, narrow nasal ridge, and micrognathia or microretrognathia (See
Ocular manifestations including microphthalmia, aniridia, hyperopia or myopia, astigmatism, cataract, corneal and retinal calcification, and pseudopapilledema
Dental manifestations including oligodontia, enamel hypoplasia, retention of primary dentition, delayed eruption of secondary dentition, increased dental caries, and loss of secondary dentition due to dental caries
Other features including small testes and infertility have been described.
Skeletal radiographs show delayed anterior fontanelle closure and short long bones with cortical thickening and stenosis of the medullary cavity (see
Brain imaging shows calcification (typically of the basal ganglia but also reported in dentate nuclei and parts of the cerebrum and cerebellum).
Other imaging findings including wormian bones, prominent odontoid process, craniosynostosis (coronal and/or basal sutures), and coxa valga have also been reported.
Intrauterine growth deficiency with micromelia and disproportionately small hands and feet
Craniofacial features such as ear anomalies, short nose, and narrow mouth
Micropenis and small testes
Respiratory insufficiency secondary to pulmonary hypoplasia
Splenic aplasia or hypoplasia
Extramedullary hematopoiesis
Cloverleaf-shaped skull (can be detected antenatally)
Decreased skull ossification (can be detected antenatally)
Slender long bones with cortical thickening, stenosis of the medullary cavity, and flared metaphyses
Thin ribs and thoracic hypoplasia
Bone fractures in some individuals, typically affecting long bones (e.g., femur, radius, ulna) and occasionally rib fractures
• Proportionate short stature, most often postnatal onset
• Dysmorphic facial features such as frontal bossing or prominent forehead with relative macrocephaly, triangular face, short palpebral fissures, deeply set eyes, midface retrusion, short nose, narrow nasal ridge, and micrognathia or microretrognathia (See
• Ocular manifestations including microphthalmia, aniridia, hyperopia or myopia, astigmatism, cataract, corneal and retinal calcification, and pseudopapilledema
• Dental manifestations including oligodontia, enamel hypoplasia, retention of primary dentition, delayed eruption of secondary dentition, increased dental caries, and loss of secondary dentition due to dental caries
• Other features including small testes and infertility have been described.
• Skeletal radiographs show delayed anterior fontanelle closure and short long bones with cortical thickening and stenosis of the medullary cavity (see
• Brain imaging shows calcification (typically of the basal ganglia but also reported in dentate nuclei and parts of the cerebrum and cerebellum).
• Other imaging findings including wormian bones, prominent odontoid process, craniosynostosis (coronal and/or basal sutures), and coxa valga have also been reported.
• Intrauterine growth deficiency with micromelia and disproportionately small hands and feet
• Craniofacial features such as ear anomalies, short nose, and narrow mouth
• Micropenis and small testes
• Respiratory insufficiency secondary to pulmonary hypoplasia
• Splenic aplasia or hypoplasia
• Extramedullary hematopoiesis
• Cloverleaf-shaped skull (can be detected antenatally)
• Decreased skull ossification (can be detected antenatally)
• Slender long bones with cortical thickening, stenosis of the medullary cavity, and flared metaphyses
• Thin ribs and thoracic hypoplasia
• Bone fractures in some individuals, typically affecting long bones (e.g., femur, radius, ulna) and occasionally rib fractures
## Kenny-Caffey Syndrome
Proportionate short stature, most often postnatal onset
Dysmorphic facial features such as frontal bossing or prominent forehead with relative macrocephaly, triangular face, short palpebral fissures, deeply set eyes, midface retrusion, short nose, narrow nasal ridge, and micrognathia or microretrognathia (See
Ocular manifestations including microphthalmia, aniridia, hyperopia or myopia, astigmatism, cataract, corneal and retinal calcification, and pseudopapilledema
Dental manifestations including oligodontia, enamel hypoplasia, retention of primary dentition, delayed eruption of secondary dentition, increased dental caries, and loss of secondary dentition due to dental caries
Other features including small testes and infertility have been described.
Skeletal radiographs show delayed anterior fontanelle closure and short long bones with cortical thickening and stenosis of the medullary cavity (see
Brain imaging shows calcification (typically of the basal ganglia but also reported in dentate nuclei and parts of the cerebrum and cerebellum).
Other imaging findings including wormian bones, prominent odontoid process, craniosynostosis (coronal and/or basal sutures), and coxa valga have also been reported.
• Proportionate short stature, most often postnatal onset
• Dysmorphic facial features such as frontal bossing or prominent forehead with relative macrocephaly, triangular face, short palpebral fissures, deeply set eyes, midface retrusion, short nose, narrow nasal ridge, and micrognathia or microretrognathia (See
• Ocular manifestations including microphthalmia, aniridia, hyperopia or myopia, astigmatism, cataract, corneal and retinal calcification, and pseudopapilledema
• Dental manifestations including oligodontia, enamel hypoplasia, retention of primary dentition, delayed eruption of secondary dentition, increased dental caries, and loss of secondary dentition due to dental caries
• Other features including small testes and infertility have been described.
• Skeletal radiographs show delayed anterior fontanelle closure and short long bones with cortical thickening and stenosis of the medullary cavity (see
• Brain imaging shows calcification (typically of the basal ganglia but also reported in dentate nuclei and parts of the cerebrum and cerebellum).
• Other imaging findings including wormian bones, prominent odontoid process, craniosynostosis (coronal and/or basal sutures), and coxa valga have also been reported.
## Osteocraniostenosis
Intrauterine growth deficiency with micromelia and disproportionately small hands and feet
Craniofacial features such as ear anomalies, short nose, and narrow mouth
Micropenis and small testes
Respiratory insufficiency secondary to pulmonary hypoplasia
Splenic aplasia or hypoplasia
Extramedullary hematopoiesis
Cloverleaf-shaped skull (can be detected antenatally)
Decreased skull ossification (can be detected antenatally)
Slender long bones with cortical thickening, stenosis of the medullary cavity, and flared metaphyses
Thin ribs and thoracic hypoplasia
Bone fractures in some individuals, typically affecting long bones (e.g., femur, radius, ulna) and occasionally rib fractures
• Intrauterine growth deficiency with micromelia and disproportionately small hands and feet
• Craniofacial features such as ear anomalies, short nose, and narrow mouth
• Micropenis and small testes
• Respiratory insufficiency secondary to pulmonary hypoplasia
• Splenic aplasia or hypoplasia
• Extramedullary hematopoiesis
• Cloverleaf-shaped skull (can be detected antenatally)
• Decreased skull ossification (can be detected antenatally)
• Slender long bones with cortical thickening, stenosis of the medullary cavity, and flared metaphyses
• Thin ribs and thoracic hypoplasia
• Bone fractures in some individuals, typically affecting long bones (e.g., femur, radius, ulna) and occasionally rib fractures
## Establishing the Diagnosis
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
## Clinical Characteristics
NA = not applicable or insufficient information due to osteocraniostenosis being a perinatally lethal condition
Refractive errors include hyperopia, myopia, and astigmatism.
Defective dentition includes enamel hypoplasia, small teeth, hypodontia/oligodontia, and abnormal eruption pattern of dentition.
Relative macrocephaly is common due to the significant reduction in height with relatively preserved head circumference [
Other organs can be affected as well as the skin and joints.
Thin ribs and thoracic hypoplasia can be detected early in the antenatal period. Pulmonary hypoplasia often leads to respiratory distress in newborns and is the main cause of early mortality [
Most
The penetrance is complete for
Kenny-Caffey syndrome has also been referred to as Kenny-Caffey syndrome type 2. "Type 2" is intended to distinguish Kenny-Caffey syndrome caused by heterozygous pathogenic variants in
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The prevalence of
• Other organs can be affected as well as the skin and joints.
## Clinical Description
NA = not applicable or insufficient information due to osteocraniostenosis being a perinatally lethal condition
Refractive errors include hyperopia, myopia, and astigmatism.
Defective dentition includes enamel hypoplasia, small teeth, hypodontia/oligodontia, and abnormal eruption pattern of dentition.
Relative macrocephaly is common due to the significant reduction in height with relatively preserved head circumference [
Other organs can be affected as well as the skin and joints.
Thin ribs and thoracic hypoplasia can be detected early in the antenatal period. Pulmonary hypoplasia often leads to respiratory distress in newborns and is the main cause of early mortality [
• Other organs can be affected as well as the skin and joints.
## Kenny-Caffey Syndrome (KCS)
Relative macrocephaly is common due to the significant reduction in height with relatively preserved head circumference [
Other organs can be affected as well as the skin and joints.
• Other organs can be affected as well as the skin and joints.
## Osteocraniostenosis (OCS)
Thin ribs and thoracic hypoplasia can be detected early in the antenatal period. Pulmonary hypoplasia often leads to respiratory distress in newborns and is the main cause of early mortality [
## Genotype-Phenotype Correlations
Most
## Penetrance
The penetrance is complete for
## Nomenclature
Kenny-Caffey syndrome has also been referred to as Kenny-Caffey syndrome type 2. "Type 2" is intended to distinguish Kenny-Caffey syndrome caused by heterozygous pathogenic variants in
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of interest in the differential diagnosis of Kenny-Caffey syndrome (KCS) are summarized in
Genes of Interest in the Differential Diagnosis of Kenny-Caffey Syndrome
Sclerosis of long bones
Dental manifestations
Normal stature
Elongated mandible
↑ calvarial density
Diaphyseal sclerosis
Frontal bossing
Tall stature
Progressive skeletal overgrowth
Thickened ribs
Facial bone hyperplasia (e.g., prominent mandible)
Hyperostosis of skull
Cranial nerve impingement
Variable syndactyly (usually fingers 2-3)
↑ serum parathyroid hormone
Thick long bones of extremities
Wide diaphyseal medullary cavities
Marrow hypocellularity
More likely to have hematologic abnormalities (e.g., anemia, leukopenia, thrombocytopenia)
Frontal bossing
Sclerosis / cortical thickening of long bones
Medullary stenosis of long bones
Macrocephaly w/skull hyperostosis
Enlargement of mandible
Proptosis
Cranial nerve impingement resulting in facial palsy
Short stature
Delayed anterior fontanelle closure
Frontal bossing / prominent forehead
Micrognathia
Micropenis/cryptorchidism
Low parathyroid hormone
Hypocalcemia
Medullary stenosis of tubular bones
Thin long bones
Patchy osteosclerosis
Severe intrauterine growth restriction
Microcephaly more common than in KCS
Recurrent infection
Intellectual disability / developmental delay (which is very rarely reported in KCS)
AD = autosomal dominant; AR = autosomal recessive; KCS = Kenny-Caffey syndrome; MOI = mode of inheritance
Genes of interest in the differential diagnosis of osteocraniostenosis (OCS) are summarized in
Genes of Interest in the Differential Diagnosis of Osteocraniostenosis
May be lethal in perinatal period or infancy
Short long bones
Narrow thorax & short ribs
Pulmonary hypoplasia
Short stature & short limbs in infancy
Absence of cloverleaf-shaped skull
Polydactyly & multisystem manifestations are common.
Survivors may manifest only mild-to-moderate short stature.
Not assoc w/hypoparathyroidism
Typically lethal in perinatal period
Absent calvarial mineralization
Large fontanelles
Shortened long bones
Severe short stature
Fractures in utero
Presence of blue sclera & markedly bowed long bones
Absence of splenic hypoplasia & cloverleaf-shaped skull
Typically lethal in perinatal period
Short stature
Micromelia
Short ribs
Poorly ossified skull in
Minimal or absent ossification of vertebral bodies, iliac & ischial bones, & limbs
Absence of cloverleaf-shaped skull
Typically lethal in perinatal period
Thin ribs
Short long bones
Extreme platyspondyly
Hypoplastic ilia
Macrocephaly
Typically lethal in perinatal period
Short stature
Flared metaphyses
Frontal bossing
Midface retrusion
Family history of achondroplasia in both parents
Megalencephaly
Upper airway obstruction
Foramen magnum stenosis
Dysplastic ilium
Severe bowing of femurs
Large anterior fontanelle
Short stature
Frontal bossing
Midface retrusion
Small chest
Not typically lethal in perinatal period
Severe tibial & clavicular bowing
Seizures
Foramen magnum stenosis / hydrocephalus
Presence of acanthosis nigricans
Usually lethal in perinatal period
Cloverleaf-shaped skull
Large anterior fontanelle
Frontal bossing
Narrow thorax
Platyspondyly
Well-ossified skull
Severely bowed femurs
Typically lethal in perinatal period
Short ribs
Irregular metaphyses
Turricephaly
Platyspondyly
Cardiac manifestations (e.g., atrial septal defect & cardiac arrhythmia)
Irregular lacy iliac crest
Typically lethal
Narrow thorax
Short stature
Flat face
Micrognathia
Cryptorchidism
Anisospondyly
Cleft palate
Encephalocele
May be lethal in perinatal period
Large fontanelles
Frontal bossing
Short nose
Small chest
Marked delay in epiphyseal appearance
Severe scoliosis
Severe platyspondyly
Hypophosphatemia in some persons
Square iliac bones
May be lethal in perinatal period
Short stature
Narrow chest w/short ribs
Frontal bossing / prominent forehead
Large fontanelles
Short nose
Wormian bones
Prominent abdomen
Round face
Severe platyspondyly
Absence of epiphyseal ossification of knees
Square iliac bones
Horizontal acetabulae w/medial & lateral spurs
Hypoplastic ischia
Bone abnormalities improve w/age
May be lethal in neonatal period
Micrognathia
Flat face
Frontal bossing
Punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities
Coronal cleft or notch of vertebral bodies
Joint contractures
Skin manifestations (e.g., ichthyosis)
Cleft palate
Lethal in perinatal period
Short stature
Narrow chest
Midface retrusion
Hypoplastic iliac bones w/characteristic appearance resembling a snail
Broad long bones
Precocious ossification of tarsus
Typically lethal in perinatal period
Short stature
Enlarged & elongated skull
Skin dimples often present
Profound hypoplasia of body of scapulae
Poorly developed & immaturely ossified tubular bones
Non-mineralized thoracic pedicles
≤75% of persons w/46,XY karyotype have either female external genitalia or ambiguous genitalia.
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; OCS = osteocraniostenosis
In addition to absence of cortical thickening and medullary stenosis of long bones
Biallelic inheritance of pathogenic variants in
• Sclerosis of long bones
• Dental manifestations
• Normal stature
• Elongated mandible
• ↑ calvarial density
• Diaphyseal sclerosis
• Frontal bossing
• Tall stature
• Progressive skeletal overgrowth
• Thickened ribs
• Facial bone hyperplasia (e.g., prominent mandible)
• Hyperostosis of skull
• Cranial nerve impingement
• Variable syndactyly (usually fingers 2-3)
• ↑ serum parathyroid hormone
• Thick long bones of extremities
• Wide diaphyseal medullary cavities
• Marrow hypocellularity
• More likely to have hematologic abnormalities (e.g., anemia, leukopenia, thrombocytopenia)
• Frontal bossing
• Sclerosis / cortical thickening of long bones
• Medullary stenosis of long bones
• Macrocephaly w/skull hyperostosis
• Enlargement of mandible
• Proptosis
• Cranial nerve impingement resulting in facial palsy
• Short stature
• Delayed anterior fontanelle closure
• Frontal bossing / prominent forehead
• Micrognathia
• Micropenis/cryptorchidism
• Low parathyroid hormone
• Hypocalcemia
• Medullary stenosis of tubular bones
• Thin long bones
• Patchy osteosclerosis
• Severe intrauterine growth restriction
• Microcephaly more common than in KCS
• Recurrent infection
• Intellectual disability / developmental delay (which is very rarely reported in KCS)
• May be lethal in perinatal period or infancy
• Short long bones
• Narrow thorax & short ribs
• Pulmonary hypoplasia
• Short stature & short limbs in infancy
• Absence of cloverleaf-shaped skull
• Polydactyly & multisystem manifestations are common.
• Survivors may manifest only mild-to-moderate short stature.
• Not assoc w/hypoparathyroidism
• Typically lethal in perinatal period
• Absent calvarial mineralization
• Large fontanelles
• Shortened long bones
• Severe short stature
• Fractures in utero
• Presence of blue sclera & markedly bowed long bones
• Absence of splenic hypoplasia & cloverleaf-shaped skull
• Typically lethal in perinatal period
• Short stature
• Micromelia
• Short ribs
• Poorly ossified skull in
• Minimal or absent ossification of vertebral bodies, iliac & ischial bones, & limbs
• Absence of cloverleaf-shaped skull
• Typically lethal in perinatal period
• Thin ribs
• Short long bones
• Extreme platyspondyly
• Hypoplastic ilia
• Macrocephaly
• Typically lethal in perinatal period
• Short stature
• Flared metaphyses
• Frontal bossing
• Midface retrusion
• Family history of achondroplasia in both parents
• Megalencephaly
• Upper airway obstruction
• Foramen magnum stenosis
• Dysplastic ilium
• Severe bowing of femurs
• Large anterior fontanelle
• Short stature
• Frontal bossing
• Midface retrusion
• Small chest
• Not typically lethal in perinatal period
• Severe tibial & clavicular bowing
• Seizures
• Foramen magnum stenosis / hydrocephalus
• Presence of acanthosis nigricans
• Usually lethal in perinatal period
• Cloverleaf-shaped skull
• Large anterior fontanelle
• Frontal bossing
• Narrow thorax
• Platyspondyly
• Well-ossified skull
• Severely bowed femurs
• Typically lethal in perinatal period
• Short ribs
• Irregular metaphyses
• Turricephaly
• Platyspondyly
• Cardiac manifestations (e.g., atrial septal defect & cardiac arrhythmia)
• Irregular lacy iliac crest
• Typically lethal
• Narrow thorax
• Short stature
• Flat face
• Micrognathia
• Cryptorchidism
• Anisospondyly
• Cleft palate
• Encephalocele
• May be lethal in perinatal period
• Large fontanelles
• Frontal bossing
• Short nose
• Small chest
• Marked delay in epiphyseal appearance
• Severe scoliosis
• Severe platyspondyly
• Hypophosphatemia in some persons
• Square iliac bones
• May be lethal in perinatal period
• Short stature
• Narrow chest w/short ribs
• Frontal bossing / prominent forehead
• Large fontanelles
• Short nose
• Wormian bones
• Prominent abdomen
• Round face
• Severe platyspondyly
• Absence of epiphyseal ossification of knees
• Square iliac bones
• Horizontal acetabulae w/medial & lateral spurs
• Hypoplastic ischia
• Bone abnormalities improve w/age
• May be lethal in neonatal period
• Micrognathia
• Flat face
• Frontal bossing
• Punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities
• Coronal cleft or notch of vertebral bodies
• Joint contractures
• Skin manifestations (e.g., ichthyosis)
• Cleft palate
• Lethal in perinatal period
• Short stature
• Narrow chest
• Midface retrusion
• Hypoplastic iliac bones w/characteristic appearance resembling a snail
• Broad long bones
• Precocious ossification of tarsus
• Typically lethal in perinatal period
• Short stature
• Enlarged & elongated skull
• Skin dimples often present
• Profound hypoplasia of body of scapulae
• Poorly developed & immaturely ossified tubular bones
• Non-mineralized thoracic pedicles
• ≤75% of persons w/46,XY karyotype have either female external genitalia or ambiguous genitalia.
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with a
Chest radiograph
Assessment of respiratory rate, effort, skin color, & oxygen saturations
Complete radiologic skeletal survey
Orthopedic consultation
Functional assessment
Assess extent of skeletal malformations.
Eval by orthopedic specialist experienced in skeletal dysplasia
Consider eval of functional limitations & ADL.
Referral to PT &/or OT as needed
Head CT to assess for hydrocephalus or other brain malformation &/or craniosynostosis
Consider brain MRI to assess for intracranial calcifications, predominantly of basal ganglia.
Serum calcium, phosphorous, 25-hydroxyvitamin D, magnesium, & parathyroid hormone
Assess for complications from acute or chronic hypocalcemia (e.g., tetany, soft tissue calcifications).
Referral to endocrinology
Exam for micropenis &/or small testes
Abdominal ultrasound to assess for splenic hypoplasia/aplasia
CBC
In those w/OCS
As needed in those w/KCS; note almost all affected persons had normal development & cognition
Assessment for adaptive needs due to short stature
Referral to support resources
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; CBC = complete blood count; KCS = Kenny-Caffey syndrome; MOI = mode of inheritance; OCS = osteocraniostenosis; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Supportive care by a multidisciplinary team often includes pediatric endocrinologists, orthopedic surgeons, pulmonologists (for those with osteocraniostenosis) ophthalmologists, dental surgeons, hematologists, occupational therapists, physical therapists, and psychologists.
Treatment of Manifestations in Individuals with a
Aggressive respiratory support
Mgmt of restrictive lung disease w/respiratory specialist
Hypocalcemic seizure can be present in early neonatal period.
Maintenance of normal serum calcium & phosphorus is recommended to minimize risk of developing cataracts & intracerebral calcification.
Environmental or occupational modifications as needed (e.g., lower desk)
Consider referral to OT
Referral to support resources
Referral to psychologist as needed
GH = growth hormone; KCS = Kenny-Caffey syndrome; OCS = osteocraniostenosis; OT = occupational therapy
Recommended Surveillance for Individuals with a
Referral for orthopedic assessment
Assess functional limitations & assessment w/PT & OT.
Measurement of serum calcium, phosphate, & vitamin D
Clinical exam for manifestations of acute or chronic hypocalcemia
Every 3 mos until calcium level is normalized on treatment
Subsequently every 6 mos
Labs may be needed more frequently in growing children w/↑ calcium & vitamin D requirements.
CBC = complete blood count; OT = occupational therapist; PT = physical therapist
See
When prenatal ultrasound was performed, the most prominent clinical features of osteocraniostenosis (OCS) detected were cloverleaf-shaped skull, intrauterine growth deficiency, limb undergrowth, and occasionally intrauterine bone fractures. Most fetuses presented with these features at 20 weeks' gestation [
See
Search
• Chest radiograph
• Assessment of respiratory rate, effort, skin color, & oxygen saturations
• Complete radiologic skeletal survey
• Orthopedic consultation
• Functional assessment
• Assess extent of skeletal malformations.
• Eval by orthopedic specialist experienced in skeletal dysplasia
• Consider eval of functional limitations & ADL.
• Referral to PT &/or OT as needed
• Head CT to assess for hydrocephalus or other brain malformation &/or craniosynostosis
• Consider brain MRI to assess for intracranial calcifications, predominantly of basal ganglia.
• Serum calcium, phosphorous, 25-hydroxyvitamin D, magnesium, & parathyroid hormone
• Assess for complications from acute or chronic hypocalcemia (e.g., tetany, soft tissue calcifications).
• Referral to endocrinology
• Exam for micropenis &/or small testes
• Abdominal ultrasound to assess for splenic hypoplasia/aplasia
• CBC
• In those w/OCS
• As needed in those w/KCS; note almost all affected persons had normal development & cognition
• Assessment for adaptive needs due to short stature
• Referral to support resources
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Aggressive respiratory support
• Mgmt of restrictive lung disease w/respiratory specialist
• Hypocalcemic seizure can be present in early neonatal period.
• Maintenance of normal serum calcium & phosphorus is recommended to minimize risk of developing cataracts & intracerebral calcification.
• Environmental or occupational modifications as needed (e.g., lower desk)
• Consider referral to OT
• Referral to support resources
• Referral to psychologist as needed
• Referral for orthopedic assessment
• Assess functional limitations & assessment w/PT & OT.
• Measurement of serum calcium, phosphate, & vitamin D
• Clinical exam for manifestations of acute or chronic hypocalcemia
• Every 3 mos until calcium level is normalized on treatment
• Subsequently every 6 mos
• Labs may be needed more frequently in growing children w/↑ calcium & vitamin D requirements.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with a
Chest radiograph
Assessment of respiratory rate, effort, skin color, & oxygen saturations
Complete radiologic skeletal survey
Orthopedic consultation
Functional assessment
Assess extent of skeletal malformations.
Eval by orthopedic specialist experienced in skeletal dysplasia
Consider eval of functional limitations & ADL.
Referral to PT &/or OT as needed
Head CT to assess for hydrocephalus or other brain malformation &/or craniosynostosis
Consider brain MRI to assess for intracranial calcifications, predominantly of basal ganglia.
Serum calcium, phosphorous, 25-hydroxyvitamin D, magnesium, & parathyroid hormone
Assess for complications from acute or chronic hypocalcemia (e.g., tetany, soft tissue calcifications).
Referral to endocrinology
Exam for micropenis &/or small testes
Abdominal ultrasound to assess for splenic hypoplasia/aplasia
CBC
In those w/OCS
As needed in those w/KCS; note almost all affected persons had normal development & cognition
Assessment for adaptive needs due to short stature
Referral to support resources
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; CBC = complete blood count; KCS = Kenny-Caffey syndrome; MOI = mode of inheritance; OCS = osteocraniostenosis; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Chest radiograph
• Assessment of respiratory rate, effort, skin color, & oxygen saturations
• Complete radiologic skeletal survey
• Orthopedic consultation
• Functional assessment
• Assess extent of skeletal malformations.
• Eval by orthopedic specialist experienced in skeletal dysplasia
• Consider eval of functional limitations & ADL.
• Referral to PT &/or OT as needed
• Head CT to assess for hydrocephalus or other brain malformation &/or craniosynostosis
• Consider brain MRI to assess for intracranial calcifications, predominantly of basal ganglia.
• Serum calcium, phosphorous, 25-hydroxyvitamin D, magnesium, & parathyroid hormone
• Assess for complications from acute or chronic hypocalcemia (e.g., tetany, soft tissue calcifications).
• Referral to endocrinology
• Exam for micropenis &/or small testes
• Abdominal ultrasound to assess for splenic hypoplasia/aplasia
• CBC
• In those w/OCS
• As needed in those w/KCS; note almost all affected persons had normal development & cognition
• Assessment for adaptive needs due to short stature
• Referral to support resources
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Supportive care by a multidisciplinary team often includes pediatric endocrinologists, orthopedic surgeons, pulmonologists (for those with osteocraniostenosis) ophthalmologists, dental surgeons, hematologists, occupational therapists, physical therapists, and psychologists.
Treatment of Manifestations in Individuals with a
Aggressive respiratory support
Mgmt of restrictive lung disease w/respiratory specialist
Hypocalcemic seizure can be present in early neonatal period.
Maintenance of normal serum calcium & phosphorus is recommended to minimize risk of developing cataracts & intracerebral calcification.
Environmental or occupational modifications as needed (e.g., lower desk)
Consider referral to OT
Referral to support resources
Referral to psychologist as needed
GH = growth hormone; KCS = Kenny-Caffey syndrome; OCS = osteocraniostenosis; OT = occupational therapy
• Aggressive respiratory support
• Mgmt of restrictive lung disease w/respiratory specialist
• Hypocalcemic seizure can be present in early neonatal period.
• Maintenance of normal serum calcium & phosphorus is recommended to minimize risk of developing cataracts & intracerebral calcification.
• Environmental or occupational modifications as needed (e.g., lower desk)
• Consider referral to OT
• Referral to support resources
• Referral to psychologist as needed
## Surveillance
Recommended Surveillance for Individuals with a
Referral for orthopedic assessment
Assess functional limitations & assessment w/PT & OT.
Measurement of serum calcium, phosphate, & vitamin D
Clinical exam for manifestations of acute or chronic hypocalcemia
Every 3 mos until calcium level is normalized on treatment
Subsequently every 6 mos
Labs may be needed more frequently in growing children w/↑ calcium & vitamin D requirements.
CBC = complete blood count; OT = occupational therapist; PT = physical therapist
• Referral for orthopedic assessment
• Assess functional limitations & assessment w/PT & OT.
• Measurement of serum calcium, phosphate, & vitamin D
• Clinical exam for manifestations of acute or chronic hypocalcemia
• Every 3 mos until calcium level is normalized on treatment
• Subsequently every 6 mos
• Labs may be needed more frequently in growing children w/↑ calcium & vitamin D requirements.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
When prenatal ultrasound was performed, the most prominent clinical features of osteocraniostenosis (OCS) detected were cloverleaf-shaped skull, intrauterine growth deficiency, limb undergrowth, and occasionally intrauterine bone fractures. Most fetuses presented with these features at 20 weeks' gestation [
See
## Therapies Under Investigation
Search
## Genetic Counseling
Kenny-Caffey syndrome (KCS) and osteocraniostenosis (OCS) are autosomal dominant disorders.
KCS is typically caused by a
OCS, the more severe phenotype, is typically caused by a
Note: In one consanguineous family, apparent autosomal recessive inheritance was suggested by the identification of biallelic compound heterozygous
Most individuals diagnosed with KCS have the disorder as the result of a
Rarely, individuals diagnosed with KCS have an affected parent.
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the
If the parents have not been tested for the
With one possible exception,* all probands reported to date with OCS whose parents have undergone molecular genetic testing have the disorder as the result of a
* In one consanguineous family, biallelic compound heterozygous
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a de novo pathogenic variant.
The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with KCS.
Note: When a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• KCS is typically caused by a
• OCS, the more severe phenotype, is typically caused by a
• Most individuals diagnosed with KCS have the disorder as the result of a
• Rarely, individuals diagnosed with KCS have an affected parent.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the
• If the parents have not been tested for the
• With one possible exception,* all probands reported to date with OCS whose parents have undergone molecular genetic testing have the disorder as the result of a
• * In one consanguineous family, biallelic compound heterozygous
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a de novo pathogenic variant.
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a de novo pathogenic variant.
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a de novo pathogenic variant.
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with KCS.
## Mode of Inheritance
Kenny-Caffey syndrome (KCS) and osteocraniostenosis (OCS) are autosomal dominant disorders.
KCS is typically caused by a
OCS, the more severe phenotype, is typically caused by a
Note: In one consanguineous family, apparent autosomal recessive inheritance was suggested by the identification of biallelic compound heterozygous
• KCS is typically caused by a
• OCS, the more severe phenotype, is typically caused by a
## Kenny-Caffey Syndrome – Risk to Family Members
Most individuals diagnosed with KCS have the disorder as the result of a
Rarely, individuals diagnosed with KCS have an affected parent.
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the
If the parents have not been tested for the
• Most individuals diagnosed with KCS have the disorder as the result of a
• Rarely, individuals diagnosed with KCS have an affected parent.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the
• If the parents have not been tested for the
## Osteocraniostenosis – Risk to Family Members
With one possible exception,* all probands reported to date with OCS whose parents have undergone molecular genetic testing have the disorder as the result of a
* In one consanguineous family, biallelic compound heterozygous
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a de novo pathogenic variant.
The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• With one possible exception,* all probands reported to date with OCS whose parents have undergone molecular genetic testing have the disorder as the result of a
• * In one consanguineous family, biallelic compound heterozygous
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a de novo pathogenic variant.
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a de novo pathogenic variant.
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a de novo pathogenic variant.
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with KCS.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with KCS.
## Prenatal Testing and Preimplantation Genetic Testing
Note: When a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Australia
•
• Australia
•
•
•
## Molecular Genetics
FAM111A-Related Skeletal Dysplasias: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FAM111A-Related Skeletal Dysplasias (
To date, all
## Molecular Pathogenesis
To date, all
## Chapter Notes
6 April 2023 (sw) Review posted live
9 December 2022 (sc) Original submission
• 6 April 2023 (sw) Review posted live
• 9 December 2022 (sc) Original submission
## Revision History
6 April 2023 (sw) Review posted live
9 December 2022 (sc) Original submission
• 6 April 2023 (sw) Review posted live
• 9 December 2022 (sc) Original submission
## References
## Literature Cited
Craniofacial features of an individual with Kenny-Caffey syndrome at age 23 years with prominent forehead, triangular face, midface retrusion, and micrognathia
Reprinted with permission from
Radiographs of the lower limbs in an individual with Kenny-Caffey syndrome (at age 13 years) showing slender femoral diaphyses with cortical thickening and medullary stenosis (black arrows)
Reprinted with permission from
|
[] |
6/4/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
fap
|
fap
|
[
"Attenuated FAP",
"Familial Adenomatous Polyposis (FAP)",
"Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS)",
"Adenomatous polyposis coli protein",
"APC",
"APC-Associated Polyposis Conditions"
] |
Timothy Yen, Peter P Stanich, Lisen Axell, Swati G Patel
|
Summary FAP is a colorectal cancer (CRC) predisposition syndrome that can manifest in either classic or attenuated form. Classic FAP is characterized by hundreds to thousands of adenomatous colonic polyps, beginning on average at age 16 years (range 7-36 years). For those with the classic form of FAP, 95% of individuals have polyps by age 35 years; CRC is inevitable without colectomy. The mean age of CRC diagnosis in untreated individuals is 39 years (range 34-43 years). The attenuated form is characterized by multiple colonic polyps (average of 30), more proximally located polyps, and a diagnosis of CRC at a later age than in classic FAP. For those with an attenuated form, there is a 70% lifetime risk of CRC and the mean age of diagnosis is 50-55 years. Extracolonic manifestations are variably present and include polyps of the stomach and duodenum, osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), benign cutaneous lesions, desmoid tumors, adrenal masses, and other associated cancers. GAPPS is characterized by proximal gastric polyposis, increased risk of gastric adenocarcinoma, and no duodenal or colonic involvement in most individuals reported. The diagnosis of an
|
Familial adenomatous polyposis (FAP)
Attenuated FAP
Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• Familial adenomatous polyposis (FAP)
• Attenuated FAP
• Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS)
## Diagnosis
The National Comprehensive Cancer Network (NCCN) has published an algorithm for consideration of the diagnosis of both familial adenomatous polyposis (FAP) and attenuated FAP [
According to the NCCN guidelines, an
Multiple colorectal adenomatous polyps (at least 10-20 cumulative)
Family history of multiple colorectal adenomatous polyps (>10 in a single individual, or fewer if >1 relative has multiple polyps, especially if diagnosed at a young age), known
Hepatoblastoma
Multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE)
Desmoid tumor
Cribriform-morular variant of papillary thyroid cancer
The diagnosis of an
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
The diagnosis of
≥100 colorectal adenomatous polyps (individuals at younger ages or those with colectomies may have <100 colorectal adenomatous polyps); OR
Multiple but <100 colorectal adenomatous polyps and a relative with confirmed classic FAP.
The diagnosis of
A relative with confirmed attenuated FAP; AND/OR
<100 colorectal adenomatous polyps; OR
>100 colorectal adenomatous polyps at an advanced age (>age 40 years).
The diagnosis of
Gastric polyps restricted to the body and fundus;
>100 polyps in the proximal stomach or >30 polyps in a first-degree relative of an individual with GAPPS;
Predominantly fundic gland polyps (FGPs) and some gastric adenomas; some having regions of dysplasia (or a family member with either dysplastic FGPs or gastric adenocarcinoma) [
No evidence of colorectal or duodenal polyposis.
Molecular genetic testing approaches can include
Note:
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Approximately 20% of simplex cases have somatic mosaicism [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletion/duplication testing should also include analysis of
• Multiple colorectal adenomatous polyps (at least 10-20 cumulative)
• Family history of multiple colorectal adenomatous polyps (>10 in a single individual, or fewer if >1 relative has multiple polyps, especially if diagnosed at a young age), known
• Hepatoblastoma
• Multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE)
• Desmoid tumor
• Cribriform-morular variant of papillary thyroid cancer
• ≥100 colorectal adenomatous polyps (individuals at younger ages or those with colectomies may have <100 colorectal adenomatous polyps); OR
• Multiple but <100 colorectal adenomatous polyps and a relative with confirmed classic FAP.
• A relative with confirmed attenuated FAP; AND/OR
• <100 colorectal adenomatous polyps; OR
• >100 colorectal adenomatous polyps at an advanced age (>age 40 years).
• Gastric polyps restricted to the body and fundus;
• >100 polyps in the proximal stomach or >30 polyps in a first-degree relative of an individual with GAPPS;
• Predominantly fundic gland polyps (FGPs) and some gastric adenomas; some having regions of dysplasia (or a family member with either dysplastic FGPs or gastric adenocarcinoma) [
• No evidence of colorectal or duodenal polyposis.
• Molecular genetic testing approaches can include
• Note:
• For an introduction to multigene panels click
## Suggestive Findings
The National Comprehensive Cancer Network (NCCN) has published an algorithm for consideration of the diagnosis of both familial adenomatous polyposis (FAP) and attenuated FAP [
According to the NCCN guidelines, an
Multiple colorectal adenomatous polyps (at least 10-20 cumulative)
Family history of multiple colorectal adenomatous polyps (>10 in a single individual, or fewer if >1 relative has multiple polyps, especially if diagnosed at a young age), known
Hepatoblastoma
Multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE)
Desmoid tumor
Cribriform-morular variant of papillary thyroid cancer
• Multiple colorectal adenomatous polyps (at least 10-20 cumulative)
• Family history of multiple colorectal adenomatous polyps (>10 in a single individual, or fewer if >1 relative has multiple polyps, especially if diagnosed at a young age), known
• Hepatoblastoma
• Multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE)
• Desmoid tumor
• Cribriform-morular variant of papillary thyroid cancer
## Establishing the Diagnosis
The diagnosis of an
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
The diagnosis of
≥100 colorectal adenomatous polyps (individuals at younger ages or those with colectomies may have <100 colorectal adenomatous polyps); OR
Multiple but <100 colorectal adenomatous polyps and a relative with confirmed classic FAP.
The diagnosis of
A relative with confirmed attenuated FAP; AND/OR
<100 colorectal adenomatous polyps; OR
>100 colorectal adenomatous polyps at an advanced age (>age 40 years).
The diagnosis of
Gastric polyps restricted to the body and fundus;
>100 polyps in the proximal stomach or >30 polyps in a first-degree relative of an individual with GAPPS;
Predominantly fundic gland polyps (FGPs) and some gastric adenomas; some having regions of dysplasia (or a family member with either dysplastic FGPs or gastric adenocarcinoma) [
No evidence of colorectal or duodenal polyposis.
Molecular genetic testing approaches can include
Note:
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Approximately 20% of simplex cases have somatic mosaicism [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletion/duplication testing should also include analysis of
• ≥100 colorectal adenomatous polyps (individuals at younger ages or those with colectomies may have <100 colorectal adenomatous polyps); OR
• Multiple but <100 colorectal adenomatous polyps and a relative with confirmed classic FAP.
• A relative with confirmed attenuated FAP; AND/OR
• <100 colorectal adenomatous polyps; OR
• >100 colorectal adenomatous polyps at an advanced age (>age 40 years).
• Gastric polyps restricted to the body and fundus;
• >100 polyps in the proximal stomach or >30 polyps in a first-degree relative of an individual with GAPPS;
• Predominantly fundic gland polyps (FGPs) and some gastric adenomas; some having regions of dysplasia (or a family member with either dysplastic FGPs or gastric adenocarcinoma) [
• No evidence of colorectal or duodenal polyposis.
• Molecular genetic testing approaches can include
• Note:
• For an introduction to multigene panels click
## Molecular Genetic Testing
Molecular genetic testing approaches can include
Note:
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Approximately 20% of simplex cases have somatic mosaicism [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletion/duplication testing should also include analysis of
• Molecular genetic testing approaches can include
• Note:
• For an introduction to multigene panels click
## Clinical Characteristics
In individuals with
Lifetime Risk for Extracolonic Cancer in Familial Adenomatous Polyposis
CNS = central nervous system
Adenomatous polyps of the periampullary region (including the duodenal papilla and ampulla of Vater), some of which can be endoscopically subtle or invisible, are seen in at least 50% of individuals with FAP, [
The lifetime risk for small bowel malignancy is 4%-12%, with the large majority occurring in the duodenum. Duodenal adenocarcinoma occurs most commonly in the periampullary area. It has been reported to occur between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years [
Data on the rate of benign thyroid disease in individuals with FAP are limited. In a systematic review and meta-analysis, 6.9% of individuals with FAP had benign endocrinologic thyroid disease (hypothyroidism, goiter, and/or thyroiditis) and 48.8% had benign thyroid nodules [
The risk for gastric cancer in individuals with FAP living in Western cultures is low, but has risen in recent years [
The incidence of desmoid tumors in individuals with FAP is highest in the second and third decades of life, with 80% occurring by age 40 years [
Desmoid tumors are best evaluated by MRI or CT scan [
GAPPS is characterized by proximal gastric FGPs and intestinal-type gastric adenocarcinoma, typically without significant duodenal or colorectal polyposis [
Although inter- and intrafamilial variability is common in FAP, there are some reported genotype-phenotype correlations (see
Of individuals with phenotypic criteria of attenuated FAP, 78% had a pathogenic variant in one of three regions: the 5' end of
Schematic representation of
Genotype-Phenotype Correlations in
5' end (codons 1-233)
Distal 3' end (1300-2843; esp 3' of codon 1585)
Exon 9 (codons 311-412)
65% attenuated FAP
30% FAP
5% no adenomas
3x ↑ risk brain tumor
13x ↑ risk medulloblastoma
CHRPE = congenital hypertrophy of the retinal pigment epithelium; FAP = familial adenomatous polyposis; GAPPS = gastric adenocarcinoma and proximal polyposis of the stomach
Variants 5' of codon 233 are the most commonly described variants associated with attenuated FAP [
Data derived from the subscription-based professional view of Human Gene Mutation Database [
In
In
In
FAP is often referred to as classic FAP when more than 100 colorectal polyps are present. Classic FAP and FAP may be used interchangeably.
Adenomatous polyposis coli (APC) was used historically to refer to FAP;
A variety of terms have been used to describe individuals with an
Estimates of the prevalence of
The prevalence of
• 5' end (codons 1-233)
• Distal 3' end (1300-2843; esp 3' of codon 1585)
• Exon 9 (codons 311-412)
• 65% attenuated FAP
• 30% FAP
• 5% no adenomas
• 3x ↑ risk brain tumor
• 13x ↑ risk medulloblastoma
## Clinical Description
In individuals with
Lifetime Risk for Extracolonic Cancer in Familial Adenomatous Polyposis
CNS = central nervous system
Adenomatous polyps of the periampullary region (including the duodenal papilla and ampulla of Vater), some of which can be endoscopically subtle or invisible, are seen in at least 50% of individuals with FAP, [
The lifetime risk for small bowel malignancy is 4%-12%, with the large majority occurring in the duodenum. Duodenal adenocarcinoma occurs most commonly in the periampullary area. It has been reported to occur between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years [
Data on the rate of benign thyroid disease in individuals with FAP are limited. In a systematic review and meta-analysis, 6.9% of individuals with FAP had benign endocrinologic thyroid disease (hypothyroidism, goiter, and/or thyroiditis) and 48.8% had benign thyroid nodules [
The risk for gastric cancer in individuals with FAP living in Western cultures is low, but has risen in recent years [
The incidence of desmoid tumors in individuals with FAP is highest in the second and third decades of life, with 80% occurring by age 40 years [
Desmoid tumors are best evaluated by MRI or CT scan [
GAPPS is characterized by proximal gastric FGPs and intestinal-type gastric adenocarcinoma, typically without significant duodenal or colorectal polyposis [
## FAP
In individuals with
## Other Features Variably Present in FAP
Lifetime Risk for Extracolonic Cancer in Familial Adenomatous Polyposis
CNS = central nervous system
Adenomatous polyps of the periampullary region (including the duodenal papilla and ampulla of Vater), some of which can be endoscopically subtle or invisible, are seen in at least 50% of individuals with FAP, [
The lifetime risk for small bowel malignancy is 4%-12%, with the large majority occurring in the duodenum. Duodenal adenocarcinoma occurs most commonly in the periampullary area. It has been reported to occur between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years [
Data on the rate of benign thyroid disease in individuals with FAP are limited. In a systematic review and meta-analysis, 6.9% of individuals with FAP had benign endocrinologic thyroid disease (hypothyroidism, goiter, and/or thyroiditis) and 48.8% had benign thyroid nodules [
The risk for gastric cancer in individuals with FAP living in Western cultures is low, but has risen in recent years [
## Non-Malignant Extraintestinal Manifestations of FAP
The incidence of desmoid tumors in individuals with FAP is highest in the second and third decades of life, with 80% occurring by age 40 years [
Desmoid tumors are best evaluated by MRI or CT scan [
## GAPPS
GAPPS is characterized by proximal gastric FGPs and intestinal-type gastric adenocarcinoma, typically without significant duodenal or colorectal polyposis [
## Genotype-Phenotype Correlations
Although inter- and intrafamilial variability is common in FAP, there are some reported genotype-phenotype correlations (see
Of individuals with phenotypic criteria of attenuated FAP, 78% had a pathogenic variant in one of three regions: the 5' end of
Schematic representation of
Genotype-Phenotype Correlations in
5' end (codons 1-233)
Distal 3' end (1300-2843; esp 3' of codon 1585)
Exon 9 (codons 311-412)
65% attenuated FAP
30% FAP
5% no adenomas
3x ↑ risk brain tumor
13x ↑ risk medulloblastoma
CHRPE = congenital hypertrophy of the retinal pigment epithelium; FAP = familial adenomatous polyposis; GAPPS = gastric adenocarcinoma and proximal polyposis of the stomach
Variants 5' of codon 233 are the most commonly described variants associated with attenuated FAP [
Data derived from the subscription-based professional view of Human Gene Mutation Database [
• 5' end (codons 1-233)
• Distal 3' end (1300-2843; esp 3' of codon 1585)
• Exon 9 (codons 311-412)
• 65% attenuated FAP
• 30% FAP
• 5% no adenomas
• 3x ↑ risk brain tumor
• 13x ↑ risk medulloblastoma
## Penetrance
In
In
In
## Nomenclature
FAP is often referred to as classic FAP when more than 100 colorectal polyps are present. Classic FAP and FAP may be used interchangeably.
Adenomatous polyposis coli (APC) was used historically to refer to FAP;
A variety of terms have been used to describe individuals with an
## Prevalence
Estimates of the prevalence of
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Selected Hereditary Polyposis and Colorectal Cancer Syndromes in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; CRC = colorectal cancer; FAP = familial adenomatous polyposis; GI = gastrointestinal; IHC = immunohistochemistry; MOI = mode of inheritance; MSI = microsatellite instability
HMPS can be caused by either a
## Hereditary Disorders to Consider in the Differential Diagnosis
Selected Hereditary Polyposis and Colorectal Cancer Syndromes in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; CRC = colorectal cancer; FAP = familial adenomatous polyposis; GI = gastrointestinal; IHC = immunohistochemistry; MOI = mode of inheritance; MSI = microsatellite instability
HMPS can be caused by either a
## Acquired Conditions to be Considered in the Differential Diagnosis
## Other
## Management
Individuals who are diagnosed with classic familial adenomatous polyposis (FAP) or attenuated FAP should be counseled about age-appropriate recommendations for
Practice parameters, including information on surgery, have been outlined by the following professional groups:
National Comprehensive Cancer Network (NCCN) [
American Society for Gastrointestinal Endoscopy [
American College of Gastroenterology [
American Society of Colon and Rectal Surgeons [
American Society of Clinical Oncology [
British Society of Gastroenterology [
Society of Surgical Oncology [
European Society of Gastrointestinal Endoscopy [
For individuals with an
Surgical options for colectomy include the following:
Total proctocolectomy with ileal pouch anal anastomosis (IPAA). This can be performed laparoscopically, laparoscopically-assisted, robotically, or open. The IPAA can be stapled, leaving 1-2 cm of anal transition epithelium and low rectal mucosa; or it can be hand-sewn after a complete anal mucosectomy. This is a multistage surgery.
Total colectomy with ileorectal anastomosis (IRA). This can also be performed with minimally invasive surgical techniques and is a single-stage surgery.
Total proctocolectomy with permanent ileostomy. This can also be performed with minimally invasive surgical techniques and is a single-stage surgery.
The choice of procedure depends on the clinical circumstances.
An IPAA is generally performed in individuals with FAP with a high rectal polyp burden (generally considered as >20 adenomas in the rectum or presence of advanced rectal neoplasia) or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically [
A study of individuals with FAP and ileal pouches found that 57% had adenomatous polyps in the ileal pouch [
An IRA is generally considered when the rectal polyp burden is minimal and deemed to be endoscopically manageable (usually in the setting of attenuated FAP). It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk of sexual or urinary dysfunction. When performed in appropriate individuals, the risk for rectal cancer or need for proctectomy after IRA is low [
A total proctocolectomy with end ileostomy is rarely required unless a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control) and a proctocolectomy is necessary (due to rectal polyp/cancer burden).
Spigelman Scoring System for Duodenal Adenomas in Familial Adenomatous Polyposis
Stage 0 = 0 points
Stage I = 1-4 points
Stage II = 5-6 points
Stage III = 7-8 points
Stage IV = 9-12 points
Endoscopic or surgical removal of duodenal and/or ampullary adenomas is recommended by standard polypectomy techniques such as snaring and endoscopic mucosal resection. If there are too many polyps to remove, the focus should be on removing polyps >1 cm in size or those with concerning features. European Society of Gastrointestinal Endoscopy guidelines [
Indications for surgery for advanced duodenal polyposis are Stage III with high-grade dysplasia, Stage IV disease, and malignancy. Surgical options for advanced duodenal polyposis include pancreaticoduodenectomy (Whipple procedure) and pancreas-sparing duodenectomy, which is a good option when the papilla is not involved and there is no suspicion for cancer. These surgeries have high associated morbidities and should be performed at high-volume centers and preferably by those with expertise in FAP.
The FDA initially approved celecoxib for FAP based on evidence of decreased colon polyp burden and size (as well as modest decrease in the duodenum) [
Aspirin has traditionally been shown to be of little or no benefit in FAP [
Interest in combination of NSAIDs with other drugs was raised when reports of sulindac plus difluoromethylornithine (DFMO) showed marked reduction in sporadic metachronous adenomas [
Note: NSAID use before colectomy remains experimental (see
Multiple professional societies have published guidelines based on the available evidence to date as well as expert consensus [
Recommended Surveillance for Individuals with FAP
Every 1-2 years or more frequently if high polyp burden
Note: Cancer may occur in remaining rectum, but risk is low.
Palpation of thyroid
Thyroid ultrasound
Fine-needle aspiration if thyroid nodules are present
Liver palpation
Abdominal ultrasound exam
Serum alpha-fetoprotein concentration
Every 6 mos-5 yrs (w/duodenal exam), beginning at age 20-25 yrs
If polyps are neoplastic or large consider annual exams.
CNS = central nervous system; EGD = esophagogastroduodenoscopy; FAP = familial adenomatous polyposis; IPAA = ileal pouch anal anastomosis
The frequency of EGD depends on the severity of duodenal adenomas; Spigelman staging criteria can help determine the frequency. The Spigelman staging criteria are summarized by
Data to support screening of desmoid tumors are limited.
It is appropriate to clarify the genetic status of all first-degree relatives (parents, sibs, and children) of an affected individual by molecular genetic testing for the
Early recognition of
Individuals diagnosed with
As colon screening for those at risk for FAP begins as early as age ten to 12 years, molecular genetic testing is generally offered to children at risk for FAP by age ten years. Genetic testing at birth may also be warranted, as some parents and pediatricians may consider hepatoblastoma screening from infancy to age five years in affected offspring. Colon screening for those with attenuated FAP begins in late adolescence; thus, molecular genetic testing may be delayed until that time. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures in a child who has not inherited the pathogenic variant.
Note: No evidence points to an optimal age at which to begin screening; thus, the ages at which testing is performed and screening initiated may vary by center, family history, hepatoblastoma screening, and/or the needs of the parents and/or child.
In another study, the prevalence of self-reported fertility problems was similar among individuals with FAP who had undergone IRA, IPAA, or proctocolectomy with ileostomy. However, those who had had their first surgical procedure at a younger age had more postoperative fertility problems [
Limited evidence supports an association between desmoid tumor development or growth and pregnancy [
Women who have undergone colectomy are considered to be at the same risk for obstetric complications as any other woman who has had major abdominal surgery and are more likely to be delivered by C-section than those without such surgery.
In a study of women with FAP at the time of their colectomy, no association was found between pregnancy history and colonic polyp severity; however, the proportion of parous women with severe duodenal disease was significantly higher than the proportion of nulliparous women [
Some studies have suggested that female hormones protect against CRC development in the general population. In one woman, reduction in polyps after use of oral contraceptives was observed [
In a single controlled trial, the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) led to a 20%-30% decrease in FAP polyp size and number [
Search
• National Comprehensive Cancer Network (NCCN) [
• American Society for Gastrointestinal Endoscopy [
• American College of Gastroenterology [
• American Society of Colon and Rectal Surgeons [
• American Society of Clinical Oncology [
• British Society of Gastroenterology [
• Society of Surgical Oncology [
• European Society of Gastrointestinal Endoscopy [
• Total proctocolectomy with ileal pouch anal anastomosis (IPAA). This can be performed laparoscopically, laparoscopically-assisted, robotically, or open. The IPAA can be stapled, leaving 1-2 cm of anal transition epithelium and low rectal mucosa; or it can be hand-sewn after a complete anal mucosectomy. This is a multistage surgery.
• Total colectomy with ileorectal anastomosis (IRA). This can also be performed with minimally invasive surgical techniques and is a single-stage surgery.
• Total proctocolectomy with permanent ileostomy. This can also be performed with minimally invasive surgical techniques and is a single-stage surgery.
• An IPAA is generally performed in individuals with FAP with a high rectal polyp burden (generally considered as >20 adenomas in the rectum or presence of advanced rectal neoplasia) or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically [
• A study of individuals with FAP and ileal pouches found that 57% had adenomatous polyps in the ileal pouch [
• An IRA is generally considered when the rectal polyp burden is minimal and deemed to be endoscopically manageable (usually in the setting of attenuated FAP). It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk of sexual or urinary dysfunction. When performed in appropriate individuals, the risk for rectal cancer or need for proctectomy after IRA is low [
• A total proctocolectomy with end ileostomy is rarely required unless a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control) and a proctocolectomy is necessary (due to rectal polyp/cancer burden).
• Every 1-2 years or more frequently if high polyp burden
• Note: Cancer may occur in remaining rectum, but risk is low.
• Palpation of thyroid
• Thyroid ultrasound
• Fine-needle aspiration if thyroid nodules are present
• Liver palpation
• Abdominal ultrasound exam
• Serum alpha-fetoprotein concentration
• Every 6 mos-5 yrs (w/duodenal exam), beginning at age 20-25 yrs
• If polyps are neoplastic or large consider annual exams.
• Early recognition of
• Individuals diagnosed with
## Evaluations Following Initial Diagnosis
Individuals who are diagnosed with classic familial adenomatous polyposis (FAP) or attenuated FAP should be counseled about age-appropriate recommendations for
## Treatment of Manifestations
Practice parameters, including information on surgery, have been outlined by the following professional groups:
National Comprehensive Cancer Network (NCCN) [
American Society for Gastrointestinal Endoscopy [
American College of Gastroenterology [
American Society of Colon and Rectal Surgeons [
American Society of Clinical Oncology [
British Society of Gastroenterology [
Society of Surgical Oncology [
European Society of Gastrointestinal Endoscopy [
For individuals with an
Surgical options for colectomy include the following:
Total proctocolectomy with ileal pouch anal anastomosis (IPAA). This can be performed laparoscopically, laparoscopically-assisted, robotically, or open. The IPAA can be stapled, leaving 1-2 cm of anal transition epithelium and low rectal mucosa; or it can be hand-sewn after a complete anal mucosectomy. This is a multistage surgery.
Total colectomy with ileorectal anastomosis (IRA). This can also be performed with minimally invasive surgical techniques and is a single-stage surgery.
Total proctocolectomy with permanent ileostomy. This can also be performed with minimally invasive surgical techniques and is a single-stage surgery.
The choice of procedure depends on the clinical circumstances.
An IPAA is generally performed in individuals with FAP with a high rectal polyp burden (generally considered as >20 adenomas in the rectum or presence of advanced rectal neoplasia) or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically [
A study of individuals with FAP and ileal pouches found that 57% had adenomatous polyps in the ileal pouch [
An IRA is generally considered when the rectal polyp burden is minimal and deemed to be endoscopically manageable (usually in the setting of attenuated FAP). It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk of sexual or urinary dysfunction. When performed in appropriate individuals, the risk for rectal cancer or need for proctectomy after IRA is low [
A total proctocolectomy with end ileostomy is rarely required unless a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control) and a proctocolectomy is necessary (due to rectal polyp/cancer burden).
Spigelman Scoring System for Duodenal Adenomas in Familial Adenomatous Polyposis
Stage 0 = 0 points
Stage I = 1-4 points
Stage II = 5-6 points
Stage III = 7-8 points
Stage IV = 9-12 points
Endoscopic or surgical removal of duodenal and/or ampullary adenomas is recommended by standard polypectomy techniques such as snaring and endoscopic mucosal resection. If there are too many polyps to remove, the focus should be on removing polyps >1 cm in size or those with concerning features. European Society of Gastrointestinal Endoscopy guidelines [
Indications for surgery for advanced duodenal polyposis are Stage III with high-grade dysplasia, Stage IV disease, and malignancy. Surgical options for advanced duodenal polyposis include pancreaticoduodenectomy (Whipple procedure) and pancreas-sparing duodenectomy, which is a good option when the papilla is not involved and there is no suspicion for cancer. These surgeries have high associated morbidities and should be performed at high-volume centers and preferably by those with expertise in FAP.
The FDA initially approved celecoxib for FAP based on evidence of decreased colon polyp burden and size (as well as modest decrease in the duodenum) [
Aspirin has traditionally been shown to be of little or no benefit in FAP [
Interest in combination of NSAIDs with other drugs was raised when reports of sulindac plus difluoromethylornithine (DFMO) showed marked reduction in sporadic metachronous adenomas [
Note: NSAID use before colectomy remains experimental (see
• National Comprehensive Cancer Network (NCCN) [
• American Society for Gastrointestinal Endoscopy [
• American College of Gastroenterology [
• American Society of Colon and Rectal Surgeons [
• American Society of Clinical Oncology [
• British Society of Gastroenterology [
• Society of Surgical Oncology [
• European Society of Gastrointestinal Endoscopy [
• Total proctocolectomy with ileal pouch anal anastomosis (IPAA). This can be performed laparoscopically, laparoscopically-assisted, robotically, or open. The IPAA can be stapled, leaving 1-2 cm of anal transition epithelium and low rectal mucosa; or it can be hand-sewn after a complete anal mucosectomy. This is a multistage surgery.
• Total colectomy with ileorectal anastomosis (IRA). This can also be performed with minimally invasive surgical techniques and is a single-stage surgery.
• Total proctocolectomy with permanent ileostomy. This can also be performed with minimally invasive surgical techniques and is a single-stage surgery.
• An IPAA is generally performed in individuals with FAP with a high rectal polyp burden (generally considered as >20 adenomas in the rectum or presence of advanced rectal neoplasia) or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically [
• A study of individuals with FAP and ileal pouches found that 57% had adenomatous polyps in the ileal pouch [
• An IRA is generally considered when the rectal polyp burden is minimal and deemed to be endoscopically manageable (usually in the setting of attenuated FAP). It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk of sexual or urinary dysfunction. When performed in appropriate individuals, the risk for rectal cancer or need for proctectomy after IRA is low [
• A total proctocolectomy with end ileostomy is rarely required unless a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control) and a proctocolectomy is necessary (due to rectal polyp/cancer burden).
## Prevention of Primary Manifestations
## Surveillance
Multiple professional societies have published guidelines based on the available evidence to date as well as expert consensus [
Recommended Surveillance for Individuals with FAP
Every 1-2 years or more frequently if high polyp burden
Note: Cancer may occur in remaining rectum, but risk is low.
Palpation of thyroid
Thyroid ultrasound
Fine-needle aspiration if thyroid nodules are present
Liver palpation
Abdominal ultrasound exam
Serum alpha-fetoprotein concentration
Every 6 mos-5 yrs (w/duodenal exam), beginning at age 20-25 yrs
If polyps are neoplastic or large consider annual exams.
CNS = central nervous system; EGD = esophagogastroduodenoscopy; FAP = familial adenomatous polyposis; IPAA = ileal pouch anal anastomosis
The frequency of EGD depends on the severity of duodenal adenomas; Spigelman staging criteria can help determine the frequency. The Spigelman staging criteria are summarized by
Data to support screening of desmoid tumors are limited.
• Every 1-2 years or more frequently if high polyp burden
• Note: Cancer may occur in remaining rectum, but risk is low.
• Palpation of thyroid
• Thyroid ultrasound
• Fine-needle aspiration if thyroid nodules are present
• Liver palpation
• Abdominal ultrasound exam
• Serum alpha-fetoprotein concentration
• Every 6 mos-5 yrs (w/duodenal exam), beginning at age 20-25 yrs
• If polyps are neoplastic or large consider annual exams.
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of all first-degree relatives (parents, sibs, and children) of an affected individual by molecular genetic testing for the
Early recognition of
Individuals diagnosed with
As colon screening for those at risk for FAP begins as early as age ten to 12 years, molecular genetic testing is generally offered to children at risk for FAP by age ten years. Genetic testing at birth may also be warranted, as some parents and pediatricians may consider hepatoblastoma screening from infancy to age five years in affected offspring. Colon screening for those with attenuated FAP begins in late adolescence; thus, molecular genetic testing may be delayed until that time. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures in a child who has not inherited the pathogenic variant.
Note: No evidence points to an optimal age at which to begin screening; thus, the ages at which testing is performed and screening initiated may vary by center, family history, hepatoblastoma screening, and/or the needs of the parents and/or child.
• Early recognition of
• Individuals diagnosed with
## Pregnancy Management
In another study, the prevalence of self-reported fertility problems was similar among individuals with FAP who had undergone IRA, IPAA, or proctocolectomy with ileostomy. However, those who had had their first surgical procedure at a younger age had more postoperative fertility problems [
Limited evidence supports an association between desmoid tumor development or growth and pregnancy [
Women who have undergone colectomy are considered to be at the same risk for obstetric complications as any other woman who has had major abdominal surgery and are more likely to be delivered by C-section than those without such surgery.
In a study of women with FAP at the time of their colectomy, no association was found between pregnancy history and colonic polyp severity; however, the proportion of parous women with severe duodenal disease was significantly higher than the proportion of nulliparous women [
Some studies have suggested that female hormones protect against CRC development in the general population. In one woman, reduction in polyps after use of oral contraceptives was observed [
## Therapies Under Investigation
In a single controlled trial, the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) led to a 20%-30% decrease in FAP polyp size and number [
Search
## Genetic Counseling
The majority of individuals diagnosed with an
Up to 25% of individuals diagnosed with FAP have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Germline mosaicism has been reported in several families [
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with an
If a parent is affected and/or is known to have the
If the
Germline mosaicism has been documented in an asymptomatic woman age 79 years who had two sons with thousands of adenomatous colonic polyps and an
Another unaffected woman was demonstrated to have germline mosaicism, as two of her children had colonic adenomatous polyposis and were subsequently found to have an
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing – including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Consideration of predictive molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
The use of molecular genetic testing for determining the genetic status of at-risk relatives when a clinically diagnosed relative is not available for testing is problematic, and test results need to be interpreted with caution. A positive test result in the at-risk family member indicates the presence of an
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The majority of individuals diagnosed with an
• Up to 25% of individuals diagnosed with FAP have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Germline mosaicism has been reported in several families [
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Germline mosaicism has been reported in several families [
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Germline mosaicism has been reported in several families [
• * A parent with somatic and germline mosaicism for an
• If a parent is affected and/or is known to have the
• If the
• Germline mosaicism has been documented in an asymptomatic woman age 79 years who had two sons with thousands of adenomatous colonic polyps and an
• Another unaffected woman was demonstrated to have germline mosaicism, as two of her children had colonic adenomatous polyposis and were subsequently found to have an
• Germline mosaicism has been documented in an asymptomatic woman age 79 years who had two sons with thousands of adenomatous colonic polyps and an
• Another unaffected woman was demonstrated to have germline mosaicism, as two of her children had colonic adenomatous polyposis and were subsequently found to have an
• Germline mosaicism has been documented in an asymptomatic woman age 79 years who had two sons with thousands of adenomatous colonic polyps and an
• Another unaffected woman was demonstrated to have germline mosaicism, as two of her children had colonic adenomatous polyposis and were subsequently found to have an
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing – including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Consideration of predictive molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
The majority of individuals diagnosed with an
Up to 25% of individuals diagnosed with FAP have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Germline mosaicism has been reported in several families [
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with an
If a parent is affected and/or is known to have the
If the
Germline mosaicism has been documented in an asymptomatic woman age 79 years who had two sons with thousands of adenomatous colonic polyps and an
Another unaffected woman was demonstrated to have germline mosaicism, as two of her children had colonic adenomatous polyposis and were subsequently found to have an
• The majority of individuals diagnosed with an
• Up to 25% of individuals diagnosed with FAP have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Germline mosaicism has been reported in several families [
• * A parent with somatic and germline mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Germline mosaicism has been reported in several families [
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Germline mosaicism has been reported in several families [
• * A parent with somatic and germline mosaicism for an
• If a parent is affected and/or is known to have the
• If the
• Germline mosaicism has been documented in an asymptomatic woman age 79 years who had two sons with thousands of adenomatous colonic polyps and an
• Another unaffected woman was demonstrated to have germline mosaicism, as two of her children had colonic adenomatous polyposis and were subsequently found to have an
• Germline mosaicism has been documented in an asymptomatic woman age 79 years who had two sons with thousands of adenomatous colonic polyps and an
• Another unaffected woman was demonstrated to have germline mosaicism, as two of her children had colonic adenomatous polyposis and were subsequently found to have an
• Germline mosaicism has been documented in an asymptomatic woman age 79 years who had two sons with thousands of adenomatous colonic polyps and an
• Another unaffected woman was demonstrated to have germline mosaicism, as two of her children had colonic adenomatous polyposis and were subsequently found to have an
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing – including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Consideration of predictive molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
The use of molecular genetic testing for determining the genetic status of at-risk relatives when a clinically diagnosed relative is not available for testing is problematic, and test results need to be interpreted with caution. A positive test result in the at-risk family member indicates the presence of an
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing – including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result – as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Consideration of predictive molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
P.O. Box 273
Suffern NY 10901
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• P.O. Box 273
• Suffern NY 10901
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## Molecular Genetics
APC-Associated Polyposis Conditions: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for APC-Associated Polyposis Conditions (
APC has also been shown to accumulate at the kinetochore during mitosis, contribute to kinetochore-microtubule attachment, and play a role in chromosome stability and segregation [
Pathogenic
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
The majority of colorectal tumors not known to be familial are associated with a somatic pathogenic variant in APC [
## Molecular Pathogenesis
APC has also been shown to accumulate at the kinetochore during mitosis, contribute to kinetochore-microtubule attachment, and play a role in chromosome stability and segregation [
Pathogenic
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
## Cancer and Benign Tumors
The majority of colorectal tumors not known to be familial are associated with a somatic pathogenic variant in APC [
## Chapter Notes
Dennis J Ahnen, MD; Gastroenterology of the Rockies (2017-2022)Lisen Axell, MS, CGC (2022-present)Randall W Burt, MD; Huntsman Cancer Institute (1998-2017)Kory W Jasperson, MS; Ambry Genetics (2008-2022)Swati G Patel, MD, MS (2017-present)Cindy Solomon, MS; Myriad Genetic Laboratories (1998-2008)Peter P Stanich, MD (2022-present)Timothy Yen, MD (2022-present)
12 May 2022 (sw) Comprehensive update posted live
2 February 2017 (sw) Comprehensive update posted live
27 March 2014 (me) Comprehensive update posted live
27 October 2011 (me) Comprehensive update posted live
24 July 2008 (me) Comprehensive update posted live
21 October 2005 (me) Comprehensive update posted live
20 September 2004 (chs) Revision: new clinical method
27 May 2004 (chs) Revision: Genetic Counseling – genetic cancer subsection added
15 March 2004 (me) Comprehensive update posted live
23 June 2003 (cd) Revision: terminology
18 January 2002 (me) Comprehensive update posted live
18 December 1998 (pb) Review posted live
11 September 1998 (ch) Original submission
• 12 May 2022 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 27 March 2014 (me) Comprehensive update posted live
• 27 October 2011 (me) Comprehensive update posted live
• 24 July 2008 (me) Comprehensive update posted live
• 21 October 2005 (me) Comprehensive update posted live
• 20 September 2004 (chs) Revision: new clinical method
• 27 May 2004 (chs) Revision: Genetic Counseling – genetic cancer subsection added
• 15 March 2004 (me) Comprehensive update posted live
• 23 June 2003 (cd) Revision: terminology
• 18 January 2002 (me) Comprehensive update posted live
• 18 December 1998 (pb) Review posted live
• 11 September 1998 (ch) Original submission
## Author History
Dennis J Ahnen, MD; Gastroenterology of the Rockies (2017-2022)Lisen Axell, MS, CGC (2022-present)Randall W Burt, MD; Huntsman Cancer Institute (1998-2017)Kory W Jasperson, MS; Ambry Genetics (2008-2022)Swati G Patel, MD, MS (2017-present)Cindy Solomon, MS; Myriad Genetic Laboratories (1998-2008)Peter P Stanich, MD (2022-present)Timothy Yen, MD (2022-present)
## Revision History
12 May 2022 (sw) Comprehensive update posted live
2 February 2017 (sw) Comprehensive update posted live
27 March 2014 (me) Comprehensive update posted live
27 October 2011 (me) Comprehensive update posted live
24 July 2008 (me) Comprehensive update posted live
21 October 2005 (me) Comprehensive update posted live
20 September 2004 (chs) Revision: new clinical method
27 May 2004 (chs) Revision: Genetic Counseling – genetic cancer subsection added
15 March 2004 (me) Comprehensive update posted live
23 June 2003 (cd) Revision: terminology
18 January 2002 (me) Comprehensive update posted live
18 December 1998 (pb) Review posted live
11 September 1998 (ch) Original submission
• 12 May 2022 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 27 March 2014 (me) Comprehensive update posted live
• 27 October 2011 (me) Comprehensive update posted live
• 24 July 2008 (me) Comprehensive update posted live
• 21 October 2005 (me) Comprehensive update posted live
• 20 September 2004 (chs) Revision: new clinical method
• 27 May 2004 (chs) Revision: Genetic Counseling – genetic cancer subsection added
• 15 March 2004 (me) Comprehensive update posted live
• 23 June 2003 (cd) Revision: terminology
• 18 January 2002 (me) Comprehensive update posted live
• 18 December 1998 (pb) Review posted live
• 11 September 1998 (ch) Original submission
## References
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003.
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2010.
Burt RW, Cannon JA, David DS, Early DS, Ford JM, Giardiello FM, Halverson AL, Hamilton SR, Hampel H, Ismail MK, Jasperson K, Klapman JB, Lazenby AJ, Lynch PM, Mayer RJ, Ness RM, Provenzale D, Rao MS, Shike M, Steinbach G, Terdiman JP, Weinberg D, Dwyer M, Freedman-Cass D. Colorectal cancer screening. Available
Church J, Simmang C, et al. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum. 2003;46:1001-12. [
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
Desmoid Tumor Working Group. The management of desmoid tumours: a joint global consensus-based guideline approach for adult and paediatric patients. Eur J Cancer. 2020;127:96-107. [
Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. 2001.
Guillem JG, Wood WC, Moley JF, Berchuck A, Karlan BY, Mutch DG, Gagel RF, Weitzel J, Morrow M, Weber BL, Giardiello F, Rodriguez-Bigas MA, Church J, Gruber S, Offit K. American Society of Clinical Oncology/Society of Surgical Oncology review of current role of risk-reducing surgery in common hereditary cancer syndromes. Available
Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). American College of Medical Genetics. Available
Herzig D, Hardiman K, Weiser M, You N, Paquette I, Feingold DL, Steele SR. The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of inherited polyposis syndromes. Dis Colon Rectum. 2017;60:881-94. [
Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, Ilyas M, Kaur A, Lalloo F, Latchford A, Rutter MD, Tomlinson I, Thomas HJW, Hill J, et al. Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG). Gut. 2020;69:411-44. [
Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. American College of Gastroenterology. Available
van Leerdam ME, Roos VH, van Hooft JE, Dekker E, Jover R, Kaminski MF, Latchford A, Neumann H, Pellisé M, Saurin JC, Tanis PJ, Wagner A, Balaguer F, Ricciardiello L. Endoscopic management of polyposis syndromes: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2019;51:877-95. [
Weiss JM, Gupta S, Burke CA, Axell L, Chen LM, Chung DC, Clayback KM, Dallas S, Felder S, Gbolahan O, Giardiello FM, Grady W, Hall MJ, Hampel H, Hodan R, Idos G, Kanth P, Katona B, Lamps L, Llor X, Lynch PM, Markowitz AJ, Pirzadeh-Miller S, Samadder NJ, Shibata D, Swanson BJ, Szymaniak BM, Wiesner GL, Wolf A, Yurgelun MB, Zakhour M, Darlow SD, Dwyer MA, Campbell M. NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021. J Natl Compr Canc Netw. 2021;19:1122-32. [
Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucii J, Ganiats T, Levin T, Woolf S, Johnson D, Kirk L, Litin S, Simmang C, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale – update based on new evidence. American Gastroenterological Association. 2003.
Yang J, Gurudu SR, Koptiuch C, Agrawal D, Buxbaum JL, Abbas Fehmi SM, Fishman DS, Khashab MA, Jamil LH, Jue TL, Law JK, Lee JK, Naveed M, Qumseya BJ, Sawhney MS, Thosani N, Wani SB, Samadder NJ. American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in familial adenomatous polyposis syndromes. Gastrointest Endosc. 2020;91:963-82.e2. [
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003.
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2010.
• Burt RW, Cannon JA, David DS, Early DS, Ford JM, Giardiello FM, Halverson AL, Hamilton SR, Hampel H, Ismail MK, Jasperson K, Klapman JB, Lazenby AJ, Lynch PM, Mayer RJ, Ness RM, Provenzale D, Rao MS, Shike M, Steinbach G, Terdiman JP, Weinberg D, Dwyer M, Freedman-Cass D. Colorectal cancer screening. Available
• Church J, Simmang C, et al. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum. 2003;46:1001-12. [
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• Desmoid Tumor Working Group. The management of desmoid tumours: a joint global consensus-based guideline approach for adult and paediatric patients. Eur J Cancer. 2020;127:96-107. [
• Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. 2001.
• Guillem JG, Wood WC, Moley JF, Berchuck A, Karlan BY, Mutch DG, Gagel RF, Weitzel J, Morrow M, Weber BL, Giardiello F, Rodriguez-Bigas MA, Church J, Gruber S, Offit K. American Society of Clinical Oncology/Society of Surgical Oncology review of current role of risk-reducing surgery in common hereditary cancer syndromes. Available
• Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). American College of Medical Genetics. Available
• Herzig D, Hardiman K, Weiser M, You N, Paquette I, Feingold DL, Steele SR. The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of inherited polyposis syndromes. Dis Colon Rectum. 2017;60:881-94. [
• Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, Ilyas M, Kaur A, Lalloo F, Latchford A, Rutter MD, Tomlinson I, Thomas HJW, Hill J, et al. Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG). Gut. 2020;69:411-44. [
• Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. American College of Gastroenterology. Available
• van Leerdam ME, Roos VH, van Hooft JE, Dekker E, Jover R, Kaminski MF, Latchford A, Neumann H, Pellisé M, Saurin JC, Tanis PJ, Wagner A, Balaguer F, Ricciardiello L. Endoscopic management of polyposis syndromes: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2019;51:877-95. [
• Weiss JM, Gupta S, Burke CA, Axell L, Chen LM, Chung DC, Clayback KM, Dallas S, Felder S, Gbolahan O, Giardiello FM, Grady W, Hall MJ, Hampel H, Hodan R, Idos G, Kanth P, Katona B, Lamps L, Llor X, Lynch PM, Markowitz AJ, Pirzadeh-Miller S, Samadder NJ, Shibata D, Swanson BJ, Szymaniak BM, Wiesner GL, Wolf A, Yurgelun MB, Zakhour M, Darlow SD, Dwyer MA, Campbell M. NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021. J Natl Compr Canc Netw. 2021;19:1122-32. [
• Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucii J, Ganiats T, Levin T, Woolf S, Johnson D, Kirk L, Litin S, Simmang C, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale – update based on new evidence. American Gastroenterological Association. 2003.
• Yang J, Gurudu SR, Koptiuch C, Agrawal D, Buxbaum JL, Abbas Fehmi SM, Fishman DS, Khashab MA, Jamil LH, Jue TL, Law JK, Lee JK, Naveed M, Qumseya BJ, Sawhney MS, Thosani N, Wani SB, Samadder NJ. American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in familial adenomatous polyposis syndromes. Gastrointest Endosc. 2020;91:963-82.e2. [
## Published Guidelines / Consensus Statements
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003.
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2010.
Burt RW, Cannon JA, David DS, Early DS, Ford JM, Giardiello FM, Halverson AL, Hamilton SR, Hampel H, Ismail MK, Jasperson K, Klapman JB, Lazenby AJ, Lynch PM, Mayer RJ, Ness RM, Provenzale D, Rao MS, Shike M, Steinbach G, Terdiman JP, Weinberg D, Dwyer M, Freedman-Cass D. Colorectal cancer screening. Available
Church J, Simmang C, et al. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum. 2003;46:1001-12. [
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
Desmoid Tumor Working Group. The management of desmoid tumours: a joint global consensus-based guideline approach for adult and paediatric patients. Eur J Cancer. 2020;127:96-107. [
Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. 2001.
Guillem JG, Wood WC, Moley JF, Berchuck A, Karlan BY, Mutch DG, Gagel RF, Weitzel J, Morrow M, Weber BL, Giardiello F, Rodriguez-Bigas MA, Church J, Gruber S, Offit K. American Society of Clinical Oncology/Society of Surgical Oncology review of current role of risk-reducing surgery in common hereditary cancer syndromes. Available
Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). American College of Medical Genetics. Available
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"RK Phillips, MH Wallace, PM Lynch, E Hawk, GB Gordon, BP Saunders, N Wakabayashi, Y Shen, S Zimmerman, L Godio, M Rodrigues-Bigas, LK Su, J Sherman, G Kelloff, B Levin, GA Steinbach. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis.. Gut. 2002;50:857-60",
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"M Quadri, A Vetro, V Gismondi, M Marabelli, L Bertario, P Sala, L Varesco, O Zuffardi, GN Ranzani. APC rearrangements in familial adenomatous polyposis: heterogeneity of deletion lengths and breakpoint sequences underlies similar phenotypes.. Fam Cancer. 2015;14:41-9",
"SG Rajaratnam, TW Eglinton, P Hider, NS Fearnhead. Impact of ileal pouch-anal anastomosis on female fertility: meta-analysis and systematic review.. Int J Colorectal Dis. 2011;26:1365-74",
"S Rechitsky, O Verlinsky, A Chistokhina, T Sharapova, S Ozen, C Masciangelo, A Kuliev, Y Verlinsky. Preimplantation genetic diagnosis for cancer predisposition.. Reprod Biomed Online. 2002;5:148-55",
"S Rehan, K Aye. In patients with a positive family history of familial adenomatous polyposis can the condition be diagnosed from the presence of congenital hypertrophy of the retinal pigment epithelium detected via an eye examination: a systematic review.. Clin Exp Ophthalmol. 2020;48:98-116",
"NM Rekik, S Ben Salah, N Kallel, M Kamoun, N Charfi, M Abid. Adrenocortical secreting mass in a patient with Gardner's syndrome: a case report.. Case Rep Med. 2010;2010",
"R Repak, D Kohoutova, M Podhola, S Rejchrt, M Minarik, L Benesova, M Lesko, J. Bures. The first European family with gastric adenocarcinoma and proximal polyposis of the stomach: case report and review of the literature.. Gastrointest Endosc. 2016;84:718-25",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"A Rohlin, Y Engwall, K Fritzell, K Göransson, A Bergsten, Z Einbeigi, M Nilbert, P Karlsson, J Björk, M. Nordling. Inactivation of promoter 1B of APC causes partial gene silencing: evidence for a significant role of the promoter in regulation and causative of familial adenomatous polyposis.. Oncogene. 2011;30:4977-89",
"VH Roos, BA Bastiaansen, FGJ Kallenberg, AS Aelvoet, PMM Bossuyt, P Fockens, E Dekker. Endoscopic management of duodenal adenomas in patients with familial adenomatous polyposis.. Gastrointest Endosc. 2021;93:457-66",
"AT Ruys, YA Alderlieste, DJ Gouma, E Dekker, EM Mathus-Vliegen. Jejunal cancer in patients with familial adenomatous polyposis.. Clin Gastroenterol Hepatol. 2010;8:731-3",
"NJ Samadder, SK Kuwada, KM Boucher, K Byrne, P Kanth, W Samowitz, D Jones, SV Tavtigian, M Westover, T Berry, K Jasperson, L Pappas, L Smith, D Sample, RW Burt, DW Neklason. Association of sulindac and erlotinib vs placebo with colorectal neoplasia in familial adenomatous polyposis: secondary analysis of a randomized clinical trial.. JAMA Oncol. 2018;4:671-7",
"NJ Samadder, DW Neklason, KM Boucher, KR Byrne, P Kanth, W Samowitz, D Jones, SV Tavtigian, MW Done, T Berry, K Jasperson, L Pappas, L Smith, D Sample, R Davis, MK Topham, P Lynch, E Strait, W McKinnon, RW Burt, SK Kuwada. Effect of sulindac and erlotinib vs placebo on duodenal neoplasia in familial adenomatous polyposis: a randomized clinical trial.. JAMA 2016;315:1266-75",
"MT Scheuner, TS McNeel, AN Freedman. Population prevalence of familial cancer and common hereditary cancer syndromes. The 2005 California Health Interview Survey.. Genet Med. 2010;12:726-35",
"AL Schwab, TM Tuohy, M Condie, DW Neklason, RW Burt. Gonadal mosaicism and familial adenomatous polyposis.. Fam Cancer. 2008;7:173-7",
"S Septer, B Bohaty, R Onikul, V Kumar, KB Williams, TM Attard, CA Friesen, LR Friesen. Dental anomalies in pediatric patients with familial adenomatous polyposis.. Fam Cancer. 2018;17:229-34",
"JS Shiroky, JP Lerner-Ellis, A Govindarajan, DR Urbach, KM Devon. Characteristics of adrenal masses in familial adenomatous polyposis.. Dis Colon Rectum. 2018;61:679-85",
"OM Sieber, S Segditsas, AL Knudsen, J Zhang, J Luz, AJ Rowan, SL Spain, C Thirlwell, KM Howarth, EE Jaeger, J Robinson, E Volikos, A Silver, G Kelly, S Aretz, I Frayling, P Hutter, M Dunlop, T Guenther, K Neale, R Phillips, K Heinimann, IP Tomlinson. Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation.. Gut. 2006;55:1440-8",
"A Sinha, PP Tekkis, DC Gibbons, RK Phillips, SK Clark. Risk factors predicting desmoid occurrence in patients with familial adenomatous polyposis: a meta-analysis.. Colorectal Dis. 2011;13:1222-9",
"V Slowik, T Attard, H Dai, R Shah, S Septer. Desmoid tumors complicating familial adenomatous polyposis: a meta-analysis mutation spectrum of affected individuals.. BMC Gastroenterol. 2015;15:84",
"AJ Smith, JJ Lewis, NB Merchant, DH Leung, JM Woodruff, MF Brennan. Surgical management of intra-abdominal desmoid tumours.. Br J Surg. 2000a;87:608-13",
"TG Smith, SK Clark, DE Katz, RH Reznek, RK Phillips. Adrenal masses are associated with familial adenomatous polyposis.. Dis Colon Rectum. 2000b;43:1739-42",
"I Spier, D Drichel, M Kerick, J Kirfel, S Horpaopan, A Laner, S Holzapfel, S Peters, R Adam, B Zhao, T Becker, RP Lifton, S Perner, P Hoffmann, G Kristiansen, B Timmermann, MM Nöthen, E Holinski-Feder, MR Schweiger, S Aretz. Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases.. J Med Genet. 2016;53:172-9",
"AD Spigelman, CB Williams, IC Talbot, P Domizio, RK Phillips. Upper gastrointestinal cancer in patients with familial adenomatous polyposis.. Lancet. 1989;2:783-5",
"L Spirio, J Green, J Robertson, M Robertson, B Otterud, J Sheldon, E Howse, R Green, J Groden, R White, M. Leppert. The identical 5' splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect.. Hum Genet. 1999;105:388-98",
"L Spirio, S Olschwang, J Groden, M Robertson, W Samowitz, G Joslyn, L Gelbert, A Thliveris, M Carlson, B Otterud, H Lynch, P Watson, P Lynch, P Laurent-Puig, R Burt, JP Hughes, G Thomas, M Leppert, R White. Alleles of the APC gene: an attenuated form of familial polyposis.. Cell. 1993;75:951-7",
"PP Stanich, R Pearlman, A Hinton, S Gutierrez, H LaDuca, H Hampel, K Jasperson. Prevalence of germline mutations in polyposis and colorectal cancer-associated genes in patients with multiple colorectal polyps.. Clin Gastroenterol Hepatol. 2019;17:2008-15.e3",
"G Steinbach, PM Lynch, RK Phillips, MH Wallace, E Hawk, GB Gordon, N Wakabayashi, B Saunders, Y Shen, T Fujimura, LK Su, B Levin. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.. N Engl J Med. 2000;342:1946-52",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"EM Stoffel, PB Mangu, PJ Limburg. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines.. J Oncol Pract. 2015;11:e437-41",
"N Suraweera, A Latchford, A McCart, P Rogers, S Spain, O Sieber, R Phillips, I Tomlinson, A Silver. Pregnancy does not influence colonic polyp multiplicity but may modulate upper gastrointestinal disease in patients with FAP.. J Med Genet. 2007;44:541-4",
"S Syngal, RE Brand, JM Church, FM Giardiello, HL Hampel, RW Burt. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.. Am J Gastroenterol 2015;110:223-62",
"I Tacheci, R Repak, M Podhola, L Benesova, J Cyrany, J Bures, D Kohoutova. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) - a helicobacter-opposite point.. Best Pract Res Clin Gastroenterol. 2021;50-51",
"F Tonelli, F Ficari, R Valanzano, ML Brandi. Treatment of desmoids and mesenteric fibromatosis in familial adenomatous polyposis with raloxifene.. Tumori. 2003;89:391-6",
"L Valle, RM de Voer, Y Goldberg, W Sjursen, A Försti, C Ruiz-Ponte, T Caldés, P Garré, MF Olsen, M Nordling, S Castellvi-Bel, K Hemminki. Update on genetic predisposition to colorectal cancer and polyposis.. Mol Aspects Med. 2019;69:10-26",
"ME van Leerdam, VH Roos, JE van Hooft, E Dekker, R Jover, MF Kaminski, A Latchford, H Neumann, M Pellisé, JC Saurin, PJ Tanis, A Wagner, F Balaguer, L Ricciardiello. Endoscopic management of polyposis syndromes: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.. Endoscopy. 2019;51:877-95",
"MH Wallace, RK Phillips. Upper gastrointestinal disease in patients with familial adenomatous polyposis.. Br J Surg. 1998;85:742-50",
"SK Warrier, MF Kalady. Familial adenomatous polyposis: challenges and pitfalls of surgical treatment.. Clinics in colon and rectal surgery. 2012;25:83-9",
"BM Wehrli, SW Weiss, S Yandow, CM Coffin. Gardner-associated fibromas (GAF) in young patients: a distinct fibrous lesion that identifies unsuspected Gardner syndrome and risk for fibromatosis.. Am J Surg Pathol. 2001;25:645-51",
"JM Weiss, S Gupta, CA Burke, L Axell, LM Chen, DC Chung, KM Clayback, S Dallas, S Felder, O Gbolahan, FM Giardiello, W Grady, MJ Hall, H Hampel, R Hodan, G Idos, P Kanth, B Katona, L Lamps, X Llor, PM Lynch, AJ Markowitz, S Pirzadeh-Miller, NJ Samadder, D Shibata, BJ Swanson, BM Szymaniak, GL Wiesner, A Wolf, MB Yurgelun, M Zakhour, SD Darlow, MA Dwyer, M Campbell. NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021.. J Natl Compr Canc Netw. 2021;19:1122-32",
"NJ West, SK Clark, RK Phillips, JM Hutchinson, RJ Leicester, A Belluzzi, MA Hull. Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis.. Gut. 2010;59:918-25",
"MO Woods, HB Younghusband, PS Parfrey, S Gallinger, J McLaughlin, E Dicks, S Stuckless, A Pollett, B Bapat, M Mrkonjic, A de la Chapelle, M Clendenning, SN Thibodeau, M Simms, A Dohey, P Williams, D Robb, C Searle, JS Green, RC Green. The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.. Gut. 2010;59:1369-77",
"DL Worthley, KD Phillips, N Wayte, KA Schrader, S Healey, P Kaurah, A Shulkes, F Grimpen, A Clouston, D Moore, D Cullen, D Ormonde, D Mounkley, X Wen, N Lindor, F Carneiro, DG Huntsman, G Chenevix-Trench, GK Suthers. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome.. Gut. 2012;61:774-9",
"HHN Yan, JCW Lai, SL Ho, WK Leung, WL Law, JFY Lee, AKW Chan, WY Tsui, ASY Chan, BCH Lee, SSK Yue, AHY Man, H Clevers, ST Yuen, SY Leung. RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation.. Gut. 2017;66:1645-56",
"J Yang, SR Gurudu, C Koptiuch, D Agrawal, JL Buxbaum, SM Abbas Fehmi, DS Fishman, MA Khashab, LH Jamil, TL Jue, JK Law, JK Lee, M Naveed, BJ Qumseya, MS Sawhney, N Thosani, SB Wani, NJ Samadder. American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in familial adenomatous polyposis syndromes.. Gastrointest Endosc. 2020;91:963-82",
"L Zhang, JW Shay. Multiple roles of APC and its therapeutic implications in colorectal cancer.. J Natl Cancer Inst. 2017;109:8"
] |
18/12/1998
|
12/5/2022
|
20/9/2004
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
fars2-def
|
fars2-def
|
[
"FARS2-Related Infantile-Onset Epileptic Mitochondrial Encephalopathy",
"FARS2-Related Later-Onset Spastic Paraplegia",
"Phenylalanine--tRNA ligase, mitochondrial",
"FARS2",
"FARS2 Deficiency"
] |
FARS2 Deficiency
|
Mohammed Almannai, Eissa Faqeih, Ayman W El-Hattab, Lee-Jun C Wong
|
Summary The spectrum of FARS2 deficiency ranges from the infantile-onset phenotype, characterized by epileptic encephalopathy with lactic acidosis and poor prognosis (70% of affected individuals), to the later-onset phenotype, characterized by spastic paraplegia, less severe neurologic manifestations, and longer survival (30% of affected individuals). To date FARS2 deficiency has been reported in 37 individuals from 25 families. The diagnosis of FARS2 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in For those with later onset: routine monitoring of OT/PT needs (e.g., mobility and activities of daily living), orthopedic complications (contractures, scoliosis, foot deformities), seizure control, speech and language development, and educational and social needs. FARS2 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the
|
For synonyms and outdated names see
For other genetic causes of these phenotypes, see
## Diagnosis
FARS2 deficiency comprises a spectrum of disease severity that ranges between two phenotypes: infantile-onset epileptic mitochondrial encephalopathy and less severe, later-onset spastic paraplegia.
Formal diagnostic criteria for FARS2 deficiency have not been established.
The two phenotypes known to date to be associated with FARS2 deficiency are infantile-onset epileptic mitochondrial encephalopathy and later-onset spastic paraplegia.
Seizures
Developmental delay
Truncal hypotonia
Elevated plasma lactate levels; seen in all affected individuals [
Elevated cerebrospinal fluid lactate
Electron transport chain enzyme activity; ranges from normal to low complex I activity, low complex IV activity, or combined deficiency of both
Elevated liver enzymes (ALT, AST) and gamma-glutamyl transferase in some affected individuals
Occasional findings:
Evidence of deep cerebellar white matter involvement and hyperintensity of the hila of the dentate nuclei [
Abnormalities in basal ganglia signal intensity [
Cystic degeneration with diffuse and symmetric swelling and abnormal signal intensity of the cerebral subcortical white matter, which was completely suppressed on fluid-attenuated inversion recovery (FLAIR) sequence
Spastic paraplegia, seen in all individuals with this phenotype, characterized by lower-extremity weakness, spasticity, and exaggerated reflexes associated with walking difficulties
Spastic paraplegia can be pure or can be complicated by other less common neurologic findings including the following:
Developmental delay / intellectual disability
Brief seizures that resolve over time
The diagnosis of FARS2 deficiency
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Because the phenotype of FARS2 deficiency is indistinguishable from many other inherited disorders presenting with infantile epileptic encephalopathy or spastic paraplegia, recommended molecular genetic testing approaches include use of a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in FARS2 Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
• Seizures
• Developmental delay
• Truncal hypotonia
• Elevated plasma lactate levels; seen in all affected individuals [
• Elevated cerebrospinal fluid lactate
• Electron transport chain enzyme activity; ranges from normal to low complex I activity, low complex IV activity, or combined deficiency of both
• Elevated liver enzymes (ALT, AST) and gamma-glutamyl transferase in some affected individuals
• Occasional findings:
• Evidence of deep cerebellar white matter involvement and hyperintensity of the hila of the dentate nuclei [
• Abnormalities in basal ganglia signal intensity [
• Cystic degeneration with diffuse and symmetric swelling and abnormal signal intensity of the cerebral subcortical white matter, which was completely suppressed on fluid-attenuated inversion recovery (FLAIR) sequence
• Evidence of deep cerebellar white matter involvement and hyperintensity of the hila of the dentate nuclei [
• Abnormalities in basal ganglia signal intensity [
• Cystic degeneration with diffuse and symmetric swelling and abnormal signal intensity of the cerebral subcortical white matter, which was completely suppressed on fluid-attenuated inversion recovery (FLAIR) sequence
• Evidence of deep cerebellar white matter involvement and hyperintensity of the hila of the dentate nuclei [
• Abnormalities in basal ganglia signal intensity [
• Cystic degeneration with diffuse and symmetric swelling and abnormal signal intensity of the cerebral subcortical white matter, which was completely suppressed on fluid-attenuated inversion recovery (FLAIR) sequence
• Spastic paraplegia, seen in all individuals with this phenotype, characterized by lower-extremity weakness, spasticity, and exaggerated reflexes associated with walking difficulties
• Spastic paraplegia can be pure or can be complicated by other less common neurologic findings including the following:
• Developmental delay / intellectual disability
• Brief seizures that resolve over time
• Developmental delay / intellectual disability
• Brief seizures that resolve over time
• Developmental delay / intellectual disability
• Brief seizures that resolve over time
• For an introduction to multigene panels click
• If exome sequencing is not diagnostic,
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
The two phenotypes known to date to be associated with FARS2 deficiency are infantile-onset epileptic mitochondrial encephalopathy and later-onset spastic paraplegia.
Seizures
Developmental delay
Truncal hypotonia
Elevated plasma lactate levels; seen in all affected individuals [
Elevated cerebrospinal fluid lactate
Electron transport chain enzyme activity; ranges from normal to low complex I activity, low complex IV activity, or combined deficiency of both
Elevated liver enzymes (ALT, AST) and gamma-glutamyl transferase in some affected individuals
Occasional findings:
Evidence of deep cerebellar white matter involvement and hyperintensity of the hila of the dentate nuclei [
Abnormalities in basal ganglia signal intensity [
Cystic degeneration with diffuse and symmetric swelling and abnormal signal intensity of the cerebral subcortical white matter, which was completely suppressed on fluid-attenuated inversion recovery (FLAIR) sequence
Spastic paraplegia, seen in all individuals with this phenotype, characterized by lower-extremity weakness, spasticity, and exaggerated reflexes associated with walking difficulties
Spastic paraplegia can be pure or can be complicated by other less common neurologic findings including the following:
Developmental delay / intellectual disability
Brief seizures that resolve over time
• Seizures
• Developmental delay
• Truncal hypotonia
• Elevated plasma lactate levels; seen in all affected individuals [
• Elevated cerebrospinal fluid lactate
• Electron transport chain enzyme activity; ranges from normal to low complex I activity, low complex IV activity, or combined deficiency of both
• Elevated liver enzymes (ALT, AST) and gamma-glutamyl transferase in some affected individuals
• Occasional findings:
• Evidence of deep cerebellar white matter involvement and hyperintensity of the hila of the dentate nuclei [
• Abnormalities in basal ganglia signal intensity [
• Cystic degeneration with diffuse and symmetric swelling and abnormal signal intensity of the cerebral subcortical white matter, which was completely suppressed on fluid-attenuated inversion recovery (FLAIR) sequence
• Evidence of deep cerebellar white matter involvement and hyperintensity of the hila of the dentate nuclei [
• Abnormalities in basal ganglia signal intensity [
• Cystic degeneration with diffuse and symmetric swelling and abnormal signal intensity of the cerebral subcortical white matter, which was completely suppressed on fluid-attenuated inversion recovery (FLAIR) sequence
• Evidence of deep cerebellar white matter involvement and hyperintensity of the hila of the dentate nuclei [
• Abnormalities in basal ganglia signal intensity [
• Cystic degeneration with diffuse and symmetric swelling and abnormal signal intensity of the cerebral subcortical white matter, which was completely suppressed on fluid-attenuated inversion recovery (FLAIR) sequence
• Spastic paraplegia, seen in all individuals with this phenotype, characterized by lower-extremity weakness, spasticity, and exaggerated reflexes associated with walking difficulties
• Spastic paraplegia can be pure or can be complicated by other less common neurologic findings including the following:
• Developmental delay / intellectual disability
• Brief seizures that resolve over time
• Developmental delay / intellectual disability
• Brief seizures that resolve over time
• Developmental delay / intellectual disability
• Brief seizures that resolve over time
## Establishing the Diagnosis
The diagnosis of FARS2 deficiency
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Because the phenotype of FARS2 deficiency is indistinguishable from many other inherited disorders presenting with infantile epileptic encephalopathy or spastic paraplegia, recommended molecular genetic testing approaches include use of a
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in FARS2 Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
• For an introduction to multigene panels click
• If exome sequencing is not diagnostic,
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
The spectrum of FARS2 deficiency ranges between two phenotypes: infantile-onset disease characterized by epileptic encephalopathy with lactic acidosis and poor prognosis (70% of affected individuals) and later-onset spastic paraplegia (30% of affected individuals) associated with less severe neurologic manifestations and longer survival.
The findings in the 37 individuals with FARS2 deficiency reported to date are summarized in
Clinical, Neuroimaging, and Metabolic Findings in FARS2 Deficiency
CSF = cerebrospinal fluid; DD = developmental delay; ETC = electron transport chain; GGT = gamma-glutamyl transferase; ID = intellectual disability; MRI = magnetic resonance imaging; MRS = magnetic resonance spectroscopy
One individual who had hypoxic-ischemic encephalopathy was not included in age-of-onset calculations. For another individual (who had seizures with a normal EEG following vaccination at age 2 months), age of onset was considered to be 3 years (the age at which he was evaluated for developmental delay [
Elevations up to 1,700 U/L were observed.
Seizures tend to be focal with associated facial or eye twitching and myoclonic jerks of the extremities. Other types of seizures include generalized tonic-clonic, infantile spasms, and epilepsia partialis continua. Seizures are difficult to control and may progress quickly at an early age to intractable seizures with frequent status epilepticus. EEG usually shows multifocal epileptic discharges. A few children had hypsarrhythmia.
Several children with the infantile-onset phenotype developed central visual impairment, usually with normal fundoscopic examination (i.e., without optic atrophy or retinal changes). One child was reported to have coarse retinal pigmentation [
Of note: Although some children were treated with valproic acid (which can induce liver failure in persons with mitochondrial disorders) [
Strabismus [
Nystagmus [
Non-epileptic myoclonus [
All individuals with the later-onset phenotype had spastic paraplegia, manifest as weakness, spasticity, and exaggerated reflexes of the lower extremities associated with walking difficulties. Spastic paraplegia could be pure or complicated by other less common neurologic findings including the following:
Developmental delay / intellectual disability that is less severe than the DD/ID seen in the infantile-onset phenotype (e.g., 5/6 affected individuals developed expressive language)
Brief seizures that resolved over time [
Less frequently reported neurologic findings:
Startle myoclonus [
Inattention tremor [
Bradykinesia [
Dystonia [
Dysarthria [
Less frequently reported manifestations:
Strabismus [
Scoliosis [
It is difficult to establish a genotype-phenotype correlation in FARS2 deficiency given the limited number of affected individuals and the complication of compound heterozygosity in such studies.
All 14 individuals homozygous for the most commonly reported variant,
Although the number of affected individuals reported to date is small, the infantile-onset and later-onset phenotypes have not shared the same genotypes.
FARS2 deficiency is rare; the exact prevalence is unknown. To date, 37 affected individuals from 25 families have been reported.
The 25 families belong to different ethnic groups.
Eleven families (all with children with the infantile-onset phenotype) were Arabs, ten from Saudi Arabia and one from Iraq. In all but two families, the parents were consanguineous.
Other affected populations include Asian, European, North American, Ashkenazi Jewish, and Hispanic.
• Strabismus [
• Nystagmus [
• Non-epileptic myoclonus [
• Developmental delay / intellectual disability that is less severe than the DD/ID seen in the infantile-onset phenotype (e.g., 5/6 affected individuals developed expressive language)
• Brief seizures that resolved over time [
• Startle myoclonus [
• Inattention tremor [
• Bradykinesia [
• Dystonia [
• Dysarthria [
• Strabismus [
• Scoliosis [
• Eleven families (all with children with the infantile-onset phenotype) were Arabs, ten from Saudi Arabia and one from Iraq. In all but two families, the parents were consanguineous.
• Other affected populations include Asian, European, North American, Ashkenazi Jewish, and Hispanic.
## Clinical Description
The spectrum of FARS2 deficiency ranges between two phenotypes: infantile-onset disease characterized by epileptic encephalopathy with lactic acidosis and poor prognosis (70% of affected individuals) and later-onset spastic paraplegia (30% of affected individuals) associated with less severe neurologic manifestations and longer survival.
The findings in the 37 individuals with FARS2 deficiency reported to date are summarized in
Clinical, Neuroimaging, and Metabolic Findings in FARS2 Deficiency
CSF = cerebrospinal fluid; DD = developmental delay; ETC = electron transport chain; GGT = gamma-glutamyl transferase; ID = intellectual disability; MRI = magnetic resonance imaging; MRS = magnetic resonance spectroscopy
One individual who had hypoxic-ischemic encephalopathy was not included in age-of-onset calculations. For another individual (who had seizures with a normal EEG following vaccination at age 2 months), age of onset was considered to be 3 years (the age at which he was evaluated for developmental delay [
Elevations up to 1,700 U/L were observed.
Seizures tend to be focal with associated facial or eye twitching and myoclonic jerks of the extremities. Other types of seizures include generalized tonic-clonic, infantile spasms, and epilepsia partialis continua. Seizures are difficult to control and may progress quickly at an early age to intractable seizures with frequent status epilepticus. EEG usually shows multifocal epileptic discharges. A few children had hypsarrhythmia.
Several children with the infantile-onset phenotype developed central visual impairment, usually with normal fundoscopic examination (i.e., without optic atrophy or retinal changes). One child was reported to have coarse retinal pigmentation [
Of note: Although some children were treated with valproic acid (which can induce liver failure in persons with mitochondrial disorders) [
Strabismus [
Nystagmus [
Non-epileptic myoclonus [
All individuals with the later-onset phenotype had spastic paraplegia, manifest as weakness, spasticity, and exaggerated reflexes of the lower extremities associated with walking difficulties. Spastic paraplegia could be pure or complicated by other less common neurologic findings including the following:
Developmental delay / intellectual disability that is less severe than the DD/ID seen in the infantile-onset phenotype (e.g., 5/6 affected individuals developed expressive language)
Brief seizures that resolved over time [
Less frequently reported neurologic findings:
Startle myoclonus [
Inattention tremor [
Bradykinesia [
Dystonia [
Dysarthria [
Less frequently reported manifestations:
Strabismus [
Scoliosis [
• Strabismus [
• Nystagmus [
• Non-epileptic myoclonus [
• Developmental delay / intellectual disability that is less severe than the DD/ID seen in the infantile-onset phenotype (e.g., 5/6 affected individuals developed expressive language)
• Brief seizures that resolved over time [
• Startle myoclonus [
• Inattention tremor [
• Bradykinesia [
• Dystonia [
• Dysarthria [
• Strabismus [
• Scoliosis [
## Infantile-Onset Epileptic Mitochondrial Encephalopathy
Seizures tend to be focal with associated facial or eye twitching and myoclonic jerks of the extremities. Other types of seizures include generalized tonic-clonic, infantile spasms, and epilepsia partialis continua. Seizures are difficult to control and may progress quickly at an early age to intractable seizures with frequent status epilepticus. EEG usually shows multifocal epileptic discharges. A few children had hypsarrhythmia.
Several children with the infantile-onset phenotype developed central visual impairment, usually with normal fundoscopic examination (i.e., without optic atrophy or retinal changes). One child was reported to have coarse retinal pigmentation [
Of note: Although some children were treated with valproic acid (which can induce liver failure in persons with mitochondrial disorders) [
Strabismus [
Nystagmus [
Non-epileptic myoclonus [
• Strabismus [
• Nystagmus [
• Non-epileptic myoclonus [
All individuals with the later-onset phenotype had spastic paraplegia, manifest as weakness, spasticity, and exaggerated reflexes of the lower extremities associated with walking difficulties. Spastic paraplegia could be pure or complicated by other less common neurologic findings including the following:
Developmental delay / intellectual disability that is less severe than the DD/ID seen in the infantile-onset phenotype (e.g., 5/6 affected individuals developed expressive language)
Brief seizures that resolved over time [
Less frequently reported neurologic findings:
Startle myoclonus [
Inattention tremor [
Bradykinesia [
Dystonia [
Dysarthria [
Less frequently reported manifestations:
Strabismus [
Scoliosis [
• Developmental delay / intellectual disability that is less severe than the DD/ID seen in the infantile-onset phenotype (e.g., 5/6 affected individuals developed expressive language)
• Brief seizures that resolved over time [
• Startle myoclonus [
• Inattention tremor [
• Bradykinesia [
• Dystonia [
• Dysarthria [
• Strabismus [
• Scoliosis [
## Genotype-Phenotype Correlations
It is difficult to establish a genotype-phenotype correlation in FARS2 deficiency given the limited number of affected individuals and the complication of compound heterozygosity in such studies.
All 14 individuals homozygous for the most commonly reported variant,
Although the number of affected individuals reported to date is small, the infantile-onset and later-onset phenotypes have not shared the same genotypes.
## Nomenclature
## Prevalence
FARS2 deficiency is rare; the exact prevalence is unknown. To date, 37 affected individuals from 25 families have been reported.
The 25 families belong to different ethnic groups.
Eleven families (all with children with the infantile-onset phenotype) were Arabs, ten from Saudi Arabia and one from Iraq. In all but two families, the parents were consanguineous.
Other affected populations include Asian, European, North American, Ashkenazi Jewish, and Hispanic.
• Eleven families (all with children with the infantile-onset phenotype) were Arabs, ten from Saudi Arabia and one from Iraq. In all but two families, the parents were consanguineous.
• Other affected populations include Asian, European, North American, Ashkenazi Jewish, and Hispanic.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Phenotypic features associated with
For children with a phenotype consistent with
For individuals with
## Management
To establish the extent of disease and needs in an individual diagnosed with FARS2 deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with FARS2 Deficiency: Infantile-Onset Epileptic Encephalopathy
FTT = failure to thrive; OT = occupational therapy; PT = physical therapy
Recommended Evaluations Following Initial Diagnosis in Individuals with FARS2 Deficiency: Later-Onset Spastic Paraplegia
OT = occupational therapy; PT = physical therapy
Treatment is symptomatic and best provided by a multidisciplinary team comprising neurodevelopmental pediatricians, neurologists, physiatrists, occupational and physical therapists, feeding specialists, speech and language therapists, and social workers to assure adequate family support.
Treatment of Manifestations in Individuals with FARS2 Deficiency: Infantile-Onset Epileptic Encephalopathy
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASM = anti-seizure medication
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
One child remained seizure-free for 23 months on vigabatrin 50 mg/kg/day. He had also received adrenocorticotropic hormone (ACTH), which was tapered off over eight weeks [
Treatment of Manifestations in Individuals with FARS2 Deficiency: Later-Onset Spastic Paraplegia
Anti-spasticity medications (e.g., oral or intrathecal baclofen)
Botulinum toxin injections
Surgical interventions to ↓ spasticity
Standard treatment w/ASM by experienced neurologist
See footnote 1.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services for those who require specially designed instruction/related services
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
Services are reviewed annually to determine if any changes are needed.
As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
A 504 (Section 504: a federal statute that prohibits discrimination based on disability) plan can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Individuals with FARS2 deficiency should be evaluated periodically by an interdisciplinary team that includes a neurologist, clinical geneticist, physiatrist, and developmental specialist to assess disease progression (
Recommended Surveillance for Individuals with FARS2 Deficiency: Infantile-Onset Epileptic Encephalopathy
PT/OT eval for contractures, scoliosis, & foot deformities
Consider need for positioning devices.
OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with FARS2 Deficiency: Later-Onset Spastic Paraplegia
OT = occupational therapy; PT = physical therapy
Valproic acid can induce liver failure in persons with mitochondrial diseases [
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with the later-onset spastic paraplegia phenotype in order to identify as early as possible those who would benefit from prompt initiation of intervention for developmental and/or neurologic problems (e.g., spasticity).
See
Search
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Anti-spasticity medications (e.g., oral or intrathecal baclofen)
• Botulinum toxin injections
• Surgical interventions to ↓ spasticity
• Standard treatment w/ASM by experienced neurologist
• See footnote 1.
• IEP services for those who require specially designed instruction/related services
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• Services are reviewed annually to determine if any changes are needed.
• As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• Services are reviewed annually to determine if any changes are needed.
• As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
• A 504 (Section 504: a federal statute that prohibits discrimination based on disability) plan can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• In the US:
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• Services are reviewed annually to determine if any changes are needed.
• As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
•
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• PT/OT eval for contractures, scoliosis, & foot deformities
• Consider need for positioning devices.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with FARS2 deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with FARS2 Deficiency: Infantile-Onset Epileptic Encephalopathy
FTT = failure to thrive; OT = occupational therapy; PT = physical therapy
Recommended Evaluations Following Initial Diagnosis in Individuals with FARS2 Deficiency: Later-Onset Spastic Paraplegia
OT = occupational therapy; PT = physical therapy
## Treatment of Manifestations
Treatment is symptomatic and best provided by a multidisciplinary team comprising neurodevelopmental pediatricians, neurologists, physiatrists, occupational and physical therapists, feeding specialists, speech and language therapists, and social workers to assure adequate family support.
Treatment of Manifestations in Individuals with FARS2 Deficiency: Infantile-Onset Epileptic Encephalopathy
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ASM = anti-seizure medication
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
One child remained seizure-free for 23 months on vigabatrin 50 mg/kg/day. He had also received adrenocorticotropic hormone (ACTH), which was tapered off over eight weeks [
Treatment of Manifestations in Individuals with FARS2 Deficiency: Later-Onset Spastic Paraplegia
Anti-spasticity medications (e.g., oral or intrathecal baclofen)
Botulinum toxin injections
Surgical interventions to ↓ spasticity
Standard treatment w/ASM by experienced neurologist
See footnote 1.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services for those who require specially designed instruction/related services
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
Services are reviewed annually to determine if any changes are needed.
As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
A 504 (Section 504: a federal statute that prohibits discrimination based on disability) plan can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Anti-spasticity medications (e.g., oral or intrathecal baclofen)
• Botulinum toxin injections
• Surgical interventions to ↓ spasticity
• Standard treatment w/ASM by experienced neurologist
• See footnote 1.
• IEP services for those who require specially designed instruction/related services
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• Services are reviewed annually to determine if any changes are needed.
• As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• Services are reviewed annually to determine if any changes are needed.
• As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
• A 504 (Section 504: a federal statute that prohibits discrimination based on disability) plan can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• In the US:
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• Services are reviewed annually to determine if any changes are needed.
• As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
•
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services for those who require specially designed instruction/related services
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
Services are reviewed annually to determine if any changes are needed.
As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
A 504 (Section 504: a federal statute that prohibits discrimination based on disability) plan can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services for those who require specially designed instruction/related services
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• Services are reviewed annually to determine if any changes are needed.
• As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• Services are reviewed annually to determine if any changes are needed.
• As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
• A 504 (Section 504: a federal statute that prohibits discrimination based on disability) plan can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• In the US:
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP services to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• Services are reviewed annually to determine if any changes are needed.
• As a child enters teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21 years.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
•
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Individuals with FARS2 deficiency should be evaluated periodically by an interdisciplinary team that includes a neurologist, clinical geneticist, physiatrist, and developmental specialist to assess disease progression (
Recommended Surveillance for Individuals with FARS2 Deficiency: Infantile-Onset Epileptic Encephalopathy
PT/OT eval for contractures, scoliosis, & foot deformities
Consider need for positioning devices.
OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with FARS2 Deficiency: Later-Onset Spastic Paraplegia
OT = occupational therapy; PT = physical therapy
• PT/OT eval for contractures, scoliosis, & foot deformities
• Consider need for positioning devices.
## Agents/Circumstances to Avoid
Valproic acid can induce liver failure in persons with mitochondrial diseases [
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with the later-onset spastic paraplegia phenotype in order to identify as early as possible those who would benefit from prompt initiation of intervention for developmental and/or neurologic problems (e.g., spasticity).
See
## Therapies Under Investigation
Search
## Genetic Counseling
FARS2 deficiency is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has
To date, individuals with
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has
• To date, individuals with
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
FARS2 deficiency is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has
To date, individuals with
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has
• To date, individuals with
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
No specific resources for FARS2 Deficiency have been identified by
## Molecular Genetics
FARS2 Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FARS2 Deficiency (
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
14 March 2019 (bp) Review posted live
9 November 2018 (ljw) Original submission
• 14 March 2019 (bp) Review posted live
• 9 November 2018 (ljw) Original submission
## Revision History
14 March 2019 (bp) Review posted live
9 November 2018 (ljw) Original submission
• 14 March 2019 (bp) Review posted live
• 9 November 2018 (ljw) Original submission
## References
## Literature Cited
|
[] |
14/3/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
fbln5-cutis-laxa
|
fbln5-cutis-laxa
|
[
"Fibulin-5",
"FBLN5",
"FBLN5-Related Cutis Laxa"
] |
Lionel Van Maldergem, Bart Loeys
|
Summary The diagnosis of Prenatal testing is possible for a pregnancy at increased risk in families in which the pathogenic variant(s) have been identified.
|
## Diagnosis
Cutis laxa
Pulmonary emphysema
Arterial involvement (e.g., peripheral pulmonary artery stenosis, supravalvar aortic stenosis)
Inguinal hernias
Hollow viscus diverticula (e.g., intestine, bladder)
Pyloric stenosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of
Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Duplication reported in one individual with autosomal dominant inheritance [
• Cutis laxa
• Pulmonary emphysema
• Arterial involvement (e.g., peripheral pulmonary artery stenosis, supravalvar aortic stenosis)
• Inguinal hernias
• Hollow viscus diverticula (e.g., intestine, bladder)
• Pyloric stenosis
• Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• For an introduction to multigene panels click
## Suggestive Findings
Cutis laxa
Pulmonary emphysema
Arterial involvement (e.g., peripheral pulmonary artery stenosis, supravalvar aortic stenosis)
Inguinal hernias
Hollow viscus diverticula (e.g., intestine, bladder)
Pyloric stenosis
• Cutis laxa
• Pulmonary emphysema
• Arterial involvement (e.g., peripheral pulmonary artery stenosis, supravalvar aortic stenosis)
• Inguinal hernias
• Hollow viscus diverticula (e.g., intestine, bladder)
• Pyloric stenosis
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of
Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Duplication reported in one individual with autosomal dominant inheritance [
• Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of
Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
For an introduction to multigene panels click
• Perform sequence analysis first. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• For an introduction to multigene panels click
## Option 2
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Duplication reported in one individual with autosomal dominant inheritance [
## Clinical Characteristics
To date, six families with autosomal recessive
Hip dislocation is not observed in
Intelligence is normal [
Note: To date, no heterozygous carriers for autosomal recessive
Electron microscopy (EM) shows paucity of elastic fibers with accumulation of elastin (ELN) globules, reflecting lack of assembly of the primary components of elastic fibers [
Based on the description of the only family reported to date to have demonstrated autosomal dominant inheritance, this form appears to be milder in clinical presentation with less internal organ involvement than the autosomal recessive form [
Due to the small number of individuals with
Of note, one individual who was heterozygous for an inherited
The prevalence is unknown, with only six families reported to date.
## Clinical Description
To date, six families with autosomal recessive
Hip dislocation is not observed in
Intelligence is normal [
Note: To date, no heterozygous carriers for autosomal recessive
Electron microscopy (EM) shows paucity of elastic fibers with accumulation of elastin (ELN) globules, reflecting lack of assembly of the primary components of elastic fibers [
Based on the description of the only family reported to date to have demonstrated autosomal dominant inheritance, this form appears to be milder in clinical presentation with less internal organ involvement than the autosomal recessive form [
## Autosomal Recessive
To date, six families with autosomal recessive
Hip dislocation is not observed in
Intelligence is normal [
Note: To date, no heterozygous carriers for autosomal recessive
Electron microscopy (EM) shows paucity of elastic fibers with accumulation of elastin (ELN) globules, reflecting lack of assembly of the primary components of elastic fibers [
## Autosomal Dominant
Based on the description of the only family reported to date to have demonstrated autosomal dominant inheritance, this form appears to be milder in clinical presentation with less internal organ involvement than the autosomal recessive form [
## Genotype-Phenotype Correlations
Due to the small number of individuals with
Of note, one individual who was heterozygous for an inherited
## Prevalence
The prevalence is unknown, with only six families reported to date.
## Genetically Related (Allelic) Disorders
The two phenotypes other than those discussed in this
## Differential Diagnosis
Other disorders characterized by cutis laxa are summarized in
Disorders to Consider in the Differential Diagnosis of Cutis Laxa
AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; GU = genitourinary; ID = intellectual disability; MOI = mode of inheritance
The subject of this
Pathogenic variants in
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Chest roentgenogram
Chest CT exam
Pulmonary function testing
Eval by pulmonologist
IV = intravenous
Treatment of Manifestations in Individuals with
Symptomatic treatment w/inhaled corticosteroids, atropine, & selective β2-adrenergic bronchodilation
Oxygen supplementation if necessary
The following are appropriate:
Attention to respiratory function prior to surgery
Prophylactic antibiotics (cotrimoxazole) in individuals with vesicoureteral reflux
Immunization against respiratory infections (influenza,
Consideration of passive immunization for respiratory syncytial virus (RSV) with palivizumab during the RSV season
Routine surveillance of the urinary tract for evidence of bladder diverticula and/or vesicoureteral reflux is indicated.
Avoid the following:
Smoking; however, the limited life span of affected individuals makes this recommendation mostly theoretic.
Positive pressure ventilation unless needed to treat life-threatening conditions
Isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain
People with respiratory infections
See
Search
• Chest roentgenogram
• Chest CT exam
• Pulmonary function testing
• Eval by pulmonologist
• Symptomatic treatment w/inhaled corticosteroids, atropine, & selective β2-adrenergic bronchodilation
• Oxygen supplementation if necessary
• Attention to respiratory function prior to surgery
• Prophylactic antibiotics (cotrimoxazole) in individuals with vesicoureteral reflux
• Immunization against respiratory infections (influenza,
• Consideration of passive immunization for respiratory syncytial virus (RSV) with palivizumab during the RSV season
• Smoking; however, the limited life span of affected individuals makes this recommendation mostly theoretic.
• Positive pressure ventilation unless needed to treat life-threatening conditions
• Isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain
• People with respiratory infections
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Chest roentgenogram
Chest CT exam
Pulmonary function testing
Eval by pulmonologist
IV = intravenous
• Chest roentgenogram
• Chest CT exam
• Pulmonary function testing
• Eval by pulmonologist
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Symptomatic treatment w/inhaled corticosteroids, atropine, & selective β2-adrenergic bronchodilation
Oxygen supplementation if necessary
• Symptomatic treatment w/inhaled corticosteroids, atropine, & selective β2-adrenergic bronchodilation
• Oxygen supplementation if necessary
## Prevention of Secondary Complications
The following are appropriate:
Attention to respiratory function prior to surgery
Prophylactic antibiotics (cotrimoxazole) in individuals with vesicoureteral reflux
Immunization against respiratory infections (influenza,
Consideration of passive immunization for respiratory syncytial virus (RSV) with palivizumab during the RSV season
• Attention to respiratory function prior to surgery
• Prophylactic antibiotics (cotrimoxazole) in individuals with vesicoureteral reflux
• Immunization against respiratory infections (influenza,
• Consideration of passive immunization for respiratory syncytial virus (RSV) with palivizumab during the RSV season
## Surveillance
Routine surveillance of the urinary tract for evidence of bladder diverticula and/or vesicoureteral reflux is indicated.
## Agents/Circumstances to Avoid
Avoid the following:
Smoking; however, the limited life span of affected individuals makes this recommendation mostly theoretic.
Positive pressure ventilation unless needed to treat life-threatening conditions
Isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain
People with respiratory infections
• Smoking; however, the limited life span of affected individuals makes this recommendation mostly theoretic.
• Positive pressure ventilation unless needed to treat life-threatening conditions
• Isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain
• People with respiratory infections
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
Rare individuals diagnosed with autosomal dominant
An individual diagnosed with autosomal dominant
Recommendations for the evaluation of parents of a proband with an apparent
The family history of some individuals diagnosed with autosomal dominant
If a parent of the proband is affected and/or is known to have an
If the
If the parents have not been tested for the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Rare individuals diagnosed with autosomal dominant
• An individual diagnosed with autosomal dominant
• Recommendations for the evaluation of parents of a proband with an apparent
• The family history of some individuals diagnosed with autosomal dominant
• If a parent of the proband is affected and/or is known to have an
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Autosomal Dominant Inheritance – Risk to Family Members
Rare individuals diagnosed with autosomal dominant
An individual diagnosed with autosomal dominant
Recommendations for the evaluation of parents of a proband with an apparent
The family history of some individuals diagnosed with autosomal dominant
If a parent of the proband is affected and/or is known to have an
If the
If the parents have not been tested for the
• Rare individuals diagnosed with autosomal dominant
• An individual diagnosed with autosomal dominant
• Recommendations for the evaluation of parents of a proband with an apparent
• The family history of some individuals diagnosed with autosomal dominant
• If a parent of the proband is affected and/or is known to have an
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
## Resources
New Zealand
France
•
• New Zealand
•
•
•
•
•
• France
•
•
•
## Molecular Genetics
FBLN5-Related Cutis Laxa: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FBLN5-Related Cutis Laxa (
Independent of the underlying molecular pathophysiology, all types of cutis laxa are characterized by alterations of elastic fibers, not collagen. In ultrastructural investigations elastic fibers are reduced in number and often appear fragmented.
The assembly of elastic fibers, a complex mechanism, takes place in the extracellular space. According to the currently accepted model, microfibrillar proteins like the fibrillins first form a lattice with fibulins into which secreted tropoelastin is deposited and then further processed [
When tropoelastin expression is insufficient, the generation of elastic fibers is disturbed. This explains why heterozygous loss-of-function
Pathogenic variants in
A more complex mechanism underlies autosomal recessive cutis laxa, Debré type (ARCL2A) (see
Patients show a glycosylation defect, which can be detected by isoelectrofocusing (IEF) of serum transferrins [
Patient cells display a delay of Golgi-to-ER trafficking. It is unknown whether the glycosylation defect impairs the function of a protein involved in the formation of elastic fibers or if it is just an epiphenomenon caused by a secretion defect also involving elastic fiber components.
Autosomal recessive
Autosomal dominant
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
One of three variant alleles of different genes thought to result in an acquired form of cutis laxa [
Variant nomenclature described in
Duplication of 22,729 nucleotides from intron 4 to exon 9 [
Duplication results in a larger transcript with a tandem duplication of 483 nucleotides that translates to a tandem duplication of four cbEGF motifs in the protein product [
• Patients show a glycosylation defect, which can be detected by isoelectrofocusing (IEF) of serum transferrins [
• Patient cells display a delay of Golgi-to-ER trafficking. It is unknown whether the glycosylation defect impairs the function of a protein involved in the formation of elastic fibers or if it is just an epiphenomenon caused by a secretion defect also involving elastic fiber components.
• Autosomal recessive
• Autosomal dominant
## Molecular Pathogenesis
Independent of the underlying molecular pathophysiology, all types of cutis laxa are characterized by alterations of elastic fibers, not collagen. In ultrastructural investigations elastic fibers are reduced in number and often appear fragmented.
The assembly of elastic fibers, a complex mechanism, takes place in the extracellular space. According to the currently accepted model, microfibrillar proteins like the fibrillins first form a lattice with fibulins into which secreted tropoelastin is deposited and then further processed [
When tropoelastin expression is insufficient, the generation of elastic fibers is disturbed. This explains why heterozygous loss-of-function
Pathogenic variants in
A more complex mechanism underlies autosomal recessive cutis laxa, Debré type (ARCL2A) (see
Patients show a glycosylation defect, which can be detected by isoelectrofocusing (IEF) of serum transferrins [
Patient cells display a delay of Golgi-to-ER trafficking. It is unknown whether the glycosylation defect impairs the function of a protein involved in the formation of elastic fibers or if it is just an epiphenomenon caused by a secretion defect also involving elastic fiber components.
Autosomal recessive
Autosomal dominant
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
One of three variant alleles of different genes thought to result in an acquired form of cutis laxa [
Variant nomenclature described in
Duplication of 22,729 nucleotides from intron 4 to exon 9 [
Duplication results in a larger transcript with a tandem duplication of 483 nucleotides that translates to a tandem duplication of four cbEGF motifs in the protein product [
• Patients show a glycosylation defect, which can be detected by isoelectrofocusing (IEF) of serum transferrins [
• Patient cells display a delay of Golgi-to-ER trafficking. It is unknown whether the glycosylation defect impairs the function of a protein involved in the formation of elastic fibers or if it is just an epiphenomenon caused by a secretion defect also involving elastic fiber components.
• Autosomal recessive
• Autosomal dominant
## Chapter Notes
We thank the families for their participation.
15 June 2023 (aa) Revision: added
16 August 2018 (sw) Comprehensive update posted live
13 March 2014 (me) Comprehensive update posted live
13 October 2011 (me) Comprehensive update posted live
19 March 2009 (et) Review posted live
10 September 2008 (lvm) Original submission
• 15 June 2023 (aa) Revision: added
• 16 August 2018 (sw) Comprehensive update posted live
• 13 March 2014 (me) Comprehensive update posted live
• 13 October 2011 (me) Comprehensive update posted live
• 19 March 2009 (et) Review posted live
• 10 September 2008 (lvm) Original submission
## Acknowledgments
We thank the families for their participation.
## Revision History
15 June 2023 (aa) Revision: added
16 August 2018 (sw) Comprehensive update posted live
13 March 2014 (me) Comprehensive update posted live
13 October 2011 (me) Comprehensive update posted live
19 March 2009 (et) Review posted live
10 September 2008 (lvm) Original submission
• 15 June 2023 (aa) Revision: added
• 16 August 2018 (sw) Comprehensive update posted live
• 13 March 2014 (me) Comprehensive update posted live
• 13 October 2011 (me) Comprehensive update posted live
• 19 March 2009 (et) Review posted live
• 10 September 2008 (lvm) Original submission
## References
## Literature Cited
|
[
"CS Adamo, A Beyens, A Schiavinato, DR Keene, SF Tufa, M Mörgelin, J Brinckmann, T Sasaki, A Niehoff, M Dreiner, L Pottie, L Muiño-Mosquera, EY Gulec, A Gezdirici, P Braghetta, P Bonaldo, R Wagener, M Paulsson, H Bornaun, R De Rycke, M De Bruyne, F Baeke, WP Devine, B Gangaram, A Tam, M Balasubramanian, S Ellard, S Moore, S Symoens, J Shen, S Cole, U Schwarze, KW Holmes, SJ Hayflick, W Wiszniewski, S Nampoothiri, EC Davis, LY Sakai, G Sengle, B Callewaert. EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.. Am J Hum Genet. 2022;109:2230-52",
"B Callewaert, CT Su, T Van Damme, P Vlummens, F Malfait, O Vanakker, B Schulz, M Mac Neal, EC Davis, JG Lee, A Salhi, S Unger, K Heimdal, S De Almeida, U Kornak, H Gaspar, JL Bresson, K Prescott, ME Gosendi, S Mansour, GE Piérard, S Madan-Khetarpal, FC Sciurba, S Symoens, PJ Coucke, L Van Maldergem, Z Urban, A De Paepe. Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa.. Hum Mutat. 2013;34:111-21",
"S Claus, J Fischer, H Mégarbané, A Mégarbané, F Jobard, R Debret, S Peyrol, S Saker, M Devillers, P Sommer, O Damour. A p.C217R mutation in fibulin-5 from cutis laxa patients is associated with incomplete extracellular matrix formation in a skin equivalent model.. J Invest Dermatol 2008;128:1442-50",
"E Elahi, R Kalhor, SS Banihosseini, N Torabi, H Pour-Jafari, M Houshmand, SS Amini, A Ramezani, B Loeys. Homozygous missense mutation in fibulin-5 in an Iranian autosomal recessive cutis laxa pedigree and associated haplotype.. J Invest Dermatol 2006;126:1506-9",
"M Forgac. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology.. Nat Rev Mol Cell Biol 2007;8:917-29",
"D Guerra, C Fornieri, B Bacchelli, L Lugli, F Balli, P Ferrari. The de Barsy syndrome.. J Cutan Pathol 2004;31:616-24",
"HC Hennies, U Kornak, H Zhang, J Egerer, X Zhang, W Seifert, J Kühnisch, B Budde, M Nätebus, F Brancati, WR Wilcox, D Müller, PB Kaplan, A Rajab, G Zampino, V Fodale, B Dallapiccola, W Newman, K Metcalfe, J Clayton-Smith, M Tassabehji, B Steinmann, FA Barr, P Nürnberg, P Wieacker, S Mundlos. Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin.. Nat Genet 2008;40:1410-2",
"Q Hu, BL Loeys, PJ Coucke, A De Paepe, RP Mecham, J Choi, EC Davis, Z Urban. Fibulin-5 mutations: mechanisms of impaired elastic fiber formation in recessive cutis laxa.. Hum Mol Genet 2006;15:3379-86",
"V Hucthagowder, N Sausgruber, KH Kim, B Angle, LY Marmorstein, Z Urban. Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome.. Am J Hum Genet 2006;78:1075-80",
"A Hurtado-Lorenzo, M Skinner, J El Annan, M Futai, GH Sun-Wada, S Bourgoin, J Casanova, A Wildeman, S Bechoua, DA Ausiello, D Brown, V Marshansky. V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway.. Nat Cell Biol 2006;8:124-36",
"PN Kantaputra, M Kaewgahya, A Wiwatwongwana, D Wiwatwongwana, R Sittiwangkul, A Iamaroon, P Dejkhamron. Cutis laxa with pulmonary emphysema, conjunctivochalasis, nasolacrimal duct obstruction, abnormal hair, and a novel FBLN5 mutation.. Am J Med Genet A. 2014;164A:2370-7",
"C Karakurt, T Sipahi, S Ceylaner, F Senocak, S Karademir, M Becer. Cutis laxa with growth and developmental delay.. Clin Pediatr (Phila) 2001;40:422-3",
"CM Kielty. Elastic fibres in health and disease.. Expert Rev Mol Med 2006;8:1-23",
"U Kornak, E Reynders, A Dimopoulou, J van Reeuwijk, B Fischer, A Rajab, B Budde, P Nürnberg, F Foulquier. Lefeber D, Urban Z, Gruenewald S, Annaert W, Brunner HG, van Bokhoven H, Wevers R, Morava E, Matthijs G, Van Maldergem L, Mundlos S. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2.. Nat Genet. 2008;40:32-4",
"M Ledoux-Corbusier. Cutis laxa: congenital form with pulmonary emphysema. An ultrastructural study.. J Cutan Pathol 1983;10:340-9",
"B Loeys, L Van Maldergem, G Mortier, P Coucke, S Gerniers, JM Naeyaert, A De Paepe. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa.. Hum Mol Genet 2002;11:2113-8",
"D Markova, Y Zou, F Ringpfeil, T Sasaki, G Kostka, R Timpl, J Uitto, ML Chu. Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene.. Am J Hum Genet 2003;72:998-1004",
"K Metcalfe, AK Rucka, L Smoot, G Hofstadler, G Tuzler, P McKeown, V Siu, A Rauch, J Dean, N Dennis, I Ellis, W Reardon, C Cytrynbaum, L Osborne, JR Yates, AP Read, D Donnai, M Tassabehji. Elastin: mutational spectrum in supravalvular aortic stenosis.. Eur J Hum Genet 2000;8:955-63",
"E Morava, S Wopereis, P Coucke, G Gillessen-Kasbach, T Voit, J Smeitink, R Wevers, S Grünewald. Defective protein glycosylation in patients with cutis laxa syndrome.. Eur J Hum Genet 2005;13:414-21",
"A Nanda, QA Alsaleh, H Al-Sabah, EE Marzouk, AM Salam, M Nanda, JT Anim. Geroderma osteodysplastica / wrinkly skin syndrome: report of three patients and brief review of the literature.. Pediatr Dermatol 2008;25:66-71",
"C Peters, MJ Bayer, S Bühler, JS Andersen, M Mann, A Mayer. Trans-complex formation by proteolipid channels in the terminal phase of membrane fusion.. Nature 2001;409:581-8",
"C Pietrement, GH Sun-Wada, ND Silva, M McKee, V Marshansky, D Brown, M Futai, S Breton. Distinct expression patterns of different subunit isoforms of the V-ATPase in the rat epididymis.. Biol Reprod 2006;74:185-94",
"H Pour-Jafari, A Sahiri. Presentation of a pedigree of an Iranian family with two members with autosomal recessive cutis laxa type 1.. Med J Islam Repub Ir 2004;18:87-9",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton. UK10K Consortium, Hurles ME. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"L Van Maldergem, E Vamos, I Liebaers, P Petit, G Vandevelde, A Simonis-Blumenfrucht, R Bouffioux, S Kulakowski, S Hanquinet, P Van Durme, M Laporte, M Ledoux-Corbusier, JF Reynolds, G Neri. Severe congenital cutis laxa with pulmonary emphysema: a family with three affected sibs.. Am J Med Genet 1988;31:455-64",
"L Van Maldergem, M Yuksel-Apak, H Kayserili, E Seemanova, S Giurgea, L Basel-Vanagaite, E Leao-Teles, J Vigneron, M Foulon, M Greally, J Jaeken, S Mundlos, WB Dobyns. Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debré-type.. Neurology 2008;71:1602-8",
"MC Zhang, L He, M Giro, SL Yong, GE Tiller, JM Davidson. Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN).. J Biol Chem 1999;274:981-6"
] |
19/3/2009
|
16/8/2018
|
15/6/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
fbxl4-mtddepl
|
fbxl4-mtddepl
|
[
"FBXL4 Deficiency",
"FBXL4-Related Early-Onset Mitochondrial Encephalopathy",
"Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), Encephalomyopathic Type",
"Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), Encephalomyopathic Type",
"FBXL4 Deficiency",
"FBXL4-Related Early-Onset Mitochondrial Encephalopathy",
"F-box/LRR-repeat protein 4",
"FBXL4",
"FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome"
] |
Mohammed Almannai, Hongzheng Dai, Ayman W El-Hattab, Lee-Jun C Wong
|
Summary The diagnosis of
|
## Diagnosis
Developmental delay. Often global with severe speech impairment and lack of ambulation
Neurologic findings, Hypotonia, seizures, movement disorders, such as ataxia, autonomic dysfunction
Feeding difficulty and failure to thrive
Abnormal growth. Intrauterine growth restriction, short stature, microcephaly (congenital and acquired)
Cardiovascular abnormalities. Hypertrophic cardiomyopathy, congenital heart malformations, arrhythmia, pulmonary hypertension
White matter abnormalities (19/32 individuals reported). T
Cerebral atrophy (14/32). Progressive; could be evident as early as age three months [
Basal ganglia abnormalities, including lesions and abnormal signal intensities (11/32)
Pervientricular cysts (9/32)
Thin corpus callosum (6/32)
Cerebellar hypoplasia (6/32)
Arachnoid cysts (4/32)
Brain stem atrophy (4/32)
Stroke-like episodes (1/32) [
Only one child (who died at age 20 months) was reported to have a normal brain MRI [
MR spectroscopy may show high lactate peak in the brain and cerebrospinal fluid [
Persistently elevated lactate levels (range: 3-21 mmol/L; median: 13 mmol/L) were observed in all individuals. When assayed, cerebrospinal fluid lactate levels were also elevated [
Hyperammonemia is seen in about 50% of individuals. Although ammonia levels close to 500 μmol/L have been reported [
Mild to moderate elevations in creatine kinase were reported in six of 13 individuals in one study [
Muscle tissue and skin fibroblasts show [
Variably reduced mtDNA content (range: 10%-70%; mean: ~30% of tissue- and age-matched controls); and
Decreased activity of multiple complexes on electron transport chain activity assay in 80% of affected individuals. There is usually combined, though variable, deficiency of all complexes.
Muscle histology can show fiber size variability, lipid and glycogen accumulation, and variable reduction in COX activity. Enlarged and structurally altered mitochondria can be seen on electron microscopy [
The diagnosis of
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Children with the suggestive clinical, laboratory, and neuroimaging findings could be diagnosed using gene-targeted testing (see
When the clinical, laboratory, and brain MRI findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other mitochondrial disorders molecular genetic testing approaches can include a combination of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Developmental delay. Often global with severe speech impairment and lack of ambulation
• Neurologic findings, Hypotonia, seizures, movement disorders, such as ataxia, autonomic dysfunction
• Feeding difficulty and failure to thrive
• Abnormal growth. Intrauterine growth restriction, short stature, microcephaly (congenital and acquired)
• Cardiovascular abnormalities. Hypertrophic cardiomyopathy, congenital heart malformations, arrhythmia, pulmonary hypertension
• White matter abnormalities (19/32 individuals reported). T
• Cerebral atrophy (14/32). Progressive; could be evident as early as age three months [
• Basal ganglia abnormalities, including lesions and abnormal signal intensities (11/32)
• Pervientricular cysts (9/32)
• Thin corpus callosum (6/32)
• Cerebellar hypoplasia (6/32)
• Arachnoid cysts (4/32)
• Brain stem atrophy (4/32)
• Stroke-like episodes (1/32) [
• Persistently elevated lactate levels (range: 3-21 mmol/L; median: 13 mmol/L) were observed in all individuals. When assayed, cerebrospinal fluid lactate levels were also elevated [
• Hyperammonemia is seen in about 50% of individuals. Although ammonia levels close to 500 μmol/L have been reported [
• Mild to moderate elevations in creatine kinase were reported in six of 13 individuals in one study [
• Muscle tissue and skin fibroblasts show [
• Variably reduced mtDNA content (range: 10%-70%; mean: ~30% of tissue- and age-matched controls); and
• Decreased activity of multiple complexes on electron transport chain activity assay in 80% of affected individuals. There is usually combined, though variable, deficiency of all complexes.
• Variably reduced mtDNA content (range: 10%-70%; mean: ~30% of tissue- and age-matched controls); and
• Decreased activity of multiple complexes on electron transport chain activity assay in 80% of affected individuals. There is usually combined, though variable, deficiency of all complexes.
• Muscle histology can show fiber size variability, lipid and glycogen accumulation, and variable reduction in COX activity. Enlarged and structurally altered mitochondria can be seen on electron microscopy [
• Variably reduced mtDNA content (range: 10%-70%; mean: ~30% of tissue- and age-matched controls); and
• Decreased activity of multiple complexes on electron transport chain activity assay in 80% of affected individuals. There is usually combined, though variable, deficiency of all complexes.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Developmental delay. Often global with severe speech impairment and lack of ambulation
Neurologic findings, Hypotonia, seizures, movement disorders, such as ataxia, autonomic dysfunction
Feeding difficulty and failure to thrive
Abnormal growth. Intrauterine growth restriction, short stature, microcephaly (congenital and acquired)
Cardiovascular abnormalities. Hypertrophic cardiomyopathy, congenital heart malformations, arrhythmia, pulmonary hypertension
White matter abnormalities (19/32 individuals reported). T
Cerebral atrophy (14/32). Progressive; could be evident as early as age three months [
Basal ganglia abnormalities, including lesions and abnormal signal intensities (11/32)
Pervientricular cysts (9/32)
Thin corpus callosum (6/32)
Cerebellar hypoplasia (6/32)
Arachnoid cysts (4/32)
Brain stem atrophy (4/32)
Stroke-like episodes (1/32) [
Only one child (who died at age 20 months) was reported to have a normal brain MRI [
MR spectroscopy may show high lactate peak in the brain and cerebrospinal fluid [
Persistently elevated lactate levels (range: 3-21 mmol/L; median: 13 mmol/L) were observed in all individuals. When assayed, cerebrospinal fluid lactate levels were also elevated [
Hyperammonemia is seen in about 50% of individuals. Although ammonia levels close to 500 μmol/L have been reported [
Mild to moderate elevations in creatine kinase were reported in six of 13 individuals in one study [
Muscle tissue and skin fibroblasts show [
Variably reduced mtDNA content (range: 10%-70%; mean: ~30% of tissue- and age-matched controls); and
Decreased activity of multiple complexes on electron transport chain activity assay in 80% of affected individuals. There is usually combined, though variable, deficiency of all complexes.
Muscle histology can show fiber size variability, lipid and glycogen accumulation, and variable reduction in COX activity. Enlarged and structurally altered mitochondria can be seen on electron microscopy [
• Developmental delay. Often global with severe speech impairment and lack of ambulation
• Neurologic findings, Hypotonia, seizures, movement disorders, such as ataxia, autonomic dysfunction
• Feeding difficulty and failure to thrive
• Abnormal growth. Intrauterine growth restriction, short stature, microcephaly (congenital and acquired)
• Cardiovascular abnormalities. Hypertrophic cardiomyopathy, congenital heart malformations, arrhythmia, pulmonary hypertension
• White matter abnormalities (19/32 individuals reported). T
• Cerebral atrophy (14/32). Progressive; could be evident as early as age three months [
• Basal ganglia abnormalities, including lesions and abnormal signal intensities (11/32)
• Pervientricular cysts (9/32)
• Thin corpus callosum (6/32)
• Cerebellar hypoplasia (6/32)
• Arachnoid cysts (4/32)
• Brain stem atrophy (4/32)
• Stroke-like episodes (1/32) [
• Persistently elevated lactate levels (range: 3-21 mmol/L; median: 13 mmol/L) were observed in all individuals. When assayed, cerebrospinal fluid lactate levels were also elevated [
• Hyperammonemia is seen in about 50% of individuals. Although ammonia levels close to 500 μmol/L have been reported [
• Mild to moderate elevations in creatine kinase were reported in six of 13 individuals in one study [
• Muscle tissue and skin fibroblasts show [
• Variably reduced mtDNA content (range: 10%-70%; mean: ~30% of tissue- and age-matched controls); and
• Decreased activity of multiple complexes on electron transport chain activity assay in 80% of affected individuals. There is usually combined, though variable, deficiency of all complexes.
• Variably reduced mtDNA content (range: 10%-70%; mean: ~30% of tissue- and age-matched controls); and
• Decreased activity of multiple complexes on electron transport chain activity assay in 80% of affected individuals. There is usually combined, though variable, deficiency of all complexes.
• Muscle histology can show fiber size variability, lipid and glycogen accumulation, and variable reduction in COX activity. Enlarged and structurally altered mitochondria can be seen on electron microscopy [
• Variably reduced mtDNA content (range: 10%-70%; mean: ~30% of tissue- and age-matched controls); and
• Decreased activity of multiple complexes on electron transport chain activity assay in 80% of affected individuals. There is usually combined, though variable, deficiency of all complexes.
## Establishing the Diagnosis
The diagnosis of
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Children with the suggestive clinical, laboratory, and neuroimaging findings could be diagnosed using gene-targeted testing (see
When the clinical, laboratory, and brain MRI findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other mitochondrial disorders molecular genetic testing approaches can include a combination of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Option 1
When the clinical, laboratory, and brain MRI findings suggest the diagnosis of
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other mitochondrial disorders molecular genetic testing approaches can include a combination of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
In two children, the disease presented prenatally: one male was born at 26 weeks' gestation following preterm labor resulting from polyhydramnios that was believed to be due to hypotonia and decreased fetal movement [
The common clinical manifestations summarized in
Clinical Manifestations of
Developmental delay
Hypotonia
Seizures
Movement disorders
Ataxia
Autonomic dysfunction
Stroke-like episodes
45/45 (100%)
39/42 (93%)
14/42 (33%)
5/17 (29%)
4/15 (27%)
3/12 (25%)
1/32 (3%)
Failure to thrive
IUGR
Short stature
Microcephaly (congenital & acquired)
25/33 (76%)
18/31 (58%)
17/31 (55%)
14/36 (39%)
Feeding difficulties
Hepatopathy
27/31 (87%)
8/24 (33%)
Cardiomyopathy
Congenital heart malformations
Arrhythmia
Pulmonary hypertension
10/37 (27%)
7/37 (19%)
6/41 (15%)
4/37 (11%)
Cataract
Strabismus
Nystagmus
Optic atrophy
5/30 (17%)
5/31 (16%)
6/30 (20%)
3/30 (10%)
Neutropenia
Hearing impairment
8/43 (19%)
4/33 (12%)
IUGR = intrauterine growth restriction, defined as birth weight <10
Movement disorders reported include dystonia, choreoathetosis, hyperkinetic movements, and tremors [
Hypotonia is severe and early onset, often presenting in the neonatal period.
Seizures started at age four months in one infant [
Other less commonly reported neurologic manifestations for which clinical information is available include:
Movement disorders including hyperkinetic movements [
Recurrent stroke-like episodes starting at age ten years in a girl who was reported at age 13 years [
Hepatopathy manifests as mildly elevated transaminases. Liver failure has not been reported to date. Of note, one individual with baseline mild increases in transaminases experienced further increase in liver enzymes following initiation of a ketogenic diet (initiated due to initial suspicion of pyruvate dehydrogenase deficiency) [
Congenital heart malformations include atrial septal defect, ventricular septal defect, patent foramen ovale, patent ductus arteriosus, tricuspid regurgitation, and tetralogy of Fallot (TOF). Other than TOF, the reported cardiac malformations are either relatively common or physiologic, bringing into question whether these are true associations or chance occurrences.
Arrhythmias include supraventricular tachycardia and Wolff-Parkinson-White syndrome [
Other reported eye findings include nystagmus and optic atrophy [
One individual had lymphopenia and hypogammaglobulinemia in addition to neutropenia [
Even without neutropenia, some individuals were prone to recurrent infections which in some cases resulted in metabolic decompensation and death [
Respiratory distress, likely due to hypotonia and weak muscles, was reported in six individuals [
Sensorineural hearing impairment was reported in four individuals [
Other uncommon features include renal tubular acidosis (5 individuals), progressive scoliosis (2 individuals), non-specified exercise intolerance (4 individuals), and sleep dysfunction.
Several males had hypospadias and/or cryptorchidism. One male had hypoplastic scrotum [
One individual developed exocrine pancreatic deficiency [
No genotype-phenotype correlations are known.
To date, 50 affected individuals from different ethnic groups – including Arabs, persons of northern European heritage, and Latin Americans/Hispanics – have been reported [
Consanguinity was reported in 64% of cases.
• Developmental delay
• Hypotonia
• Seizures
• Movement disorders
• Ataxia
• Autonomic dysfunction
• Stroke-like episodes
• 45/45 (100%)
• 39/42 (93%)
• 14/42 (33%)
• 5/17 (29%)
• 4/15 (27%)
• 3/12 (25%)
• 1/32 (3%)
• Failure to thrive
• IUGR
• Short stature
• Microcephaly (congenital & acquired)
• 25/33 (76%)
• 18/31 (58%)
• 17/31 (55%)
• 14/36 (39%)
• Feeding difficulties
• Hepatopathy
• 27/31 (87%)
• 8/24 (33%)
• Cardiomyopathy
• Congenital heart malformations
• Arrhythmia
• Pulmonary hypertension
• 10/37 (27%)
• 7/37 (19%)
• 6/41 (15%)
• 4/37 (11%)
• Cataract
• Strabismus
• Nystagmus
• Optic atrophy
• 5/30 (17%)
• 5/31 (16%)
• 6/30 (20%)
• 3/30 (10%)
• Neutropenia
• Hearing impairment
• 8/43 (19%)
• 4/33 (12%)
• Movement disorders including hyperkinetic movements [
• Recurrent stroke-like episodes starting at age ten years in a girl who was reported at age 13 years [
• Respiratory distress, likely due to hypotonia and weak muscles, was reported in six individuals [
• Sensorineural hearing impairment was reported in four individuals [
• Other uncommon features include renal tubular acidosis (5 individuals), progressive scoliosis (2 individuals), non-specified exercise intolerance (4 individuals), and sleep dysfunction.
• Several males had hypospadias and/or cryptorchidism. One male had hypoplastic scrotum [
• One individual developed exocrine pancreatic deficiency [
## Clinical Description
In two children, the disease presented prenatally: one male was born at 26 weeks' gestation following preterm labor resulting from polyhydramnios that was believed to be due to hypotonia and decreased fetal movement [
The common clinical manifestations summarized in
Clinical Manifestations of
Developmental delay
Hypotonia
Seizures
Movement disorders
Ataxia
Autonomic dysfunction
Stroke-like episodes
45/45 (100%)
39/42 (93%)
14/42 (33%)
5/17 (29%)
4/15 (27%)
3/12 (25%)
1/32 (3%)
Failure to thrive
IUGR
Short stature
Microcephaly (congenital & acquired)
25/33 (76%)
18/31 (58%)
17/31 (55%)
14/36 (39%)
Feeding difficulties
Hepatopathy
27/31 (87%)
8/24 (33%)
Cardiomyopathy
Congenital heart malformations
Arrhythmia
Pulmonary hypertension
10/37 (27%)
7/37 (19%)
6/41 (15%)
4/37 (11%)
Cataract
Strabismus
Nystagmus
Optic atrophy
5/30 (17%)
5/31 (16%)
6/30 (20%)
3/30 (10%)
Neutropenia
Hearing impairment
8/43 (19%)
4/33 (12%)
IUGR = intrauterine growth restriction, defined as birth weight <10
Movement disorders reported include dystonia, choreoathetosis, hyperkinetic movements, and tremors [
Hypotonia is severe and early onset, often presenting in the neonatal period.
Seizures started at age four months in one infant [
Other less commonly reported neurologic manifestations for which clinical information is available include:
Movement disorders including hyperkinetic movements [
Recurrent stroke-like episodes starting at age ten years in a girl who was reported at age 13 years [
Hepatopathy manifests as mildly elevated transaminases. Liver failure has not been reported to date. Of note, one individual with baseline mild increases in transaminases experienced further increase in liver enzymes following initiation of a ketogenic diet (initiated due to initial suspicion of pyruvate dehydrogenase deficiency) [
Congenital heart malformations include atrial septal defect, ventricular septal defect, patent foramen ovale, patent ductus arteriosus, tricuspid regurgitation, and tetralogy of Fallot (TOF). Other than TOF, the reported cardiac malformations are either relatively common or physiologic, bringing into question whether these are true associations or chance occurrences.
Arrhythmias include supraventricular tachycardia and Wolff-Parkinson-White syndrome [
Other reported eye findings include nystagmus and optic atrophy [
One individual had lymphopenia and hypogammaglobulinemia in addition to neutropenia [
Even without neutropenia, some individuals were prone to recurrent infections which in some cases resulted in metabolic decompensation and death [
Respiratory distress, likely due to hypotonia and weak muscles, was reported in six individuals [
Sensorineural hearing impairment was reported in four individuals [
Other uncommon features include renal tubular acidosis (5 individuals), progressive scoliosis (2 individuals), non-specified exercise intolerance (4 individuals), and sleep dysfunction.
Several males had hypospadias and/or cryptorchidism. One male had hypoplastic scrotum [
One individual developed exocrine pancreatic deficiency [
• Developmental delay
• Hypotonia
• Seizures
• Movement disorders
• Ataxia
• Autonomic dysfunction
• Stroke-like episodes
• 45/45 (100%)
• 39/42 (93%)
• 14/42 (33%)
• 5/17 (29%)
• 4/15 (27%)
• 3/12 (25%)
• 1/32 (3%)
• Failure to thrive
• IUGR
• Short stature
• Microcephaly (congenital & acquired)
• 25/33 (76%)
• 18/31 (58%)
• 17/31 (55%)
• 14/36 (39%)
• Feeding difficulties
• Hepatopathy
• 27/31 (87%)
• 8/24 (33%)
• Cardiomyopathy
• Congenital heart malformations
• Arrhythmia
• Pulmonary hypertension
• 10/37 (27%)
• 7/37 (19%)
• 6/41 (15%)
• 4/37 (11%)
• Cataract
• Strabismus
• Nystagmus
• Optic atrophy
• 5/30 (17%)
• 5/31 (16%)
• 6/30 (20%)
• 3/30 (10%)
• Neutropenia
• Hearing impairment
• 8/43 (19%)
• 4/33 (12%)
• Movement disorders including hyperkinetic movements [
• Recurrent stroke-like episodes starting at age ten years in a girl who was reported at age 13 years [
• Respiratory distress, likely due to hypotonia and weak muscles, was reported in six individuals [
• Sensorineural hearing impairment was reported in four individuals [
• Other uncommon features include renal tubular acidosis (5 individuals), progressive scoliosis (2 individuals), non-specified exercise intolerance (4 individuals), and sleep dysfunction.
• Several males had hypospadias and/or cryptorchidism. One male had hypoplastic scrotum [
• One individual developed exocrine pancreatic deficiency [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
## Prevalence
To date, 50 affected individuals from different ethnic groups – including Arabs, persons of northern European heritage, and Latin Americans/Hispanics – have been reported [
Consanguinity was reported in 64% of cases.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (e.g.,
Mitochondrial DNA depletion syndromes are phenotypically classified into myopathic, encephalomyopathic, hepatocerebral, and neurogastrointestinal forms (
Mitochondrial DNA Depletion Syndromes
Within each phenotypic category, mtDNA depletion syndromes are ordered by relative prevalence.
See hyperlinked
## Management
To establish the extent of the disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis
Neurology consultation incl comprehensive neurologic exam
Brain MRI to evaluate extent of disease
Management is best provided by a multidisciplinary team including neurology, nutrition, clinical genetics / metabolism, and developmental pediatrics. Other specialties including gastroenterology, cardiology, hematology, immunology, ophthalmology, and nephrology may be involved based on the associated complications.
No definite treatment is available to date; thus, treatment is mainly supportive (
Treatment of Manifestations in Individuals with
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Regular immunization to prevent life-threatening infections is indicated.
Antibiotic prophylaxis may be indicated for those with immunodeficiency [
No surveillance guidelines have been published. The following evaluations should be performed on a regular basis, with the treating physician determining the frequency based on initial presentation and severity of the condition.
Recommended Surveillance for Individuals with
See
Search
• Neurology consultation incl comprehensive neurologic exam
• Brain MRI to evaluate extent of disease
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations Following Initial Diagnosis
To establish the extent of the disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis
Neurology consultation incl comprehensive neurologic exam
Brain MRI to evaluate extent of disease
• Neurology consultation incl comprehensive neurologic exam
• Brain MRI to evaluate extent of disease
## Treatment of Manifestations
Management is best provided by a multidisciplinary team including neurology, nutrition, clinical genetics / metabolism, and developmental pediatrics. Other specialties including gastroenterology, cardiology, hematology, immunology, ophthalmology, and nephrology may be involved based on the associated complications.
No definite treatment is available to date; thus, treatment is mainly supportive (
Treatment of Manifestations in Individuals with
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Prevention of Secondary Complications
Regular immunization to prevent life-threatening infections is indicated.
Antibiotic prophylaxis may be indicated for those with immunodeficiency [
## Surveillance
No surveillance guidelines have been published. The following evaluations should be performed on a regular basis, with the treating physician determining the frequency based on initial presentation and severity of the condition.
Recommended Surveillance for Individuals with
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are typically heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
In the (usual) instance in which both parents are carriers: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are typically heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• In the (usual) instance in which both parents are carriers: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are typically heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
In the (usual) instance in which both parents are carriers: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are typically heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• In the (usual) instance in which both parents are carriers: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion Syndrome (
## References
## Literature Cited
## Chapter Notes
6 April 2017 (bp) Review posted live
6 October 2016 (ma) Original submission
• 6 April 2017 (bp) Review posted live
• 6 October 2016 (ma) Original submission
## Revision History
6 April 2017 (bp) Review posted live
6 October 2016 (ma) Original submission
• 6 April 2017 (bp) Review posted live
• 6 October 2016 (ma) Original submission
|
[
"G Antoun, S McBride, JR Vanstone, T Naas, J Michaud, S Redpath, HJ McMillan, J Brophy, H Daoud, P Chakraborty, D Dyment, M Holcik, ME Harper, MA Lines. Detailed biochemical and bioenergetic characterization of FBXL4-related encephalomyopathic mitochondrial DNA depletion.. JIMD Rep. 2016;27:1-9",
"PE Bonnen, JW Yarham, A Besse, P Wu, EA Faqeih, AM Al-Asmari, MA Saleh, W Eyaid, A Hadeel, L He, F Smith, S Yau, EM Simcox, S Miwa, T Donti, KK Abu-Amero, LJ Wong, WJ Craigen, BH Graham, KL Scott, R McFarland, RW Taylor. Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.. Am J Hum Genet. 2013;93:471-81",
"T Barøy, CR Pedurupillay, YT Bliksrud, M Rasmussen, A Holmgren, MD Vigeland, T Hughes, M Brink, R Rodenburg, B Nedregaard, P Strømme, E Frengen, D Misceo. A novel mutation in FBXL4 in a Norwegian child with encephalomyopathic mitochondrial DNA depletion syndrome 13.. Eur J Med Genet. 2016;59:342-6",
"H Dai, VW Zhang, AW El-Hattab, C Ficicioglu, M Shinawi, M Lines, A Schulze, M McNutt, G Gotway, X Tian, S Chen, J Wang, WJ Craigen, LJ Wong. FBXL4 defects are common in patients with congenital lactic acidemia and encephalomyopathic mitochondrial DNA depletion syndrome.. Clin Genet. 2017;91:634-9",
"D Ebrahimi-Fakhari, A Seitz, S Kölker, GF Hoffmann. Recurrent stroke-like episodes in FBXL4-associated early-onset mitochondrial encephalomyopathy.. Pediatr Neurol. 2015;53:549-50",
"AW El-Hattab, F Scaglia. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options.. Neurotherapeutics. 2013;10:186-98",
"X Gai, D Ghezzi, MA Johnson, CA Biagosch, HE Shamseldin, TB Haack, A Reyes, M Tsukikawa, CA Sheldon, S Srinivasan, M Gorza, LS Kremer, T Wieland, TM Strom, E Polyak, E Place, M Consugar, J Ostrovsky, S Vidoni, AJ Robinson, LJ Wong, N Sondheimer, MA Salih, E Al-Jishi, CP Raab, C Bean, F Furlan, R Parini, C Lamperti, JA Mayr, V Konstantopoulou, M Huemer, EA Pierce, T Meitinger, P Freisinger, W Sperl, H Prokisch, FS Alkuraya, MJ Falk, M Zeviani. Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.. Am J Hum Genet. 2013;93:482-95",
"M Huemer, D Karall, A Schossig, JE Abdenur, F Al Jasmi, C Biagosch, F Distelmaier, P Freisinger, BH Graham, TB Haack, N Hauser, J Hertecant, D Ebrahimi-Fakhari, V Konstantopoulou, K Leydiker, CM Lourenco, S Scholl-Bürgi, E Wilichowski, NI Wolf, SB Wortmann, RW Taylor, JA Mayr, PE Bonnen, W Sperl, H Prokisch, R McFarland. Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations.. J Inherit Metab Dis. 2015;38:905-14",
"SU Morton, EG Neilan, RW Peake, J Shi, K Schmitz-Abe, M Towne, K Markianos, SP Prabhu, PB Agrawal. Hyperammonemia as a presenting feature in two siblings with FBXL4 variants.. JIMD Rep. 2017;35:7-15",
"E Pronicka, D Piekutowska-Abramczuk, E Ciara, J Trubicka, D Rokicki, A Karkucińska-Więckowska, M Pajdowska, E Jurkiewicz, P Halat, J Kosińska, A Pollak, M Rydzanicz, P Stawinski, M Pronicki, M Krajewska-Walasek, R. Płoski. New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.. J Transl Med. 2016;14:174",
"MC van Rij, FA Jansen, DM Hellebrekers, W Onkenhout, HJ Smeets, AT Hendrickx, RW Gottschalk, SJ Steggerda, CM Peeters-Scholte, MC Haak, Y Hilhorst-Hofstee. Polyhydramnios and cerebellar atrophy: a prenatal presentation of mitochondrial encephalomyopathy caused by mutations in the FBXL4 gene.. Clin Case Rep. 2016;4:425-8",
"SB Wortmann, DA Koolen, JA Smeitink, L van den Heuvel, RJ Rodenburg. Whole exome sequencing of suspected mitochondrial patients in clinical practice.. J Inherit Metab Dis. 2015;38:437-43"
] |
6/4/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
fch
|
fch
|
[
"Angiopoietin-Like Protein 3 (ANGPTL3) Deficiency",
"Familial Combined Hypobetalipoproteinemia Type 2 (FHBL2)",
"Angiopoietin-Like Protein 3 (ANGPTL3) Deficiency",
"Familial Combined Hypobetalipoproteinemia Type 2 (FHBL2)",
"Angiopoietin-related protein 3",
"ANGPTL3",
"Familial Combined Hypolipidemia"
] |
Familial Combined Hypolipidemia
|
John R Burnett, Amanda J Hooper, Robert A Hegele
|
Summary Familial combined hypolipidemia is not associated with any pathologic signs or symptoms; diagnosis is suggested by low plasma concentrations of lipids. The lipid profile is one of hypocholesterolemia with low plasma low-density lipoprotein (LDL) cholesterol, low plasma high-density lipoprotein (HDL) cholesterol, low plasma triglycerides, and low plasma apolipoprotein (apo) B and apo A-I levels. The molecular diagnosis of familial combined hypolipidemia is established in a proband with suggestive laboratory findings and biallelic pathogenic variants in No specific evaluation, management, or surveillance is required for individuals who have familial combined hypolipidemia; however, consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and lack of specific clinical implications of familial combined hypolipidemia should be considered. Familial combined hypolipidemia is inherited in an autosomal recessive manner. At conception, each sib of a person with FCH has a 25% chance of also having FCH, a 50% chance of being a heterozygous carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes for
|
## Diagnosis
Familial combined hypolipidemia
Hypocholesterolemia with a total cholesterol of 1.9 ± 0.5 mmol/L (1.3-2.8)
Low plasma low-density lipoprotein (LDL) cholesterol of 1.3 ± 0.6 mmol/L (0.5-1.4)
Low plasma high-density lipoprotein (HDL) cholesterol of 0.6 ± 1.3 mmol/L (0.3-1.2)
Low plasma triglycerides of 0.4 ± 0.1 mmol/L (0.2-0.7)
Low plasma apolipoprotein (apo) B of 0.5 ± 0.1 g/L (0.3-0.7)
Low plasma apo A-I of 0.7 ± 0.2 mmol/L (0.4-1.1)
* Data reported are mean ± standard deviation (range) [
Note: Heterozygous individuals who have one
The molecular diagnosis of familial combined hypolipidemia
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive laboratory findings described in
When the lipid laboratory findings suggest the diagnosis of familial combined hypolipidemia, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of familial combined hypolipidemia has not been considered because an individual has atypical laboratory findings, then genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Combined Hypolipidemia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Hypocholesterolemia with a total cholesterol of 1.9 ± 0.5 mmol/L (1.3-2.8)
• Low plasma low-density lipoprotein (LDL) cholesterol of 1.3 ± 0.6 mmol/L (0.5-1.4)
• Low plasma high-density lipoprotein (HDL) cholesterol of 0.6 ± 1.3 mmol/L (0.3-1.2)
• Low plasma triglycerides of 0.4 ± 0.1 mmol/L (0.2-0.7)
• Low plasma apolipoprotein (apo) B of 0.5 ± 0.1 g/L (0.3-0.7)
• Low plasma apo A-I of 0.7 ± 0.2 mmol/L (0.4-1.1)
• For an introduction to multigene panels click
## Suggestive Findings
Familial combined hypolipidemia
Hypocholesterolemia with a total cholesterol of 1.9 ± 0.5 mmol/L (1.3-2.8)
Low plasma low-density lipoprotein (LDL) cholesterol of 1.3 ± 0.6 mmol/L (0.5-1.4)
Low plasma high-density lipoprotein (HDL) cholesterol of 0.6 ± 1.3 mmol/L (0.3-1.2)
Low plasma triglycerides of 0.4 ± 0.1 mmol/L (0.2-0.7)
Low plasma apolipoprotein (apo) B of 0.5 ± 0.1 g/L (0.3-0.7)
Low plasma apo A-I of 0.7 ± 0.2 mmol/L (0.4-1.1)
* Data reported are mean ± standard deviation (range) [
Note: Heterozygous individuals who have one
• Hypocholesterolemia with a total cholesterol of 1.9 ± 0.5 mmol/L (1.3-2.8)
• Low plasma low-density lipoprotein (LDL) cholesterol of 1.3 ± 0.6 mmol/L (0.5-1.4)
• Low plasma high-density lipoprotein (HDL) cholesterol of 0.6 ± 1.3 mmol/L (0.3-1.2)
• Low plasma triglycerides of 0.4 ± 0.1 mmol/L (0.2-0.7)
• Low plasma apolipoprotein (apo) B of 0.5 ± 0.1 g/L (0.3-0.7)
• Low plasma apo A-I of 0.7 ± 0.2 mmol/L (0.4-1.1)
## Establishing the Diagnosis
The molecular diagnosis of familial combined hypolipidemia
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive laboratory findings described in
When the lipid laboratory findings suggest the diagnosis of familial combined hypolipidemia, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of familial combined hypolipidemia has not been considered because an individual has atypical laboratory findings, then genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Combined Hypolipidemia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
## Option 1
When the lipid laboratory findings suggest the diagnosis of familial combined hypolipidemia, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of familial combined hypolipidemia has not been considered because an individual has atypical laboratory findings, then genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Combined Hypolipidemia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
To date, approximately 30 individuals from a small number of families have been identified with biallelic pathogenic variants in
Familial combined hypolipidemia is not associated with any pathologic signs or symptoms, and diagnosis is suggested by low plasma concentrations of lipids. Using a mendelian randomization approach, familial combined hypolipidemia has been associated with a reduced risk of atherosclerotic cardiovascular disease [
No genotype-phenotype correlations for familial combined hypolipidemia have been identified.
The prevalence of familial combined hypolipidemia is not known, but it appears to be very rare; approximately 30 individuals have been reported in the literature. However, the condition is probably underdiagnosed, as in the absence of a clinical phenotype, many clinicians fail to follow up on low plasma lipid levels.
## Clinical Description
To date, approximately 30 individuals from a small number of families have been identified with biallelic pathogenic variants in
Familial combined hypolipidemia is not associated with any pathologic signs or symptoms, and diagnosis is suggested by low plasma concentrations of lipids. Using a mendelian randomization approach, familial combined hypolipidemia has been associated with a reduced risk of atherosclerotic cardiovascular disease [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for familial combined hypolipidemia have been identified.
## Prevalence
The prevalence of familial combined hypolipidemia is not known, but it appears to be very rare; approximately 30 individuals have been reported in the literature. However, the condition is probably underdiagnosed, as in the absence of a clinical phenotype, many clinicians fail to follow up on low plasma lipid levels.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Familial Combined Hypolipidemia
Assoc w/clinical symptoms (e.g. failure to thrive, steatorrhea)
HDL cholesterol levels are lower in FCH.
Not assoc w/any clinical symptoms
Low plasma levels of LDL cholesterol
Assoc w/clinical symptoms (e.g. failure to thrive, steatorrhea)
Plasma triglycerides are not low.
AD = autosomal dominant; AR = autosomal recessive; FCH = familial combined hypolipidemia; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MOI = mode of inheritance
Individuals with a heterozygous, typically truncating pathogenic variant in
Population- and clinic-based studies of individuals with marked hypocholesterolemia have shown that of those without a known monogenic cause, a significant proportion are genetically predisposed to low LDL cholesterol, suggesting a polygenic cause for hypocholesterolemia [
• Assoc w/clinical symptoms (e.g. failure to thrive, steatorrhea)
• HDL cholesterol levels are lower in FCH.
• Not assoc w/any clinical symptoms
• Low plasma levels of LDL cholesterol
• Assoc w/clinical symptoms (e.g. failure to thrive, steatorrhea)
• Plasma triglycerides are not low.
## Management
No clinical practice guidelines for familial combined hypolipidemia have been published.
No specific evaluation, management, or surveillance is required for individuals who have familial combined hypolipidemia [
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and lack of specific clinical implications of familial combined hypolipidemia should be considered
See
Search
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Familial combined hypolipidemia is inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for an
Molecular genetic testing should be considered for the parents of the proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes for
If both parents are known to be heterozygous for an
Heterozygotes for
Heterozygote testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for an
• Molecular genetic testing should be considered for the parents of the proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes for
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes for
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being carriers.
## Mode of Inheritance
Familial combined hypolipidemia is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for an
Molecular genetic testing should be considered for the parents of the proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes for
If both parents are known to be heterozygous for an
Heterozygotes for
• The parents of an affected individual are presumed to be heterozygous for an
• Molecular genetic testing should be considered for the parents of the proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes for
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes for
## Heterozygote Detection
Heterozygote testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygotes, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Familial Combined Hypolipidemia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Familial Combined Hypolipidemia (
Angiopoietin-related protein 3 (ANGPTL3) is a regulatory protein secreted by the liver that modulates plasma triglycerides [
A gene-dosage effect can be observed such that heterozygotes for
## Molecular Pathogenesis
Angiopoietin-related protein 3 (ANGPTL3) is a regulatory protein secreted by the liver that modulates plasma triglycerides [
A gene-dosage effect can be observed such that heterozygotes for
## Chapter Notes
RAH is supported by the Jacob J Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair, and the Martha G Blackburn Chair in Cardiovascular Research. RAH holds operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario.
20 July 2023 (ma) Review posted live
28 November 2022 (jb) Original submission
• 20 July 2023 (ma) Review posted live
• 28 November 2022 (jb) Original submission
## Acknowledgments
RAH is supported by the Jacob J Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair, and the Martha G Blackburn Chair in Cardiovascular Research. RAH holds operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario.
## Revision History
20 July 2023 (ma) Review posted live
28 November 2022 (jb) Original submission
• 20 July 2023 (ma) Review posted live
• 28 November 2022 (jb) Original submission
## References
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"JW Balder, A Rimbert, X Zhang, M Viel, R Kanninga, F van Dijk, P Lansberg, R Sinke, JA Kuivenhoven. Genetics, lifestyle, and low-density lipoprotein cholesterol in young and apparently healthy women.. Circulation. 2018;137:820-31",
"F Blanco-Vaca, JM Martin-Campos, Á Beteta-Vicente, M Canyelles, S Martínez, R Roig, N Farré, J Julve, M Tondo. Molecular analysis of APOB, SAR1B, ANGPTL3, and MTTP in patients with primary hypocholesterolemia in a clinical laboratory setting: evidence supporting polygenicity in mutation-negative patients.. Atherosclerosis. 2019;283:52-60",
"C Bredefeld, MM Hussain, M Averna, DD Black, MF Brin, JR Burnett, S Charrière, C Cuerq, NO Davidson, RJ Deckelbaum, IJ Goldberg, E Granot, RA Hegele, S Ishibashi, W Karmally, E Levy, P Moulin, H Okazaki, P Poinsot, DJ Rader, M Takahashi, P Tarugi, MG Traber, M Di Fillippo, N Peretti. Guidance for the diagnosis and treatment of hypolipidemia disorders.. J Clin Lipidol. 2022;16:797-812",
"AB Cefalù, R Spina, D Noto, C Rabacchi, A Giammanco, ML Simone, F Brucato, C Scrimali, MG Gueli-Alletti, CM Barbagallo, P Tarugi, MR Averna. Comparison of two polygenic risk scores to identify non-monogenic primary hypocholesterolemias in a large cohort of Italian hypocholesterolemic subjects.. J Clin Lipidol. 2022;16:530-7",
"J Cohen, A Pertsemlidis, IK Kotowski, R Graham, CK Garcia, HH Hobbs. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.. Nat Genet. 2005;37:161-5",
"FE Dewey, V Gusarova, RL Dunbar, C O'Dushlaine, C Schurmann, O Gottesman, S McCarthy, CV Van Hout, S Bruse, HM Dansky, JB Leader, MF Murray, MD Ritchie, HL Kirchner, L Habegger, A Lopez, J Penn, A Zhao, W Shao, N Stahl, AJ Murphy, S Hamon, A Bouzelmat, R Zhang, B Shumel, R Pordy, D Gipe, GA Herman, WHH Sheu, IT Lee, KW Liang, X Guo, JI Rotter, YI Chen, WE Kraus, SH Shah, S Damrauer, A Small, DJ Rader, AB Wulff, BG Nordestgaard, A Tybjærg-Hansen, AM van den Hoek, HMG Princen, DH Ledbetter, DJ Carey, JD Overton, JG Reid, WJ Sasiela, P Banerjee, AR Shuldiner, IB Borecki, TM Teslovich, GD Yancopoulos, SJ Mellis, J Gromada, A Baras. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease.. N Engl J Med. 2017;377:211-21",
"A Di Costanzo, E Di Leo, D Noto, AB Cefalù, I Minicocci, L Polito, L D'Erasmo, V Cantisani, R Spina, P Tarugi, M Averna, M Arca. Clinical and biochemical characteristics of individuals with low cholesterol syndromes: a comparison between familial hypobetalipoproteinemia and familial combined hypolipidemia.. J Clin Lipidol. 2017;11:1234-42",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"S. Kersten. Angiopoietin-like 3 in lipoprotein metabolism.. Nat Rev Endocrinol. 2017;13:731-9",
"I Minicocci, A Montali, MR Robciuc, F Quagliarini, V Censi, G Labbadia, C Gabiati, G Pigna, ML Sepe, F Pannozzo, D Lütjohann, S Fazio, M Jauhiainen, C Ehnholm, M Arca. Mutations in the. J Clin Endocrinol Metab. 2012;97:E1266-75",
"I Minicocci, S Santini, V Cantisani, N Stitziel, S Kathiresan, JA Arroyo, G Marti, L Pisciotta, D Noto, AB Cefalù, M Maranghi, G Labbadia, G Pigna, F Pannozzo, F Ceci, E Ciociola, S Bertolini, S Calandra, P Tarugi, M Averna, M Arca. Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis.. J Lipid Res. 2013;54:3481-90",
"I Minicocci, A Tikka, E Poggiogalle, J Metso, A Montali, F Ceci, G Labbadia, M Fontana, A Di Costanzo, M Maranghi, A Rosano, C Ehnholm, LM Donini, M Jauhianen, M Arca. Effects of angiopoietin-like protein 3 deficiency postprandial lipid and lipoprotein metabolism.. J Lipid Res. 2016;57:1097-107",
"K Musunuru, JP Pirruccello, R Do, GM Peloso, C Guiducci, C Sougnez, KV Garimella, S Fisher, J Abreu, AJ Barry, T Fennell, E Banks, L Ambrogio, K Cibulskis, A Kernytsky, E Gonzalez, N Rudzicz, JC Engert, MA DePristo, MJ Daly, JC Cohen, HH Hobbs, D Altshuler, G Schonfeld, SB Gabriel, P Yue, S Kathiresan. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.. N Engl J Med. 2010;363:2220-7",
"D Noto, AB Cefalù, V Valenti, F Fayer, E Pinotti, M Ditta, R Spina, G Vigna, P Yue, S Kathiresan, P Tarugi, MR Averna. Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia.. Arterioscler Thromb Vasc Biol. 2012;32:805-9",
"L Pisciotta, E Favari, L Magnolo, S Simonelli, MP Adorni, R Sallo, T Fancello, I Zavaroni, D Ardigò, F Bernini, L Calabresi, G Franceschini, P Tarugi, S Calandra, S Bertolini. Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.. Circ Cardiovasc Genet. 2012;5:42-50",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"A Rimbert, X Vanhoye, D Coulibaly, M Marrec, M Pichelin, S Charrière, N Peretti, R Valéro, M Wargny, A Carrié, P Lindenbaum, JF Deleuze, E Genin, R Redon, PA Rollat-Farnier, D Goxe, G Degraef, O Marmontel, E Divry, E Bigot-Corbel, P Moulin, B Cariou, M Di Filippo. Phenotypic differences between polygenic and monogenic hypobetalipoproteinemia.. Arterioscler Thromb Vasc Biol 2021;41:e63-e71",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"NO Stitziel, AV Khera, X Wang, AJ Bierhals, AC Vourakis, AE Sperry, P Natarajan, D Klarin, CA Emdin, SM Zekavat, A Nomura, J Erdmann, H Schunkert, NJ Samani, WE Kraus, SH Shah, B Yu, E Boerwinkle, DJ Rader, N Gupta, PM Frossard, A Rasheed, J Danesh, ES Lander, S Gabriel, D Saleheen, K Musunuru, S Kathiresan. ANGPTL3 deficiency and protection against coronary artery disease.. J Am Coll Cardiol. 2017;69:2054-63",
"P Tarugi, S Bertolini, S. Calandra. Angiopoietin-like protein 3 (ANGPTL3) deficiency and familial combined hypolipidemia.. J Biomed Res. 2019;33:73-81",
"E Tikkanen, I Minicocci, J Hällfors, A Di Costanzo, L D'Erasmo, E Poggiogalle, LM Donini, P Würtz, M Jauhiainen, VM Olkkonen, M Arca. Metabolomic signature of angiopoietin-like protein 3 deficiency in fasting and postprandial state.. Arterioscler Thromb Vasc Biol. 2019;39:665-74",
"YX Xu, V Redon, H Yu, W Querbes, J Pirrucello, A Liebow, A Deik, K Trindade, X Wang, K Musunuru, CB Clish, C Cowan, K Fizgerald, D Rader. Kathiresan. Role of angiopoietin-like 3 (ANGPTL3) in regulating plasma level of low-density lipoproteins.. Atherosclerosis. 2018;268:196-206"
] |
20/7/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
fcmd
|
fcmd
|
[
"FCMD",
"FCMD",
"Ribitol-5-phosphate transferase FKTN",
"FKTN",
"Fukuyama Congenital Muscular Dystrophy"
] |
Fukuyama Congenital Muscular Dystrophy
|
Kayoko Saito
|
Summary Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and brain malformations including, classically, cobblestone lissencephaly with cerebral and cerebellar dysplasia. There is a spectrum of severity and mild, typical, and severe phenotypes are recognized. Disease onset typically occurs in early infancy with poor suck/swallow, weak cry, and floppiness. Serum creatine kinase (CK) levels are usually in the thousands (10-60 times higher than normal). Motor development peaks at around age five to six years and thereafter regresses as muscle atrophy progresses. In the typical case, sitting without support or sliding along the floor on the buttocks may be the peak motor function. Deep tendon reflexes are diminished or absent after early infancy. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later-onset features include a myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech delays, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement after age ten years. Swallowing disturbance occurs in individuals with severe FCMD and in individuals older than age ten years, leading to recurrent aspiration pneumonia and death. The diagnosis of FCMD is established in a proband with biallelic pathogenic variants in FCMD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
No consensus clinical diagnostic criteria for Fukuyama congenital muscular dystrophy (FCMD) have been published.
FCMD
Early-infantile-onset hypotonia and weakness with contractures of the hips, knees, and interphalangeal joints. Muscle weakness is typically progressive with age of onset younger than nine months.
Severe motor and speech delays and intellectual disability with relative preservation of social skills
A static course until early childhood, followed by diffuse and extensive muscle wasting (most prominent proximally) and progressive joint contractures
Myopathic facial appearance
Pseudohypertrophy of the calves and forearms in late infancy
Seizures (febrile and/or nonfebrile)
Ophthalmologic abnormalities, including visual impairment and retinal abnormalities. Retinal abnormalities, when present, are usually mild and focal. Retinal dysplasia, a pathologic diagnosis, is based on the finding of rosettes of immature photoreceptors.
Dysphagia and other swallowing issues
Respiratory issues
Cardiomyopathy
Cortical malformations including, classically, cobblestone lissencephaly with an irregular or pebbled brain surface; broad gyri with a thick cortex (pachygyria) in the frontal, parietal, and temporal regions; and sometimes areas of small and irregular gyri that resemble polymicrogyria
Dilated lateral ventricles
White matter abnormalities with hyperintensity on T
Cerebellar polymicrogyria and cerebellar cysts
Mild brain stem hypoplasia in some individuals
Additional findings include:
The opercula are poorly developed, leaving an open Sylvian fissure.
The cortex is typically no more than approximately 1 cm in thickness.
Age <6 years: 10-60 times above normal
Age ≥7 years: 5-20 times above normal
Bedridden individuals: normal
Findings characteristic of muscular dystrophy. Primary feature is interstitial fibrosis without muscle degeneration and regeneration, which distinguishes FCMD from
Immunohistochemical staining using alpha-dystroglycan antibody reveals selective deficiency of alpha-dystroglycan on the surface membrane of skeletal muscle.
Note: With the advent of molecular genetic testing, a muscle biopsy is no longer necessary to establish the diagnosis of FCMD (see
The diagnosis of FCMD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FCMD is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of FCMD, molecular genetic testing approaches can include
Note: (1) In individuals of Japanese, Korean, and/or Chinese ancestry, targeted analysis for the Japanese founder variant, a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by muscular dystrophy,
Note: While most reported pathogenic
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fukuyama Congenital Muscular Dystrophy
See
See
Generally, targeted analysis with allele-specific PCR [
In an analysis of 62 Japanese individuals with FCMD, 54 (87%) had the 3062 bp-insertion founder variant; 42(78%) were homozygous for the 3062-bp insertion founder variant and 12 (22%) were compound heterozygous, including three (6%) who were compound heterozygous with the
In an analysis of 13 Korean individuals with FCMD, three (23%) were homozygous for the 3062-bp insertion founder variant and seven (54%) were compound heterozygous for the 3062-bp insertion founder variant, including five (38%) who were compound heterozygous with c.648-1243G>T [
Three reported affected individuals were from China [
In individuals of Japanese ancestry, 6% (3/54) [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• Early-infantile-onset hypotonia and weakness with contractures of the hips, knees, and interphalangeal joints. Muscle weakness is typically progressive with age of onset younger than nine months.
• Severe motor and speech delays and intellectual disability with relative preservation of social skills
• A static course until early childhood, followed by diffuse and extensive muscle wasting (most prominent proximally) and progressive joint contractures
• Myopathic facial appearance
• Pseudohypertrophy of the calves and forearms in late infancy
• Seizures (febrile and/or nonfebrile)
• Ophthalmologic abnormalities, including visual impairment and retinal abnormalities. Retinal abnormalities, when present, are usually mild and focal. Retinal dysplasia, a pathologic diagnosis, is based on the finding of rosettes of immature photoreceptors.
• Dysphagia and other swallowing issues
• Respiratory issues
• Cardiomyopathy
• Cortical malformations including, classically, cobblestone lissencephaly with an irregular or pebbled brain surface; broad gyri with a thick cortex (pachygyria) in the frontal, parietal, and temporal regions; and sometimes areas of small and irregular gyri that resemble polymicrogyria
• Dilated lateral ventricles
• White matter abnormalities with hyperintensity on T
• Cerebellar polymicrogyria and cerebellar cysts
• Mild brain stem hypoplasia in some individuals
• The opercula are poorly developed, leaving an open Sylvian fissure.
• The cortex is typically no more than approximately 1 cm in thickness.
• Age <6 years: 10-60 times above normal
• Age ≥7 years: 5-20 times above normal
• Bedridden individuals: normal
• Findings characteristic of muscular dystrophy. Primary feature is interstitial fibrosis without muscle degeneration and regeneration, which distinguishes FCMD from
• Immunohistochemical staining using alpha-dystroglycan antibody reveals selective deficiency of alpha-dystroglycan on the surface membrane of skeletal muscle.
• Note: (1) In individuals of Japanese, Korean, and/or Chinese ancestry, targeted analysis for the Japanese founder variant, a
• For an introduction to multigene panels click
## Suggestive Findings
FCMD
Early-infantile-onset hypotonia and weakness with contractures of the hips, knees, and interphalangeal joints. Muscle weakness is typically progressive with age of onset younger than nine months.
Severe motor and speech delays and intellectual disability with relative preservation of social skills
A static course until early childhood, followed by diffuse and extensive muscle wasting (most prominent proximally) and progressive joint contractures
Myopathic facial appearance
Pseudohypertrophy of the calves and forearms in late infancy
Seizures (febrile and/or nonfebrile)
Ophthalmologic abnormalities, including visual impairment and retinal abnormalities. Retinal abnormalities, when present, are usually mild and focal. Retinal dysplasia, a pathologic diagnosis, is based on the finding of rosettes of immature photoreceptors.
Dysphagia and other swallowing issues
Respiratory issues
Cardiomyopathy
Cortical malformations including, classically, cobblestone lissencephaly with an irregular or pebbled brain surface; broad gyri with a thick cortex (pachygyria) in the frontal, parietal, and temporal regions; and sometimes areas of small and irregular gyri that resemble polymicrogyria
Dilated lateral ventricles
White matter abnormalities with hyperintensity on T
Cerebellar polymicrogyria and cerebellar cysts
Mild brain stem hypoplasia in some individuals
Additional findings include:
The opercula are poorly developed, leaving an open Sylvian fissure.
The cortex is typically no more than approximately 1 cm in thickness.
Age <6 years: 10-60 times above normal
Age ≥7 years: 5-20 times above normal
Bedridden individuals: normal
Findings characteristic of muscular dystrophy. Primary feature is interstitial fibrosis without muscle degeneration and regeneration, which distinguishes FCMD from
Immunohistochemical staining using alpha-dystroglycan antibody reveals selective deficiency of alpha-dystroglycan on the surface membrane of skeletal muscle.
Note: With the advent of molecular genetic testing, a muscle biopsy is no longer necessary to establish the diagnosis of FCMD (see
• Early-infantile-onset hypotonia and weakness with contractures of the hips, knees, and interphalangeal joints. Muscle weakness is typically progressive with age of onset younger than nine months.
• Severe motor and speech delays and intellectual disability with relative preservation of social skills
• A static course until early childhood, followed by diffuse and extensive muscle wasting (most prominent proximally) and progressive joint contractures
• Myopathic facial appearance
• Pseudohypertrophy of the calves and forearms in late infancy
• Seizures (febrile and/or nonfebrile)
• Ophthalmologic abnormalities, including visual impairment and retinal abnormalities. Retinal abnormalities, when present, are usually mild and focal. Retinal dysplasia, a pathologic diagnosis, is based on the finding of rosettes of immature photoreceptors.
• Dysphagia and other swallowing issues
• Respiratory issues
• Cardiomyopathy
• Cortical malformations including, classically, cobblestone lissencephaly with an irregular or pebbled brain surface; broad gyri with a thick cortex (pachygyria) in the frontal, parietal, and temporal regions; and sometimes areas of small and irregular gyri that resemble polymicrogyria
• Dilated lateral ventricles
• White matter abnormalities with hyperintensity on T
• Cerebellar polymicrogyria and cerebellar cysts
• Mild brain stem hypoplasia in some individuals
• The opercula are poorly developed, leaving an open Sylvian fissure.
• The cortex is typically no more than approximately 1 cm in thickness.
• Age <6 years: 10-60 times above normal
• Age ≥7 years: 5-20 times above normal
• Bedridden individuals: normal
• Findings characteristic of muscular dystrophy. Primary feature is interstitial fibrosis without muscle degeneration and regeneration, which distinguishes FCMD from
• Immunohistochemical staining using alpha-dystroglycan antibody reveals selective deficiency of alpha-dystroglycan on the surface membrane of skeletal muscle.
## Establishing the Diagnosis
The diagnosis of FCMD
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FCMD is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of FCMD, molecular genetic testing approaches can include
Note: (1) In individuals of Japanese, Korean, and/or Chinese ancestry, targeted analysis for the Japanese founder variant, a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by muscular dystrophy,
Note: While most reported pathogenic
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fukuyama Congenital Muscular Dystrophy
See
See
Generally, targeted analysis with allele-specific PCR [
In an analysis of 62 Japanese individuals with FCMD, 54 (87%) had the 3062 bp-insertion founder variant; 42(78%) were homozygous for the 3062-bp insertion founder variant and 12 (22%) were compound heterozygous, including three (6%) who were compound heterozygous with the
In an analysis of 13 Korean individuals with FCMD, three (23%) were homozygous for the 3062-bp insertion founder variant and seven (54%) were compound heterozygous for the 3062-bp insertion founder variant, including five (38%) who were compound heterozygous with c.648-1243G>T [
Three reported affected individuals were from China [
In individuals of Japanese ancestry, 6% (3/54) [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• Note: (1) In individuals of Japanese, Korean, and/or Chinese ancestry, targeted analysis for the Japanese founder variant, a
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of FCMD, molecular genetic testing approaches can include
Note: (1) In individuals of Japanese, Korean, and/or Chinese ancestry, targeted analysis for the Japanese founder variant, a
For an introduction to multigene panels click
• Note: (1) In individuals of Japanese, Korean, and/or Chinese ancestry, targeted analysis for the Japanese founder variant, a
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by muscular dystrophy,
Note: While most reported pathogenic
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fukuyama Congenital Muscular Dystrophy
See
See
Generally, targeted analysis with allele-specific PCR [
In an analysis of 62 Japanese individuals with FCMD, 54 (87%) had the 3062 bp-insertion founder variant; 42(78%) were homozygous for the 3062-bp insertion founder variant and 12 (22%) were compound heterozygous, including three (6%) who were compound heterozygous with the
In an analysis of 13 Korean individuals with FCMD, three (23%) were homozygous for the 3062-bp insertion founder variant and seven (54%) were compound heterozygous for the 3062-bp insertion founder variant, including five (38%) who were compound heterozygous with c.648-1243G>T [
Three reported affected individuals were from China [
In individuals of Japanese ancestry, 6% (3/54) [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
## Clinical Characteristics
Fukuyama congenital muscular dystrophy (FCMD) is characterized by dystrophic changes in the skeletal muscle and by central nervous system migration abnormalities resulting in cerebral and cerebellar cortical dysplasia. Clinical manifestations include hypotonia, weakness, and neurodevelopmental delays. Mild, typical, and severe phenotypes are recognized. The phenotypic spectrum ranges from a Walker-Warburg syndrome-like phenotype at the severe end [
To date, at least 500 individuals have been identified with biallelic pathogenic variants in
Fukuyama Congenital Muscular Dystrophy: Frequency of Select Features
Myopia: 7/11, 10/33 (30%), 18/207 (8.6%)
Optic nerve atrophy: 5/11, 12/33 (36%), 2/207 (1%)
Retinal detachment: 1/33 (3%), 2/207 (1%)
GERD = gastroesophageal reflux;
Myopia is a relatively common ophthalmologic finding in FCMD; in severe phenotypes, the prevalence of retinal abnormalities is high [
Predominantly proximal hypotonia manifests as hyperextensibility of the shoulders and trunk. Limitation of hip extension, hip abduction, and knee extension is also observed and increases with time. "Puffy" cheeks and pseudohypertrophy of the calves and forearms are evident in late infancy. Up to age three years, the cheeks are round, enlarged, and hard to the touch, and the skin above the cheeks appears shiny, but afterward they become atrophic. Deep tendon reflexes are diminished or absent after early infancy. Facial muscle involvement (myopathic facies) is obvious from age six to 12 months and increases with age [
In a few individuals with severe FCMD confirmed with molecular genetic testing, severe ocular anomalies include microphthalmia, retinal detachment, retinal hypoplasia, cataracts, and glaucoma [
Infants can have extensive areas of pachygyria involving both cerebral hemispheres, a feature that is more prominent over the frontal and temporal lobes than the parietal and occipital lobes.
Cerebellar cysts, lined with the molecular layer and containing leptomeningeal tissue, were observed beneath the malformed cerebellar cortex or areas of polymicrogyria [
In juvenile and adult cases, agyric areas are more focal and restricted to the occipital lobes. Lissencephalic or agyric areas of malformed cortex may alternate with regions of polymicrogyria, based on fusion of gyri and excessive migration of glio-mesenchymal tissue extending into the subarachnoid space.
A malformed or flat ventral surface of the medulla caused by secondary hypoplasia associated with a small basis pontis and grooves in the spinal cord has been observed [
In fetal cases, neurons and glia migrate through focal defects in the glia limitans, forming verrucous nodules, the initial manifestation of cortical dysplasia. Thus, the overmigration of central nervous system parenchyma into subarachnoid spaces is a pathologic process that is considered essential to the development of cortical dysplasia [
FCMD is classified into three clinical types based on the individual's maximum motor abilities. (1) The
FCMD is pan ethnic but is most common in individuals of Japanese ancestry. FCMD is second in prevalence to DMD among all subtypes of childhood progressive muscular dystrophy in Japan, with an incidence of 0.7-1.2 in 10,000 births. Chromosomes bearing the
The average occurrence of heterozygous carriers identified in various regions of Japan is estimated to be one in 188. However, in Korean populations, one carrier was detected in 935 individuals, and researchers were unable to detect any heterozygous pathogenic variants in 203 individuals of Mongolian ancestry and 766 individuals from mainland China [
• Myopia: 7/11, 10/33 (30%), 18/207 (8.6%)
• Optic nerve atrophy: 5/11, 12/33 (36%), 2/207 (1%)
• Retinal detachment: 1/33 (3%), 2/207 (1%)
## Clinical Description
Fukuyama congenital muscular dystrophy (FCMD) is characterized by dystrophic changes in the skeletal muscle and by central nervous system migration abnormalities resulting in cerebral and cerebellar cortical dysplasia. Clinical manifestations include hypotonia, weakness, and neurodevelopmental delays. Mild, typical, and severe phenotypes are recognized. The phenotypic spectrum ranges from a Walker-Warburg syndrome-like phenotype at the severe end [
To date, at least 500 individuals have been identified with biallelic pathogenic variants in
Fukuyama Congenital Muscular Dystrophy: Frequency of Select Features
Myopia: 7/11, 10/33 (30%), 18/207 (8.6%)
Optic nerve atrophy: 5/11, 12/33 (36%), 2/207 (1%)
Retinal detachment: 1/33 (3%), 2/207 (1%)
GERD = gastroesophageal reflux;
Myopia is a relatively common ophthalmologic finding in FCMD; in severe phenotypes, the prevalence of retinal abnormalities is high [
Predominantly proximal hypotonia manifests as hyperextensibility of the shoulders and trunk. Limitation of hip extension, hip abduction, and knee extension is also observed and increases with time. "Puffy" cheeks and pseudohypertrophy of the calves and forearms are evident in late infancy. Up to age three years, the cheeks are round, enlarged, and hard to the touch, and the skin above the cheeks appears shiny, but afterward they become atrophic. Deep tendon reflexes are diminished or absent after early infancy. Facial muscle involvement (myopathic facies) is obvious from age six to 12 months and increases with age [
In a few individuals with severe FCMD confirmed with molecular genetic testing, severe ocular anomalies include microphthalmia, retinal detachment, retinal hypoplasia, cataracts, and glaucoma [
Infants can have extensive areas of pachygyria involving both cerebral hemispheres, a feature that is more prominent over the frontal and temporal lobes than the parietal and occipital lobes.
Cerebellar cysts, lined with the molecular layer and containing leptomeningeal tissue, were observed beneath the malformed cerebellar cortex or areas of polymicrogyria [
In juvenile and adult cases, agyric areas are more focal and restricted to the occipital lobes. Lissencephalic or agyric areas of malformed cortex may alternate with regions of polymicrogyria, based on fusion of gyri and excessive migration of glio-mesenchymal tissue extending into the subarachnoid space.
A malformed or flat ventral surface of the medulla caused by secondary hypoplasia associated with a small basis pontis and grooves in the spinal cord has been observed [
In fetal cases, neurons and glia migrate through focal defects in the glia limitans, forming verrucous nodules, the initial manifestation of cortical dysplasia. Thus, the overmigration of central nervous system parenchyma into subarachnoid spaces is a pathologic process that is considered essential to the development of cortical dysplasia [
• Myopia: 7/11, 10/33 (30%), 18/207 (8.6%)
• Optic nerve atrophy: 5/11, 12/33 (36%), 2/207 (1%)
• Retinal detachment: 1/33 (3%), 2/207 (1%)
## Genotype-Phenotype Correlations
FCMD is classified into three clinical types based on the individual's maximum motor abilities. (1) The
## Prevalence
FCMD is pan ethnic but is most common in individuals of Japanese ancestry. FCMD is second in prevalence to DMD among all subtypes of childhood progressive muscular dystrophy in Japan, with an incidence of 0.7-1.2 in 10,000 births. Chromosomes bearing the
The average occurrence of heterozygous carriers identified in various regions of Japan is estimated to be one in 188. However, in Korean populations, one carrier was detected in 935 individuals, and researchers were unable to detect any heterozygous pathogenic variants in 203 individuals of Mongolian ancestry and 766 individuals from mainland China [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Fukuyama congenital muscular dystrophy, WWS, & muscle-eye-brain disease have been consolidated under the single designation "congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (MDDGA)" in OMIM, given the phenotypic and molecular overlap between these entities (see
## Differential Diagnosis
Fukuyama congenital muscular dystrophy (FCMD) is one of the
Alpha-dystroglycanopathies (see
CMD type 1A (see
Congenital myopathy 3 with rigid spine (associated with pathogenic variants in
Ullrich CMD (see
The three major phenotypes of the
FCMD;
Walker-Warburg syndrome (WWS);
Muscle-eye-brain disease (MEBD).
The alpha-dystroglycanopathies are characterized by CMD associated with characteristic brain malformations (cobblestone lissencephaly and cerebellar malformations), eye malformations (typically involving the retina), profound intellectual disability, and early death. These entities have been consolidated under the single designation "congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (MDDGA)" in OMIM. FCMD is milder than WWS and MEBD, particularly with respect to brain and ophthalmologic involvement [
Distinguishing Features Between the Major Phenotypes of the Alpha-Dystroglycanopathies: FCMD, MEBD, and WWS
FCMD = Fukuyama congenital muscular dystrophy; ID = intellectual disability; MD = muscle dystrophy; MEBD = muscle-eye-brain disease; WWS = Walker-Warburg syndrome
Severe congenital myopia, congenital glaucoma, pallor of the optic discs, retinal hypoplasia
Microphthalmia, retinal detachment, retinal hypoplasia, anterior chamber malformation, cataracts
FCMD, MEBD, and WWS: Associated Genes
FCMD = Fukuyama congenital muscular dystrophy; MEBD = muscle-eye-brain disease; WWS = Walker-Warburg syndrome
OMIM
• Alpha-dystroglycanopathies (see
• CMD type 1A (see
• Congenital myopathy 3 with rigid spine (associated with pathogenic variants in
• Ullrich CMD (see
• FCMD;
• Walker-Warburg syndrome (WWS);
• Muscle-eye-brain disease (MEBD).
## Management
No clinical practice guidelines for Fukuyama congenital muscular dystrophy (FCMD) have been published. Consensus statements on standard of care and medical management for congenital muscular dystrophies (CMD) broadly have been published [
To establish the extent of disease and needs in an individual diagnosed with FCMD, the evaluations summarized in
Fukuyama Congenital Muscular Dystrophy: Recommended Evaluations Following Initial Diagnosis
At initial diagnosis & at least once every 3 mos
Prolonged video EEGs may be required to fully characterize seizure burden &/or spells of unclear clinical etiology.
To incl early brain imaging to characterize & assess brain malformation; when hypomyelination is present, eval after 1 year is recommended to check for white matter maturation; when ventricular enlargement is significant, repeat brain imaging to monitor progression of hydrocephalus & indications for surgery is recommended.
To incl motor, adaptive, cognitive, & speech-language evals
Eval for early intervention / special education
To incl eval of aspiration risk, caloric intake, & nutritional status
GERD and gastrointestinal dysmotility, i.e., delayed gastric emptying & constipation, are common.
A videofluoroscopic exam, upper GI exam, & esophageal pH monitoring are performed to evaluate swallowing function & GERD. Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (> 30 minutes/meal), &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
FCMD = Fukuyama congenital muscular dystrophy; GERD = gastroesophageal reflux disease; GI = gastrointestinal; LV = left ventricular; MOI = mode of inheritance; NPPV = non-invasive positive pressure ventilation
Children younger than age 12 months with severe or worsening medical issues (e.g., refractory seizures, severe hypotonia, and respiratory and nutritional issues) should be evaluated at least every three to four months; individuals older than age 12 months who are in stable condition can be evaluated every four to six months [
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for Fukuyama congenital muscular dystrophy. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Fukuyama Congenital Muscular Dystrophy: Treatment of Manifestations
Approach should balance seizure control w/side effects w/goal of limiting number of ASMs.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Stool softeners, prokinetics, osmotic agents, or laxatives as needed. Continuous use of these agents is safe.
Medical &/or surgical treatment for GERD when indicated
Gastrostomy tube placement when indicated to assure adequate caloric intake
PT/OT
Referral for orthopedic surveillance & correction
Vitamin D supplementation if indicated
PT helps maintain & promote mobility & prevent contractures. Orthotics & special adaptive chairs or positioners or other measures may support sitting & mobility.
OT may help improve fine motor skills & oral motor control.
Orthopedic surgery may be indicated for scoliosis &/or large joint displacements. When scoliosis is present, spinal fusion to preserve breathing function & improve sitting balance.
Steroid therapy has been shown to contribute to maintenance & improvement of motor functions in persons w/deteriorating motor function.
Although autistic features are rare, if applicable, therapies to address features of ASD such as ABA can be considered.
Pharmacologic therapies for anxiety
Use of respiratory aids such as NIPPV when indicated
Non-invasive ventilation should be considered, particularly at night, before respiratory distress becomes acute.
Prompt treatment of acute respiratory tract infections is particularly important, as these infections are most common cause of hospital admissions & death in persons w/FCMD. Persons who survive beyond age 20 yrs may require tracheostomy or non-invasive respiratory support.
Appropriate positioning for sleeping, sitting, & standing
Correct fit & use of orthoses
Ensure appropriate social work involvement to connect families w/local resources, respite & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
Referral to community or online family support
ABA = applied behavior analysis; ASD = autism spectrum disorder; ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; NIPPV = nasal intermittent positive pressure ventilator; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Fukuyama Congenital Muscular Dystrophy: Recommended Surveillance
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Low vision services
Retinal observation by fundoscopy
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
See
Search
• At initial diagnosis & at least once every 3 mos
• Prolonged video EEGs may be required to fully characterize seizure burden &/or spells of unclear clinical etiology.
• To incl early brain imaging to characterize & assess brain malformation; when hypomyelination is present, eval after 1 year is recommended to check for white matter maturation; when ventricular enlargement is significant, repeat brain imaging to monitor progression of hydrocephalus & indications for surgery is recommended.
• To incl motor, adaptive, cognitive, & speech-language evals
• Eval for early intervention / special education
• To incl eval of aspiration risk, caloric intake, & nutritional status
• GERD and gastrointestinal dysmotility, i.e., delayed gastric emptying & constipation, are common.
• A videofluoroscopic exam, upper GI exam, & esophageal pH monitoring are performed to evaluate swallowing function & GERD. Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (> 30 minutes/meal), &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Approach should balance seizure control w/side effects w/goal of limiting number of ASMs.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Stool softeners, prokinetics, osmotic agents, or laxatives as needed. Continuous use of these agents is safe.
• Medical &/or surgical treatment for GERD when indicated
• Gastrostomy tube placement when indicated to assure adequate caloric intake
• PT/OT
• Referral for orthopedic surveillance & correction
• Vitamin D supplementation if indicated
• PT helps maintain & promote mobility & prevent contractures. Orthotics & special adaptive chairs or positioners or other measures may support sitting & mobility.
• OT may help improve fine motor skills & oral motor control.
• Orthopedic surgery may be indicated for scoliosis &/or large joint displacements. When scoliosis is present, spinal fusion to preserve breathing function & improve sitting balance.
• Steroid therapy has been shown to contribute to maintenance & improvement of motor functions in persons w/deteriorating motor function.
• Although autistic features are rare, if applicable, therapies to address features of ASD such as ABA can be considered.
• Pharmacologic therapies for anxiety
• Use of respiratory aids such as NIPPV when indicated
• Non-invasive ventilation should be considered, particularly at night, before respiratory distress becomes acute.
• Prompt treatment of acute respiratory tract infections is particularly important, as these infections are most common cause of hospital admissions & death in persons w/FCMD. Persons who survive beyond age 20 yrs may require tracheostomy or non-invasive respiratory support.
• Appropriate positioning for sleeping, sitting, & standing
• Correct fit & use of orthoses
• Ensure appropriate social work involvement to connect families w/local resources, respite & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• Referral to community or online family support
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Low vision services
• Retinal observation by fundoscopy
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with FCMD, the evaluations summarized in
Fukuyama Congenital Muscular Dystrophy: Recommended Evaluations Following Initial Diagnosis
At initial diagnosis & at least once every 3 mos
Prolonged video EEGs may be required to fully characterize seizure burden &/or spells of unclear clinical etiology.
To incl early brain imaging to characterize & assess brain malformation; when hypomyelination is present, eval after 1 year is recommended to check for white matter maturation; when ventricular enlargement is significant, repeat brain imaging to monitor progression of hydrocephalus & indications for surgery is recommended.
To incl motor, adaptive, cognitive, & speech-language evals
Eval for early intervention / special education
To incl eval of aspiration risk, caloric intake, & nutritional status
GERD and gastrointestinal dysmotility, i.e., delayed gastric emptying & constipation, are common.
A videofluoroscopic exam, upper GI exam, & esophageal pH monitoring are performed to evaluate swallowing function & GERD. Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (> 30 minutes/meal), &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
FCMD = Fukuyama congenital muscular dystrophy; GERD = gastroesophageal reflux disease; GI = gastrointestinal; LV = left ventricular; MOI = mode of inheritance; NPPV = non-invasive positive pressure ventilation
Children younger than age 12 months with severe or worsening medical issues (e.g., refractory seizures, severe hypotonia, and respiratory and nutritional issues) should be evaluated at least every three to four months; individuals older than age 12 months who are in stable condition can be evaluated every four to six months [
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• At initial diagnosis & at least once every 3 mos
• Prolonged video EEGs may be required to fully characterize seizure burden &/or spells of unclear clinical etiology.
• To incl early brain imaging to characterize & assess brain malformation; when hypomyelination is present, eval after 1 year is recommended to check for white matter maturation; when ventricular enlargement is significant, repeat brain imaging to monitor progression of hydrocephalus & indications for surgery is recommended.
• To incl motor, adaptive, cognitive, & speech-language evals
• Eval for early intervention / special education
• To incl eval of aspiration risk, caloric intake, & nutritional status
• GERD and gastrointestinal dysmotility, i.e., delayed gastric emptying & constipation, are common.
• A videofluoroscopic exam, upper GI exam, & esophageal pH monitoring are performed to evaluate swallowing function & GERD. Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (> 30 minutes/meal), &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for Fukuyama congenital muscular dystrophy. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Fukuyama Congenital Muscular Dystrophy: Treatment of Manifestations
Approach should balance seizure control w/side effects w/goal of limiting number of ASMs.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Stool softeners, prokinetics, osmotic agents, or laxatives as needed. Continuous use of these agents is safe.
Medical &/or surgical treatment for GERD when indicated
Gastrostomy tube placement when indicated to assure adequate caloric intake
PT/OT
Referral for orthopedic surveillance & correction
Vitamin D supplementation if indicated
PT helps maintain & promote mobility & prevent contractures. Orthotics & special adaptive chairs or positioners or other measures may support sitting & mobility.
OT may help improve fine motor skills & oral motor control.
Orthopedic surgery may be indicated for scoliosis &/or large joint displacements. When scoliosis is present, spinal fusion to preserve breathing function & improve sitting balance.
Steroid therapy has been shown to contribute to maintenance & improvement of motor functions in persons w/deteriorating motor function.
Although autistic features are rare, if applicable, therapies to address features of ASD such as ABA can be considered.
Pharmacologic therapies for anxiety
Use of respiratory aids such as NIPPV when indicated
Non-invasive ventilation should be considered, particularly at night, before respiratory distress becomes acute.
Prompt treatment of acute respiratory tract infections is particularly important, as these infections are most common cause of hospital admissions & death in persons w/FCMD. Persons who survive beyond age 20 yrs may require tracheostomy or non-invasive respiratory support.
Appropriate positioning for sleeping, sitting, & standing
Correct fit & use of orthoses
Ensure appropriate social work involvement to connect families w/local resources, respite & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
Referral to community or online family support
ABA = applied behavior analysis; ASD = autism spectrum disorder; ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; NIPPV = nasal intermittent positive pressure ventilator; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Approach should balance seizure control w/side effects w/goal of limiting number of ASMs.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Stool softeners, prokinetics, osmotic agents, or laxatives as needed. Continuous use of these agents is safe.
• Medical &/or surgical treatment for GERD when indicated
• Gastrostomy tube placement when indicated to assure adequate caloric intake
• PT/OT
• Referral for orthopedic surveillance & correction
• Vitamin D supplementation if indicated
• PT helps maintain & promote mobility & prevent contractures. Orthotics & special adaptive chairs or positioners or other measures may support sitting & mobility.
• OT may help improve fine motor skills & oral motor control.
• Orthopedic surgery may be indicated for scoliosis &/or large joint displacements. When scoliosis is present, spinal fusion to preserve breathing function & improve sitting balance.
• Steroid therapy has been shown to contribute to maintenance & improvement of motor functions in persons w/deteriorating motor function.
• Although autistic features are rare, if applicable, therapies to address features of ASD such as ABA can be considered.
• Pharmacologic therapies for anxiety
• Use of respiratory aids such as NIPPV when indicated
• Non-invasive ventilation should be considered, particularly at night, before respiratory distress becomes acute.
• Prompt treatment of acute respiratory tract infections is particularly important, as these infections are most common cause of hospital admissions & death in persons w/FCMD. Persons who survive beyond age 20 yrs may require tracheostomy or non-invasive respiratory support.
• Appropriate positioning for sleeping, sitting, & standing
• Correct fit & use of orthoses
• Ensure appropriate social work involvement to connect families w/local resources, respite & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• Referral to community or online family support
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Fukuyama Congenital Muscular Dystrophy: Recommended Surveillance
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Low vision services
Retinal observation by fundoscopy
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Low vision services
• Retinal observation by fundoscopy
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Fukuyama congenital muscular dystrophy (FCMD) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestral background. Founder variants have been identified in Japanese, Korean, and Chinese populations (see
Once the
Note: In families segregating the 3062-bp insertion (nt.5889) Japanese founder variant, prenatal testing using haplotype analysis is considered the most accurate method for prenatal testing [K Saito, personal observation]. In Japanese individuals, as detection of the ancestral haplotype facilitates the most accurate prenatal diagnosis of FCMD, prenatal diagnosis is performed by haplotype analysis by markers closest to the gene using fetal DNA from chorionic villus sampling (CVS) at 10-12 weeks' gestation [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestral background. Founder variants have been identified in Japanese, Korean, and Chinese populations (see
## Mode of Inheritance
Fukuyama congenital muscular dystrophy (FCMD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestral background. Founder variants have been identified in Japanese, Korean, and Chinese populations (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestral background. Founder variants have been identified in Japanese, Korean, and Chinese populations (see
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Note: In families segregating the 3062-bp insertion (nt.5889) Japanese founder variant, prenatal testing using haplotype analysis is considered the most accurate method for prenatal testing [K Saito, personal observation]. In Japanese individuals, as detection of the ancestral haplotype facilitates the most accurate prenatal diagnosis of FCMD, prenatal diagnosis is performed by haplotype analysis by markers closest to the gene using fetal DNA from chorionic villus sampling (CVS) at 10-12 weeks' gestation [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Japan
United Kingdom
CMDIR/Cure CMD
•
•
•
•
•
• Japan
•
•
•
•
• United Kingdom
•
•
•
• CMDIR/Cure CMD
•
## Molecular Genetics
Fukuyama Congenital Muscular Dystrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Fukuyama Congenital Muscular Dystrophy (
The dystroglycanopathy genes
Dystroglycans bind to laminin in the basement membrane via sugar chains outside the cell and bind to dystrophin inside the cell, thereby linking the basement membrane with the cytoskeleton. Glycosylation is required for the binding of alpha-dystroglycan to laminin, so sugar chain abnormalities can disrupt the coordination between laminin (basement membrane), dystroglycan, dystrophin, and actin (cytoskeleton), making muscle fibers vulnerable. The foundation structure for the elongation of sugar chains with laminin-binding ability is ribitol-phosphate. FKTN is a ribitol-phosphate transferase, and in individuals with FCMD, ribitol-phosphate structures are not formed; thus, sugar chains with laminin-binding ability are not formed, leading to disease [
Variants listed in the table have been provided by the author.
A 3-kb retrotransposon insertion of tandemly repeated sequences in the 3' untranslated region [
Also known as
This variant has also been reported in the literature as c.647+2084G>T. This is a deep intronic variant that is predicted to create a pseudoexon between exons 5 and 6 resulting in a frameshift and a premature stop codon [
## Molecular Pathogenesis
The dystroglycanopathy genes
Dystroglycans bind to laminin in the basement membrane via sugar chains outside the cell and bind to dystrophin inside the cell, thereby linking the basement membrane with the cytoskeleton. Glycosylation is required for the binding of alpha-dystroglycan to laminin, so sugar chain abnormalities can disrupt the coordination between laminin (basement membrane), dystroglycan, dystrophin, and actin (cytoskeleton), making muscle fibers vulnerable. The foundation structure for the elongation of sugar chains with laminin-binding ability is ribitol-phosphate. FKTN is a ribitol-phosphate transferase, and in individuals with FCMD, ribitol-phosphate structures are not formed; thus, sugar chains with laminin-binding ability are not formed, leading to disease [
Variants listed in the table have been provided by the author.
A 3-kb retrotransposon insertion of tandemly repeated sequences in the 3' untranslated region [
Also known as
This variant has also been reported in the literature as c.647+2084G>T. This is a deep intronic variant that is predicted to create a pseudoexon between exons 5 and 6 resulting in a frameshift and a premature stop codon [
## Chapter Notes
Diagnostic guidelines have been developed by the Information Center for Specific Pediatric Chronic Diseases, Japan (see
Thanks to Dr Eri Kondo-Iida for her advice, Mr Mamoru Yokomura for genetic testing, and Dr Naoko Sato for her advice on the interpretation of
8 May 2025 (gm) Comprehensive update posted live
3 July 2019 (sw) Comprehensive update posted live
10 May 2012 (me) Comprehensive update posted live
26 January 2006 (me) Review posted live
8 October 2004 (ks) Original submission
• 8 May 2025 (gm) Comprehensive update posted live
• 3 July 2019 (sw) Comprehensive update posted live
• 10 May 2012 (me) Comprehensive update posted live
• 26 January 2006 (me) Review posted live
• 8 October 2004 (ks) Original submission
## Author Notes
Diagnostic guidelines have been developed by the Information Center for Specific Pediatric Chronic Diseases, Japan (see
## Acknowledgements
Thanks to Dr Eri Kondo-Iida for her advice, Mr Mamoru Yokomura for genetic testing, and Dr Naoko Sato for her advice on the interpretation of
## Revision History
8 May 2025 (gm) Comprehensive update posted live
3 July 2019 (sw) Comprehensive update posted live
10 May 2012 (me) Comprehensive update posted live
26 January 2006 (me) Review posted live
8 October 2004 (ks) Original submission
• 8 May 2025 (gm) Comprehensive update posted live
• 3 July 2019 (sw) Comprehensive update posted live
• 10 May 2012 (me) Comprehensive update posted live
• 26 January 2006 (me) Review posted live
• 8 October 2004 (ks) Original submission
## References
Kang PB, Morrison L, Iannaccone ST, Graham RJ, Bönnemann CG, Rutkowski A, Hornyak J, Wang CH, North K, Oskoui M, Getchius TS, Cox JA, Hagen EE, Gronseth G, Griggs RC, et al. Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015;84:1369–78.
Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K, Cohn RD, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R, et al. Consensus statement on standard of care for congenital muscular dystrophies. J Child Neurol. 2010;25:1559–81.
• Kang PB, Morrison L, Iannaccone ST, Graham RJ, Bönnemann CG, Rutkowski A, Hornyak J, Wang CH, North K, Oskoui M, Getchius TS, Cox JA, Hagen EE, Gronseth G, Griggs RC, et al. Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015;84:1369–78.
• Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K, Cohn RD, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R, et al. Consensus statement on standard of care for congenital muscular dystrophies. J Child Neurol. 2010;25:1559–81.
## Published Guidelines / Consensus Statements
Kang PB, Morrison L, Iannaccone ST, Graham RJ, Bönnemann CG, Rutkowski A, Hornyak J, Wang CH, North K, Oskoui M, Getchius TS, Cox JA, Hagen EE, Gronseth G, Griggs RC, et al. Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015;84:1369–78.
Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K, Cohn RD, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R, et al. Consensus statement on standard of care for congenital muscular dystrophies. J Child Neurol. 2010;25:1559–81.
• Kang PB, Morrison L, Iannaccone ST, Graham RJ, Bönnemann CG, Rutkowski A, Hornyak J, Wang CH, North K, Oskoui M, Getchius TS, Cox JA, Hagen EE, Gronseth G, Griggs RC, et al. Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015;84:1369–78.
• Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K, Cohn RD, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R, et al. Consensus statement on standard of care for congenital muscular dystrophies. J Child Neurol. 2010;25:1559–81.
## Literature Cited
Diagnostic algorithm for FCMD
|
[] |
26/1/2006
|
8/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
fd
|
fd
|
[
"Hereditary Sensory and Autonomic Neuropathy Type III (HSAN III)",
"Riley-Day Syndrome",
"Riley-Day Syndrome",
"Hereditary Sensory and Autonomic Neuropathy Type III (HSAN III)",
"Elongator complex protein 1",
"ELP1",
"Familial Dysautonomia"
] |
Familial Dysautonomia
|
Bat-El Bar-Aluma
|
Summary Familial dysautonomia, which affects the development and survival of sensory, sympathetic, and parasympathetic neurons, is a debilitating disorder present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability. Hypotonia contributes to delay in acquisition of motor milestones. Optic neuropathy results in progressive vision loss. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased. The diagnosis of familial dysautonomia is established in a proband with suggestive findings and biallelic pathogenic variants in Familial dysautonomia is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
The five cardinal clinical diagnostic criteria for familial dysautonomia are absence of fungiform papillae on the tongue, absence of flare after injection of intradermal histamine, decreased or absent deep-tendon reflexes, absence of overflow emotional tears, and Ashkenazi Jewish descent [
Gastrointestinal dysfunction with vomiting crises
Recurrent aspiration pneumonia
Altered sensitivity to pain and temperature
Extreme blood pressure variability with postural hypotension
Hypotonia
Decreased or absent deep tendon reflexes
Decreased taste and absence of fungiform papillae of the tongue, giving it a smooth, pale appearance
Absence of overflow tears with emotional crying (alacrima) determined either by history in infants older than age three months or the Schirmer test (See
The diagnosis of familial dysautonomia is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
In individuals of Ashkenazi Jewish heritage, targeted analysis for the
For an introduction to multigene panels click
When the diagnosis of familial dysautonomia has not been considered because an individual has atypical phenotypic features and/or is not known to have Ashkenazi Jewish heritage,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Dysautonomia
See
See
For pathogenic variants
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Gastrointestinal dysfunction with vomiting crises
• Recurrent aspiration pneumonia
• Altered sensitivity to pain and temperature
• Extreme blood pressure variability with postural hypotension
• Hypotonia
• Decreased or absent deep tendon reflexes
• Decreased taste and absence of fungiform papillae of the tongue, giving it a smooth, pale appearance
• Absence of overflow tears with emotional crying (alacrima) determined either by history in infants older than age three months or the Schirmer test (See
## Suggestive Findings
Gastrointestinal dysfunction with vomiting crises
Recurrent aspiration pneumonia
Altered sensitivity to pain and temperature
Extreme blood pressure variability with postural hypotension
Hypotonia
Decreased or absent deep tendon reflexes
Decreased taste and absence of fungiform papillae of the tongue, giving it a smooth, pale appearance
Absence of overflow tears with emotional crying (alacrima) determined either by history in infants older than age three months or the Schirmer test (See
• Gastrointestinal dysfunction with vomiting crises
• Recurrent aspiration pneumonia
• Altered sensitivity to pain and temperature
• Extreme blood pressure variability with postural hypotension
• Hypotonia
• Decreased or absent deep tendon reflexes
• Decreased taste and absence of fungiform papillae of the tongue, giving it a smooth, pale appearance
• Absence of overflow tears with emotional crying (alacrima) determined either by history in infants older than age three months or the Schirmer test (See
## Establishing the Diagnosis
The diagnosis of familial dysautonomia is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
In individuals of Ashkenazi Jewish heritage, targeted analysis for the
For an introduction to multigene panels click
When the diagnosis of familial dysautonomia has not been considered because an individual has atypical phenotypic features and/or is not known to have Ashkenazi Jewish heritage,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Dysautonomia
See
See
For pathogenic variants
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
In individuals of Ashkenazi Jewish heritage, targeted analysis for the
For an introduction to multigene panels click
## Option 2
When the diagnosis of familial dysautonomia has not been considered because an individual has atypical phenotypic features and/or is not known to have Ashkenazi Jewish heritage,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Dysautonomia
See
See
For pathogenic variants
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (I.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and cardiovascular instability. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased [
Clinical Manifestations of Familial Dysautonomia
Oropharyngeal incoordination (60% of neonates)
Esophageal dysmotility, GERD
Insensitivity to hypercapnia and hypoxia
Breath holding
Orthostatic hypotension w/o compensatory tachycardia
Supine hypertension
Autonomic crises (i.e., hypertensive vomiting attacks) (40%)
Insensitivity to pain (sparing hands, soles of feet, neck, & genital areas)
Abnormal temperature perception on trunk & lower extremities
Depressed patellar reflexes
Hypotonia
Mild/moderate motor DD
Broad-based or mildly ataxic gait
Spinal curvature (95%; esp kyphosis)
Absence of overflow tears
Depressed corneal reflexes
Optic nerve atrophy
Strabismus
Deficient taste, esp sweet
Dysarthric, nasal speech
Chronic aspiration & recurrent aspiration pneumonia
Suppurative lung disease & bronchiectasis
Restrictive lung disease
Upper-airway obstruction due to cranial dimorphism & ↓ muscle tone of pharyngeal muscles, → obstructive sleep apnea
Obstructive lung disease & airway hyperreactivity
Sleep-disordered breathing (obstructive & central sleep apnea)
Daytime hypoventilation
CKD w/histopathologic features of chronic hypertensive nephrosclerosis
Tubular atrophy
Lack of sympathetic innervation of renal vasculature
↑ incidence of rare kidney malformations & hydronephrosis
Usually normal intellect (verbal skills better than motor)
Concrete or literal thinking
Skin picking (esp fingers & nose)
Resistance to change (phobias)
Adapted from
CKD = chronic kidney disease; DD = developmental delay; GERD = gastroesophageal reflux disease
Progressive neurologic abnormalities
Most infants with familial dysautonomia are born after an uncomplicated term pregnancy. However, there is an increased rate of polyhydramnios and breech presentation.
Infants with FD may have difficulties maintaining normal body temperature and may be indifferent to pain stimuli.
Sympathetic nervous system involvement results in orthostatic hypotension that is exacerbated by exercise and warm environments. Syncope is surprisingly infrequent, and usually indicates volume depletion, anemia, or hypoxia.
Urinary stress incontinence is common in adolescent and adult women [
Episodic somnolence has been reported.
Autonomic crises, also described as hypertensive vomiting attacks, occur in about 40% of individuals. Attacks occur when stimuli increase sympathetic outflow causing an uncontrolled release of catecholamines (neurotransmitters such as epinephrine and dopamine) into the circulation. Common triggers include emotion, illness, abdominal discomfort, and bladder distension; however, sometimes the crises are unpredictable and without obvious cause. Dopamine, which is believed to activate receptors in the chemoreceptor trigger zone of the area postrema (located in the medulla oblongata), cause cyclic vomiting (or retching in persons who have undergone fundoplication). These dopaminergic crises can also be associated with tachycardia, hyperhidrosis, irritability, and personality changes. Crises may last several days.
Older individuals often have a broad-based, ataxic gait that progressively deteriorates over time. Individuals with FD have difficulty performing rapid movements and maintaining their balance while changing direction or turning. By age 20 years 3% of affected individuals require assistance walking; this percentage increases linearly to 14% by age 30 years, 27% by age 40 years, and 49% by age 50 years [
The major cause of visual loss in FD is optic neuropathy affecting mostly the P-type retinal ganglion cells. Beginning early in life, all individuals with FD experience progressive loss of retinal ganglion cell axons. The temporal retinal nerve fiber layer (RNFL) is the most affected. The less energy-dependent ganglion cells are relatively spared, whereas the more energy-dependent maculopapillary ganglion cells are selectively damaged [
Eye movement disorders such as strabismus are very common.
Although most individuals undergo gastrostomy with Nissen fundoplication upon diagnosis, recurrent lower-airway infections remain common. Most individuals with FD develop chronic lung disease secondary to recurrent aspiration. CT imaging of the lungs shows bronchiectasis in 26% of affected individuals.
Lack of input from the peripheral chemoreceptors results in almost absent ventilatory responses to hypoxemia; the chemoreceptor ventilatory responses to hypercapnia are also reduced, but to a lesser extent.
The majority of children and adults with FD have some degree of sleep-disordered breathing. Central apnea is more frequent in children; obstructive apnea is more frequent in adults.
The increased incidence of sudden death during sleep can be attributed to the following risk factors: treatment with fludrocortisone, plasma potassium concentrations <4 mEq/L, and untreated sleep apnea [
Baroreflex failure, manifest as excessive increases or decreases in blood pressure with wide fluctuations, is associated with a faster progression of renal disease. Some individuals progress to end-stage renal disease and may require dialysis. A few renal transplants have been performed.
Renal tubular acidosis, requiring treatment, is common. Hyperkalemia, which is also common, is not always explained by the degree of renal insufficiency.
There is also an increased incidence of congenital renal defects, including a single kidney, horseshoe kidney, and crossed renal ectopia (i.e., a kidney that has crossed from its side to the other side such that the kidneys are both located on one side of the body) [
Although poor linear growth velocity, low-to-normal insulin-like growth factor-I (IGFI) levels, and delayed skeletal age are reported in FD, challenge tests for growth hormone deficiency have been inconclusive. Growth hormone treatment in individuals in an open-label study resulted in growth velocity that exceeded pre-treatment rates in 12 of the 13 treated individuals [
No genotype-phenotype correlations have been observed [
The
The incidence of FD among the Ashkenazim is 1:3,700 live births, which corresponds to a carrier frequency of 1:36 [
A study by
• Oropharyngeal incoordination (60% of neonates)
• Esophageal dysmotility, GERD
• Insensitivity to hypercapnia and hypoxia
• Breath holding
• Orthostatic hypotension w/o compensatory tachycardia
• Supine hypertension
• Autonomic crises (i.e., hypertensive vomiting attacks) (40%)
• Insensitivity to pain (sparing hands, soles of feet, neck, & genital areas)
• Abnormal temperature perception on trunk & lower extremities
• Depressed patellar reflexes
• Hypotonia
• Mild/moderate motor DD
• Broad-based or mildly ataxic gait
• Spinal curvature (95%; esp kyphosis)
• Absence of overflow tears
• Depressed corneal reflexes
• Optic nerve atrophy
• Strabismus
• Deficient taste, esp sweet
• Dysarthric, nasal speech
• Chronic aspiration & recurrent aspiration pneumonia
• Suppurative lung disease & bronchiectasis
• Restrictive lung disease
• Upper-airway obstruction due to cranial dimorphism & ↓ muscle tone of pharyngeal muscles, → obstructive sleep apnea
• Obstructive lung disease & airway hyperreactivity
• Sleep-disordered breathing (obstructive & central sleep apnea)
• Daytime hypoventilation
• CKD w/histopathologic features of chronic hypertensive nephrosclerosis
• Tubular atrophy
• Lack of sympathetic innervation of renal vasculature
• ↑ incidence of rare kidney malformations & hydronephrosis
• Usually normal intellect (verbal skills better than motor)
• Concrete or literal thinking
• Skin picking (esp fingers & nose)
• Resistance to change (phobias)
• Although poor linear growth velocity, low-to-normal insulin-like growth factor-I (IGFI) levels, and delayed skeletal age are reported in FD, challenge tests for growth hormone deficiency have been inconclusive. Growth hormone treatment in individuals in an open-label study resulted in growth velocity that exceeded pre-treatment rates in 12 of the 13 treated individuals [
## Clinical Description
Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (I.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and cardiovascular instability. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased [
Clinical Manifestations of Familial Dysautonomia
Oropharyngeal incoordination (60% of neonates)
Esophageal dysmotility, GERD
Insensitivity to hypercapnia and hypoxia
Breath holding
Orthostatic hypotension w/o compensatory tachycardia
Supine hypertension
Autonomic crises (i.e., hypertensive vomiting attacks) (40%)
Insensitivity to pain (sparing hands, soles of feet, neck, & genital areas)
Abnormal temperature perception on trunk & lower extremities
Depressed patellar reflexes
Hypotonia
Mild/moderate motor DD
Broad-based or mildly ataxic gait
Spinal curvature (95%; esp kyphosis)
Absence of overflow tears
Depressed corneal reflexes
Optic nerve atrophy
Strabismus
Deficient taste, esp sweet
Dysarthric, nasal speech
Chronic aspiration & recurrent aspiration pneumonia
Suppurative lung disease & bronchiectasis
Restrictive lung disease
Upper-airway obstruction due to cranial dimorphism & ↓ muscle tone of pharyngeal muscles, → obstructive sleep apnea
Obstructive lung disease & airway hyperreactivity
Sleep-disordered breathing (obstructive & central sleep apnea)
Daytime hypoventilation
CKD w/histopathologic features of chronic hypertensive nephrosclerosis
Tubular atrophy
Lack of sympathetic innervation of renal vasculature
↑ incidence of rare kidney malformations & hydronephrosis
Usually normal intellect (verbal skills better than motor)
Concrete or literal thinking
Skin picking (esp fingers & nose)
Resistance to change (phobias)
Adapted from
CKD = chronic kidney disease; DD = developmental delay; GERD = gastroesophageal reflux disease
Progressive neurologic abnormalities
Most infants with familial dysautonomia are born after an uncomplicated term pregnancy. However, there is an increased rate of polyhydramnios and breech presentation.
Infants with FD may have difficulties maintaining normal body temperature and may be indifferent to pain stimuli.
Sympathetic nervous system involvement results in orthostatic hypotension that is exacerbated by exercise and warm environments. Syncope is surprisingly infrequent, and usually indicates volume depletion, anemia, or hypoxia.
Urinary stress incontinence is common in adolescent and adult women [
Episodic somnolence has been reported.
Autonomic crises, also described as hypertensive vomiting attacks, occur in about 40% of individuals. Attacks occur when stimuli increase sympathetic outflow causing an uncontrolled release of catecholamines (neurotransmitters such as epinephrine and dopamine) into the circulation. Common triggers include emotion, illness, abdominal discomfort, and bladder distension; however, sometimes the crises are unpredictable and without obvious cause. Dopamine, which is believed to activate receptors in the chemoreceptor trigger zone of the area postrema (located in the medulla oblongata), cause cyclic vomiting (or retching in persons who have undergone fundoplication). These dopaminergic crises can also be associated with tachycardia, hyperhidrosis, irritability, and personality changes. Crises may last several days.
Older individuals often have a broad-based, ataxic gait that progressively deteriorates over time. Individuals with FD have difficulty performing rapid movements and maintaining their balance while changing direction or turning. By age 20 years 3% of affected individuals require assistance walking; this percentage increases linearly to 14% by age 30 years, 27% by age 40 years, and 49% by age 50 years [
The major cause of visual loss in FD is optic neuropathy affecting mostly the P-type retinal ganglion cells. Beginning early in life, all individuals with FD experience progressive loss of retinal ganglion cell axons. The temporal retinal nerve fiber layer (RNFL) is the most affected. The less energy-dependent ganglion cells are relatively spared, whereas the more energy-dependent maculopapillary ganglion cells are selectively damaged [
Eye movement disorders such as strabismus are very common.
Although most individuals undergo gastrostomy with Nissen fundoplication upon diagnosis, recurrent lower-airway infections remain common. Most individuals with FD develop chronic lung disease secondary to recurrent aspiration. CT imaging of the lungs shows bronchiectasis in 26% of affected individuals.
Lack of input from the peripheral chemoreceptors results in almost absent ventilatory responses to hypoxemia; the chemoreceptor ventilatory responses to hypercapnia are also reduced, but to a lesser extent.
The majority of children and adults with FD have some degree of sleep-disordered breathing. Central apnea is more frequent in children; obstructive apnea is more frequent in adults.
The increased incidence of sudden death during sleep can be attributed to the following risk factors: treatment with fludrocortisone, plasma potassium concentrations <4 mEq/L, and untreated sleep apnea [
Baroreflex failure, manifest as excessive increases or decreases in blood pressure with wide fluctuations, is associated with a faster progression of renal disease. Some individuals progress to end-stage renal disease and may require dialysis. A few renal transplants have been performed.
Renal tubular acidosis, requiring treatment, is common. Hyperkalemia, which is also common, is not always explained by the degree of renal insufficiency.
There is also an increased incidence of congenital renal defects, including a single kidney, horseshoe kidney, and crossed renal ectopia (i.e., a kidney that has crossed from its side to the other side such that the kidneys are both located on one side of the body) [
Although poor linear growth velocity, low-to-normal insulin-like growth factor-I (IGFI) levels, and delayed skeletal age are reported in FD, challenge tests for growth hormone deficiency have been inconclusive. Growth hormone treatment in individuals in an open-label study resulted in growth velocity that exceeded pre-treatment rates in 12 of the 13 treated individuals [
• Oropharyngeal incoordination (60% of neonates)
• Esophageal dysmotility, GERD
• Insensitivity to hypercapnia and hypoxia
• Breath holding
• Orthostatic hypotension w/o compensatory tachycardia
• Supine hypertension
• Autonomic crises (i.e., hypertensive vomiting attacks) (40%)
• Insensitivity to pain (sparing hands, soles of feet, neck, & genital areas)
• Abnormal temperature perception on trunk & lower extremities
• Depressed patellar reflexes
• Hypotonia
• Mild/moderate motor DD
• Broad-based or mildly ataxic gait
• Spinal curvature (95%; esp kyphosis)
• Absence of overflow tears
• Depressed corneal reflexes
• Optic nerve atrophy
• Strabismus
• Deficient taste, esp sweet
• Dysarthric, nasal speech
• Chronic aspiration & recurrent aspiration pneumonia
• Suppurative lung disease & bronchiectasis
• Restrictive lung disease
• Upper-airway obstruction due to cranial dimorphism & ↓ muscle tone of pharyngeal muscles, → obstructive sleep apnea
• Obstructive lung disease & airway hyperreactivity
• Sleep-disordered breathing (obstructive & central sleep apnea)
• Daytime hypoventilation
• CKD w/histopathologic features of chronic hypertensive nephrosclerosis
• Tubular atrophy
• Lack of sympathetic innervation of renal vasculature
• ↑ incidence of rare kidney malformations & hydronephrosis
• Usually normal intellect (verbal skills better than motor)
• Concrete or literal thinking
• Skin picking (esp fingers & nose)
• Resistance to change (phobias)
• Although poor linear growth velocity, low-to-normal insulin-like growth factor-I (IGFI) levels, and delayed skeletal age are reported in FD, challenge tests for growth hormone deficiency have been inconclusive. Growth hormone treatment in individuals in an open-label study resulted in growth velocity that exceeded pre-treatment rates in 12 of the 13 treated individuals [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been observed [
The
## Prevalence
The incidence of FD among the Ashkenazim is 1:3,700 live births, which corresponds to a carrier frequency of 1:36 [
A study by
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes and Disorders of Interest in the Differential Diagnosis
Loss of pain & temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); facultative deafness; no visceral signs of autonomic involvement
Similar to HSN1D
Inability to perceive pain from birth from any noxious stimuli leading to repeated injuries & prevention of normal healing. Painless fractures & joint damage frequently occur & can lead to permanent damage; corneal injuries; anhidrosis that disturbs thermoregulation & can lead to recurrent episodes of unexplained fever (Note: marked hyperhidrosis is observed in assoc w/
Self-mutilating injuries of the fingers (biting off fingertips) & oral cavity (incl loss of the tongue tip, injuries to the inside of the teeth/gums, & avulsion of teeth) are common.
Loss of pain & temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); facultative deafness; no visceral signs of autonomic involvement
Distinguished by hearing loss, dementia, & narcolepsy
Acral ulcero-mutilating sensory neuropathy; sensory loss of all modalities w/a high frequency of foot ulcers necessitating amputations
Motor features are common; distal muscle weakness & wasting are often the 1st & most prominent features.
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; FD = familial dysautonomia; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance; SNHL = sensorineural hearing loss; XL = X-linked
Only one affected family has been reported to date [
• Loss of pain & temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); facultative deafness; no visceral signs of autonomic involvement
• Similar to HSN1D
• Inability to perceive pain from birth from any noxious stimuli leading to repeated injuries & prevention of normal healing. Painless fractures & joint damage frequently occur & can lead to permanent damage; corneal injuries; anhidrosis that disturbs thermoregulation & can lead to recurrent episodes of unexplained fever (Note: marked hyperhidrosis is observed in assoc w/
• Self-mutilating injuries of the fingers (biting off fingertips) & oral cavity (incl loss of the tongue tip, injuries to the inside of the teeth/gums, & avulsion of teeth) are common.
• Loss of pain & temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); facultative deafness; no visceral signs of autonomic involvement
• Distinguished by hearing loss, dementia, & narcolepsy
• Acral ulcero-mutilating sensory neuropathy; sensory loss of all modalities w/a high frequency of foot ulcers necessitating amputations
• Motor features are common; distal muscle weakness & wasting are often the 1st & most prominent features.
## Management
Clinical practice guidelines have been published [
To establish the extent of disease and needs in an individual diagnosed with familial dysautonomia, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Dysautonomia
Comprehensive neurologic exam w/attn to sensory ataxia, abnormalities in proprioception
Positive Romberg sign; ↓ or absent deep tendon & H-reflexes
Consider: (1) MRI if concerns re worsening gait ataxia &/or balance; (2) EEG if concerns re seizures.
To incl motor, adaptive, & cognitive eval
Eval by speech-language pathologist
Eval for early childhood intervention programs / special education
Spirometry & response to bronchodilators may help assess airway obstruction.
Obtain culture from lower airways when clinical evidence suggests suppurative lung disease.
Acute respiratory exacerbation may present w/minimal symptoms despite significant hypoxemia & hypercarbia; because respiratory drive remains depressed even during acute respiratory exacerbations, patients do not appear dyspneic or tachypneic.
Dysautonomic crises may occur during acute respiratory exacerbations & are often the presenting manifestation.
Incl assessment of best corrected visual acuity, cornea for possible injury due to ↓ corneal sensation, fundoscopic exam for evidence of optic atrophy.
Assessment of retina to incl OCT w/measurements of mean RNFL & macular GCIPL thickness
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Need for AFOs, specialized shoes
Mobility, activities of daily living, & need for adaptive devices/durable equipment
↑ saliva flow may ↓ incidence of dental caries, but changes in composition of saliva → more plaque & ↑ in periodontal disease.
Evaluate for dental, gingival, & tongue trauma (usually due to self-mutilation).
Use of community or
Need for social work involvement for parental support.
AFO = ankle/foot orthoses; FD = familial dysautonomia; GCIPL = ganglion cell and inner plexiform layer; MOI = mode of inheritance; OCT = optic coherence tomography; RNFL = retinal nerve fiber layer
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no curative therapy for familial dysautonomia. Treatment is supportive.
Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, speech-language pathologists, pulmonologists, and social workers (see
Treatment of Manifestations in Individuals with Familial Dysautonomia
GH stimulation testing may not be reliable.
Monitor spinal curvature, as it tends to worsen during accelerated growth.
Cough augmentation is most effective in clearing airway mucus & best achieved by mechanical insufflation/exsufflation methods.
Inhaled hypertonic saline may be beneficial.
Treat acute exacerbation promptly w/antibiotics.
Oral antibiotics for 14 days
Initiation of IV antibiotics depends on baseline respiratory status; consider when no improvement after oral antibiotics.
Early diagnosis & treatment of pneumonia & infections (secondary to aspiration)
Treatment w/oseltamivir is indicated for influenza virus infections.
Instructions to manage crises at home w/fluids & medications via gastrostomy
Guidance re when to visit ER for more extensive eval & treatment
Physical countermaneuvers to ↑ venous return & PT to ↑ muscle strength in legs help prevent orthostatic hypotension.
Treatment w/midodrine may be effective for short periods; use as needed prior to physical activity that may cause orthostatic hypotension.
Hydration is useful only for short periods due to impaired osmopressor response (most likely due to ↓ function of peripheral osmosensory pathway).
Adequate control of blood pressure
Treat renal tubular acidosis w/bicarbonate.
Low-potassium diet for hyperkalemia
Soft contact lenses can promote healing.
Tarsorrhaphy only for corneal injury unresponsive to routine measures
Corneal transplantation offers limited success.
AFOs = ankle/foot orthoses; BiPAP = bi-level positive airway pressure; CKD = chronic kidney disease; CPAP = continuous positive airway pressure; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Recommended Surveillance for Individuals with Familial Dysautonomia
In growing children: routinely
In adults: when respiratory function ↓s or respiratory infections ↑
Spirometry before & after bronchodilator challenge to diagnose reversible obstructive disease
Quantitative measure of MIP & MEP to document disease progression & inform mgmt
Annually regardless of previous normal studies
Before & 6-8 weeks after starting growth hormone therapy
Persons w/normal kidney function: annually
Persons w/CKD: per treating nephrologist
BP = blood pressure; GCIPL = ganglion cell and inner plexiform layer; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; OT = occupational therapist; PT = physical therapist; RNFL = retinal nerve fiber layer
Symptoms tend to be worse in hot or humid weather; affected individuals should try to avoid being outdoors in such conditions as much as possible.
Other situations that can exacerbate disease manifestations include a full bladder; frequent visits to the lavatory are recommended [
Since long car rides, coming out of a movie theater, or fatigue can also worsen symptoms, such situations should be avoided as much as possible [
Episodic hypertension can occur in response to emotional stress or visceral pain, and therefore should be avoided when possible [
Environmental situations associated with hypobaric hypoxia (e.g., aircraft flight or ascent to high altitude) pose a potential risk to individuals with daytime hypercapnia [
See
Pregnancies in women with FD are considered high risk because of abrupt changes in blood pressure.
High blood pressure secondary to FD is difficult to differentiate from toxemia or other causes of pregnancy-related high blood pressure.
Awareness of volume loss and low blood pressure is important because of the absence of reflex tachycardia to low blood pressure.
Visceral pain related to contractions during labor is perceived normally; therefore, analgesia should be provided. Epidural anesthesia is preferable due to blood pressure lability during general anesthesia or spinal block [
Search
• Comprehensive neurologic exam w/attn to sensory ataxia, abnormalities in proprioception
• Positive Romberg sign; ↓ or absent deep tendon & H-reflexes
• Consider: (1) MRI if concerns re worsening gait ataxia &/or balance; (2) EEG if concerns re seizures.
• To incl motor, adaptive, & cognitive eval
• Eval by speech-language pathologist
• Eval for early childhood intervention programs / special education
• Spirometry & response to bronchodilators may help assess airway obstruction.
• Obtain culture from lower airways when clinical evidence suggests suppurative lung disease.
• Acute respiratory exacerbation may present w/minimal symptoms despite significant hypoxemia & hypercarbia; because respiratory drive remains depressed even during acute respiratory exacerbations, patients do not appear dyspneic or tachypneic.
• Dysautonomic crises may occur during acute respiratory exacerbations & are often the presenting manifestation.
• Incl assessment of best corrected visual acuity, cornea for possible injury due to ↓ corneal sensation, fundoscopic exam for evidence of optic atrophy.
• Assessment of retina to incl OCT w/measurements of mean RNFL & macular GCIPL thickness
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Need for AFOs, specialized shoes
• Mobility, activities of daily living, & need for adaptive devices/durable equipment
• ↑ saliva flow may ↓ incidence of dental caries, but changes in composition of saliva → more plaque & ↑ in periodontal disease.
• Evaluate for dental, gingival, & tongue trauma (usually due to self-mutilation).
• Use of community or
• Need for social work involvement for parental support.
• GH stimulation testing may not be reliable.
• Monitor spinal curvature, as it tends to worsen during accelerated growth.
• Cough augmentation is most effective in clearing airway mucus & best achieved by mechanical insufflation/exsufflation methods.
• Inhaled hypertonic saline may be beneficial.
• Treat acute exacerbation promptly w/antibiotics.
• Oral antibiotics for 14 days
• Initiation of IV antibiotics depends on baseline respiratory status; consider when no improvement after oral antibiotics.
• Early diagnosis & treatment of pneumonia & infections (secondary to aspiration)
• Treatment w/oseltamivir is indicated for influenza virus infections.
• Instructions to manage crises at home w/fluids & medications via gastrostomy
• Guidance re when to visit ER for more extensive eval & treatment
• Physical countermaneuvers to ↑ venous return & PT to ↑ muscle strength in legs help prevent orthostatic hypotension.
• Treatment w/midodrine may be effective for short periods; use as needed prior to physical activity that may cause orthostatic hypotension.
• Hydration is useful only for short periods due to impaired osmopressor response (most likely due to ↓ function of peripheral osmosensory pathway).
• Adequate control of blood pressure
• Treat renal tubular acidosis w/bicarbonate.
• Low-potassium diet for hyperkalemia
• Soft contact lenses can promote healing.
• Tarsorrhaphy only for corneal injury unresponsive to routine measures
• Corneal transplantation offers limited success.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• In growing children: routinely
• In adults: when respiratory function ↓s or respiratory infections ↑
• Spirometry before & after bronchodilator challenge to diagnose reversible obstructive disease
• Quantitative measure of MIP & MEP to document disease progression & inform mgmt
• Annually regardless of previous normal studies
• Before & 6-8 weeks after starting growth hormone therapy
• Persons w/normal kidney function: annually
• Persons w/CKD: per treating nephrologist
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with familial dysautonomia, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Dysautonomia
Comprehensive neurologic exam w/attn to sensory ataxia, abnormalities in proprioception
Positive Romberg sign; ↓ or absent deep tendon & H-reflexes
Consider: (1) MRI if concerns re worsening gait ataxia &/or balance; (2) EEG if concerns re seizures.
To incl motor, adaptive, & cognitive eval
Eval by speech-language pathologist
Eval for early childhood intervention programs / special education
Spirometry & response to bronchodilators may help assess airway obstruction.
Obtain culture from lower airways when clinical evidence suggests suppurative lung disease.
Acute respiratory exacerbation may present w/minimal symptoms despite significant hypoxemia & hypercarbia; because respiratory drive remains depressed even during acute respiratory exacerbations, patients do not appear dyspneic or tachypneic.
Dysautonomic crises may occur during acute respiratory exacerbations & are often the presenting manifestation.
Incl assessment of best corrected visual acuity, cornea for possible injury due to ↓ corneal sensation, fundoscopic exam for evidence of optic atrophy.
Assessment of retina to incl OCT w/measurements of mean RNFL & macular GCIPL thickness
Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Need for AFOs, specialized shoes
Mobility, activities of daily living, & need for adaptive devices/durable equipment
↑ saliva flow may ↓ incidence of dental caries, but changes in composition of saliva → more plaque & ↑ in periodontal disease.
Evaluate for dental, gingival, & tongue trauma (usually due to self-mutilation).
Use of community or
Need for social work involvement for parental support.
AFO = ankle/foot orthoses; FD = familial dysautonomia; GCIPL = ganglion cell and inner plexiform layer; MOI = mode of inheritance; OCT = optic coherence tomography; RNFL = retinal nerve fiber layer
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Comprehensive neurologic exam w/attn to sensory ataxia, abnormalities in proprioception
• Positive Romberg sign; ↓ or absent deep tendon & H-reflexes
• Consider: (1) MRI if concerns re worsening gait ataxia &/or balance; (2) EEG if concerns re seizures.
• To incl motor, adaptive, & cognitive eval
• Eval by speech-language pathologist
• Eval for early childhood intervention programs / special education
• Spirometry & response to bronchodilators may help assess airway obstruction.
• Obtain culture from lower airways when clinical evidence suggests suppurative lung disease.
• Acute respiratory exacerbation may present w/minimal symptoms despite significant hypoxemia & hypercarbia; because respiratory drive remains depressed even during acute respiratory exacerbations, patients do not appear dyspneic or tachypneic.
• Dysautonomic crises may occur during acute respiratory exacerbations & are often the presenting manifestation.
• Incl assessment of best corrected visual acuity, cornea for possible injury due to ↓ corneal sensation, fundoscopic exam for evidence of optic atrophy.
• Assessment of retina to incl OCT w/measurements of mean RNFL & macular GCIPL thickness
• Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Need for AFOs, specialized shoes
• Mobility, activities of daily living, & need for adaptive devices/durable equipment
• ↑ saliva flow may ↓ incidence of dental caries, but changes in composition of saliva → more plaque & ↑ in periodontal disease.
• Evaluate for dental, gingival, & tongue trauma (usually due to self-mutilation).
• Use of community or
• Need for social work involvement for parental support.
## Treatment of Manifestations
There is no curative therapy for familial dysautonomia. Treatment is supportive.
Affected individuals are often managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical and occupational therapists, speech-language pathologists, pulmonologists, and social workers (see
Treatment of Manifestations in Individuals with Familial Dysautonomia
GH stimulation testing may not be reliable.
Monitor spinal curvature, as it tends to worsen during accelerated growth.
Cough augmentation is most effective in clearing airway mucus & best achieved by mechanical insufflation/exsufflation methods.
Inhaled hypertonic saline may be beneficial.
Treat acute exacerbation promptly w/antibiotics.
Oral antibiotics for 14 days
Initiation of IV antibiotics depends on baseline respiratory status; consider when no improvement after oral antibiotics.
Early diagnosis & treatment of pneumonia & infections (secondary to aspiration)
Treatment w/oseltamivir is indicated for influenza virus infections.
Instructions to manage crises at home w/fluids & medications via gastrostomy
Guidance re when to visit ER for more extensive eval & treatment
Physical countermaneuvers to ↑ venous return & PT to ↑ muscle strength in legs help prevent orthostatic hypotension.
Treatment w/midodrine may be effective for short periods; use as needed prior to physical activity that may cause orthostatic hypotension.
Hydration is useful only for short periods due to impaired osmopressor response (most likely due to ↓ function of peripheral osmosensory pathway).
Adequate control of blood pressure
Treat renal tubular acidosis w/bicarbonate.
Low-potassium diet for hyperkalemia
Soft contact lenses can promote healing.
Tarsorrhaphy only for corneal injury unresponsive to routine measures
Corneal transplantation offers limited success.
AFOs = ankle/foot orthoses; BiPAP = bi-level positive airway pressure; CKD = chronic kidney disease; CPAP = continuous positive airway pressure; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• GH stimulation testing may not be reliable.
• Monitor spinal curvature, as it tends to worsen during accelerated growth.
• Cough augmentation is most effective in clearing airway mucus & best achieved by mechanical insufflation/exsufflation methods.
• Inhaled hypertonic saline may be beneficial.
• Treat acute exacerbation promptly w/antibiotics.
• Oral antibiotics for 14 days
• Initiation of IV antibiotics depends on baseline respiratory status; consider when no improvement after oral antibiotics.
• Early diagnosis & treatment of pneumonia & infections (secondary to aspiration)
• Treatment w/oseltamivir is indicated for influenza virus infections.
• Instructions to manage crises at home w/fluids & medications via gastrostomy
• Guidance re when to visit ER for more extensive eval & treatment
• Physical countermaneuvers to ↑ venous return & PT to ↑ muscle strength in legs help prevent orthostatic hypotension.
• Treatment w/midodrine may be effective for short periods; use as needed prior to physical activity that may cause orthostatic hypotension.
• Hydration is useful only for short periods due to impaired osmopressor response (most likely due to ↓ function of peripheral osmosensory pathway).
• Adequate control of blood pressure
• Treat renal tubular acidosis w/bicarbonate.
• Low-potassium diet for hyperkalemia
• Soft contact lenses can promote healing.
• Tarsorrhaphy only for corneal injury unresponsive to routine measures
• Corneal transplantation offers limited success.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
Recommended Surveillance for Individuals with Familial Dysautonomia
In growing children: routinely
In adults: when respiratory function ↓s or respiratory infections ↑
Spirometry before & after bronchodilator challenge to diagnose reversible obstructive disease
Quantitative measure of MIP & MEP to document disease progression & inform mgmt
Annually regardless of previous normal studies
Before & 6-8 weeks after starting growth hormone therapy
Persons w/normal kidney function: annually
Persons w/CKD: per treating nephrologist
BP = blood pressure; GCIPL = ganglion cell and inner plexiform layer; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; OT = occupational therapist; PT = physical therapist; RNFL = retinal nerve fiber layer
• In growing children: routinely
• In adults: when respiratory function ↓s or respiratory infections ↑
• Spirometry before & after bronchodilator challenge to diagnose reversible obstructive disease
• Quantitative measure of MIP & MEP to document disease progression & inform mgmt
• Annually regardless of previous normal studies
• Before & 6-8 weeks after starting growth hormone therapy
• Persons w/normal kidney function: annually
• Persons w/CKD: per treating nephrologist
## Agents/Circumstances to Avoid
Symptoms tend to be worse in hot or humid weather; affected individuals should try to avoid being outdoors in such conditions as much as possible.
Other situations that can exacerbate disease manifestations include a full bladder; frequent visits to the lavatory are recommended [
Since long car rides, coming out of a movie theater, or fatigue can also worsen symptoms, such situations should be avoided as much as possible [
Episodic hypertension can occur in response to emotional stress or visceral pain, and therefore should be avoided when possible [
Environmental situations associated with hypobaric hypoxia (e.g., aircraft flight or ascent to high altitude) pose a potential risk to individuals with daytime hypercapnia [
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Pregnancies in women with FD are considered high risk because of abrupt changes in blood pressure.
High blood pressure secondary to FD is difficult to differentiate from toxemia or other causes of pregnancy-related high blood pressure.
Awareness of volume loss and low blood pressure is important because of the absence of reflex tachycardia to low blood pressure.
Visceral pain related to contractions during labor is perceived normally; therefore, analgesia should be provided. Epidural anesthesia is preferable due to blood pressure lability during general anesthesia or spinal block [
## Therapies Under Investigation
Search
## Genetic Counseling
Familial dysautonomia (FD) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
All offspring of an individual with FD inherit a pathogenic variant in
The risk that the Ashkenazi Jewish reproductive partner of an individual with FD is heterozygous for an
It is appropriate to offer molecular genetic testing of
Carrier testing for at-risk relatives requires prior identification of the
See
Because of the increased carrier rate for FD in individuals of Ashkenazi Jewish heritage (see
If an individual has FD or is known to be a carrier of an
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• All offspring of an individual with FD inherit a pathogenic variant in
• The risk that the Ashkenazi Jewish reproductive partner of an individual with FD is heterozygous for an
• It is appropriate to offer molecular genetic testing of
• Because of the increased carrier rate for FD in individuals of Ashkenazi Jewish heritage (see
• If an individual has FD or is known to be a carrier of an
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Familial dysautonomia (FD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
All offspring of an individual with FD inherit a pathogenic variant in
The risk that the Ashkenazi Jewish reproductive partner of an individual with FD is heterozygous for an
It is appropriate to offer molecular genetic testing of
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• All offspring of an individual with FD inherit a pathogenic variant in
• The risk that the Ashkenazi Jewish reproductive partner of an individual with FD is heterozygous for an
• It is appropriate to offer molecular genetic testing of
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
See
## Related Genetic Counseling Issues
Because of the increased carrier rate for FD in individuals of Ashkenazi Jewish heritage (see
If an individual has FD or is known to be a carrier of an
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Because of the increased carrier rate for FD in individuals of Ashkenazi Jewish heritage (see
• If an individual has FD or is known to be a carrier of an
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
315 West 39th Street
Suite 701
New York NY 10018
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• 315 West 39th Street
• Suite 701
• New York NY 10018
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## Molecular Genetics
Familial Dysautonomia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Familial Dysautonomia (
ELP1 protein is one of the six subunits of the Elongator complex, which facilitates transcriptional elongation, and is required for efficient translation of proteins. During embryogenesis, ELP1 is expressed first in the central and peripheral nervous systems and in the gastrointestinal tract. It is then expressed in secretory tissues and cartilage, and finally in muscle. Once the organs are formed, ELP1 expression appears in the skin and mucosal tissue. Overall, expression is more prominent in the nervous system and retina, and to a lesser extent in other organs. The complete absence of ELP1 leads to embryonic lethality with failure of vasculogenesis and neurulation [
Notable
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
ELP1 protein is one of the six subunits of the Elongator complex, which facilitates transcriptional elongation, and is required for efficient translation of proteins. During embryogenesis, ELP1 is expressed first in the central and peripheral nervous systems and in the gastrointestinal tract. It is then expressed in secretory tissues and cartilage, and finally in muscle. Once the organs are formed, ELP1 expression appears in the skin and mucosal tissue. Overall, expression is more prominent in the nervous system and retina, and to a lesser extent in other organs. The complete absence of ELP1 leads to embryonic lethality with failure of vasculogenesis and neurulation [
Notable
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
## Chapter Notes
I would like to thank my supervisor, Professor Ori Efrati, Head of the Pediatric Pulmonary Unit at Sheba Medical Center, for establishing the National Center for Familial Dysautonomia as a part of our unit.
I would also like to thank Professor Horacio Kaufmann, Head of the Dysautonomia Center, New York University School of Medicine, for his support and guidance during my training at the Dysautonomia Center.
Bat-El Bar-Aluma, MD (2021-present)Gabrielle J Halpern, MB, ChB; Beilinson Hospital, Petah Tikva (1999-2014)Mordechai Shohat, MD; Sheba Medical Center at Tel HaShomer (1999-2021)Monika Weisz Hubshman, MD, PhD; Rabin Medical Center, Beilinson Hospital (2014-2021)
4 November 2021 (bp) Comprehensive update posted live
18 December 2014 (me) Comprehensive update posted live
1 June 2010 (me) Comprehensive update posted live
22 October 2007 (me) Comprehensive update posted live
10 January 2005 (me) Comprehensive update posted live
21 January 2003 (me) Review posted live
6 November 1999 (bp) Original submission
• 4 November 2021 (bp) Comprehensive update posted live
• 18 December 2014 (me) Comprehensive update posted live
• 1 June 2010 (me) Comprehensive update posted live
• 22 October 2007 (me) Comprehensive update posted live
• 10 January 2005 (me) Comprehensive update posted live
• 21 January 2003 (me) Review posted live
• 6 November 1999 (bp) Original submission
## Acknowledgments
I would like to thank my supervisor, Professor Ori Efrati, Head of the Pediatric Pulmonary Unit at Sheba Medical Center, for establishing the National Center for Familial Dysautonomia as a part of our unit.
I would also like to thank Professor Horacio Kaufmann, Head of the Dysautonomia Center, New York University School of Medicine, for his support and guidance during my training at the Dysautonomia Center.
## Author History
Bat-El Bar-Aluma, MD (2021-present)Gabrielle J Halpern, MB, ChB; Beilinson Hospital, Petah Tikva (1999-2014)Mordechai Shohat, MD; Sheba Medical Center at Tel HaShomer (1999-2021)Monika Weisz Hubshman, MD, PhD; Rabin Medical Center, Beilinson Hospital (2014-2021)
## Revision History
4 November 2021 (bp) Comprehensive update posted live
18 December 2014 (me) Comprehensive update posted live
1 June 2010 (me) Comprehensive update posted live
22 October 2007 (me) Comprehensive update posted live
10 January 2005 (me) Comprehensive update posted live
21 January 2003 (me) Review posted live
6 November 1999 (bp) Original submission
• 4 November 2021 (bp) Comprehensive update posted live
• 18 December 2014 (me) Comprehensive update posted live
• 1 June 2010 (me) Comprehensive update posted live
• 22 October 2007 (me) Comprehensive update posted live
• 10 January 2005 (me) Comprehensive update posted live
• 21 January 2003 (me) Review posted live
• 6 November 1999 (bp) Original submission
## References
## Literature Cited
|
[
"FB Axelrod, JD Goldberg, XY Ye, C Maayan. Survival in familial dysautonomia: Impact of early intervention.. J Pediatr. 2002;141:518-23",
"FB Axelrod, G Gold-von Simson. Hereditary sensory and autonomic neuropathies: types II, III, and IV.. Orphanet J Rare Dis 2007;2:39",
"FB Axelrod, J Pearson. Congenital sensory neuropathies: diagnostic distinction from familial dysautonomia.. American Journal of Diseases of Children. 1984;138:947-54",
"L Bernardi, M Hilz, B Stemper, C Passino, G Welsch, FB Axelrod. Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia.. Am J Respir Crit Care Med 2003;167:141-9",
"A Blumenfeld, SA Slaugenhaupt, CB Liebert, V Temper, C Maayan, S Gill, DE Lucente, M Idelson, K MacCormack, MA Monahan, J Mull, M Leyne, M Mendillo, T Schiripo, E Mishori, X Breakefield, FB Axelrod, JF Gusella. Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31.. Am J Hum Genet 1999;64:1110-8",
"CM Brown, B Stemper, G Welsch, M Brys, FB Axelrod, MJ Hilz. Orthostatic challenge reveals impaired vascular resistance control, but normal venous pooling and capillary filtration in familial dysautonomia.. Clin Sci (Lond) 2003;104:163-9",
"M Di Rocco, G Stella, C Bruno, L Doria Lamba, M Bado, A Superti-Furga. Long-term survival in Stuve-Wiedemann syndrome: a neuro-myo-skeletal disorder with manifestations of dysautonomia.. Am J Med Genet A. 2003;118A:362-8",
"RC Dillon, JA Palma, CL Spalink, D Altshuler, L Norcliffe-Kaufmann, D Fridman, J Papadopoulos, H Kaufmann. Dexmedetomidine for refractory adrenergic crisis in familial dysautonomia.. Clin Auton Res. 2017;27:7-15",
"J Dong, L Edelmann, AM Bajwa, R Kornreich, RJ Desnick. Familial dysautonomia: detection of the IKBKAP IVS20+6T --> C and R696P mutations and frequencies among Ashkenazi Jews.. Am J Med Genet 2002;110:253-7",
"S Edvardson, Y Cinnamon, C Jalas, A Shaag, C Maayan, FB Axelrod, O Elpeleg. Hereditary sensory autonomic neuropathy caused by a mutation in dystonin.. Ann Neurol. 2012;71:569-72",
"L Elkayam, A Matalon, CH Tseng, F Axelrod. Prevalence and severity of renal disease in familial dysautonomia.. Am J Kidney Dis 2006;48:780-6",
"D Fischer, M Schabhüttl, T Wieland, R Windhager, TM Strom, M Auer-Grumbach. A novel missense mutation confirms ATL3 as a genefor hereditary sensory neuropathy type 1.. Brain. 2014;137",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"MK Kamboj, FB Axelrod, R David, ME Geffner, M Novogroder, SE Oberfield, JH Turco, C Maayan, B Kohn. Growth hormone treatment in children with familial dysautonomia.. J Pediatr. 2004;144:63-7",
"M Kazachkov, JA Palma, L Norcliffe-Kaufmann, BE Bar-Aluma, CL Spalink, EP Barnes, NE Amoroso, SM Balou, S Bess, A Chopra, R Condos, O Efrati, K Fitzgerald, D Fridman, RM Goldenberg, A Goldhaber, DA Kaufman, SV Kothare, J Levine, J Levy, AS Lubinsky, C Maayan, LC Moy, PJ Rivera, AJ Rodriguez, G Sokol, MF Sloane, T Tan, H Kaufmann. Respiratory care in familial dysautonomia: systematic review and expert consensus recommendations.. Respir Med. 2018;141:37-46",
"J Kfir, M Wu, M Liu, L Raju, JS Schuman, H Ishikawa, IM Vanegas, CE Mendoza-Santiesteban, JA Palma, L Norcliffe-Kaufmann, B Morgenstein, H Kaufmann, G Wollstein. Longitudinal changes in the macula and optic nerve in familial dysautonomia.. J Neurol. 2021;268:1402-9",
"U Kornak, I Mademan, M Schinke, M Voigt, P Krawitz, J Hecht, F Barvencik, T Schinke, S Gießelmann, FT Beil, A Pou-Serradell, JJ Vílchez, C Beetz, T Deconinck, V Timmerman, C Kaether, P De Jonghe, CA Hübner, A Gal, M Amling, S Mundlos, J Baets, I Kurth. Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.. Brain. 2014;137:683-92",
"O Lehavi, O Aizenstein, D Bercovich, D Pavzner, R Shomrat, A Orr-Urtreger, Y Yaron. Screening for familial dysautonomia in Israel: evidence for higher carrier rate among Polish Ashkenazi Jews.. Genet Test 2003;7:139-42",
"M Leyne, J Mull, SP Gill, MP Cuajungco, C Oddoux, A Blumenfeld, C Maayan, JF Gusella, FB Axelrod, SA Slaugenhaupt. Identification of the first non-Jewish mutation in familial dysautonomia.. Am J Med Genet A. 2003;118A:305-8",
"C Maayan, O Sela, F Axelrod, D Kidron, D Hochner-Celnikier. Gynecological aspects of female familial dysautonomia.. Isr Med Assoc J. 2000;2:679-83",
"VG Macefield, L Norcliffe-Kaufmann, J Gutiérrez, FB Axelrod, H Kaufmann. Can loss of muscle spindle afferents explain the ataxic gait in Riley-Day syndrome?. Brain. 2011;134:3198-208",
"E. Mass. Harefuah. 2016;155:490-4",
"CE Mendoza-Santiesteban, TR Hedges Iii, L Norcliffe-Kaufmann, F Axelrod, H Kaufmann. Selective retinal ganglion cell loss in familial dysautonomia.. J Neurol. 2014;261:702-9",
"L Norcliffe-Kaufmann, FB Axelrod, H Kaufmann. Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome.. J Hum Hypertens. 2013a;27:51-5",
"L Norcliffe-Kaufmann, J Martinez, F Axelrod, H Kaufmann. Hyperdopaminergic crises in familial dysautonomia: a randomized trial of carbidopa.. Neurology. 2013b;80:1611-7",
"L Norcliffe-Kaufmann, JA Palma, J Martinez, H Kaufmann. Carbidopa for afferent baroreflex failure in familial dysautonomia: a double-blind randomized crossover clinical trial.. Hypertension. 2020;76:724-31",
"L Norcliffe-Kaufmann, SA Slaugenhaupt, H Kaufmann. Familial dysautonomia: history, genotype, phenotype and translational research.. Prog Neurobiol. 2017;152:131-48",
"JA Palma, A Gileles-Hillel, L Norcliffe-Kaufmann, H Kaufmann. Chemoreflex failure and sleep-disordered breathing in familial dysautonomia: Implications for sudden death during sleep.. Auton Neurosci. 2019;218:10-15",
"JA Palma, L Norcliffe-Kaufmann, C Fuente-Mora, L Percival, C Mendoza-Santiesteban, H Kaufmann. Current treatments in familial dysautonomia.. Expert Opin Pharmacother. 2014;15:2653-71",
"JA Palma, L Norcliffe-Kaufmann, MA Perez, CL Spalink, H Kaufmann. Sudden unexpected death during sleep in familial dysautonomia: a case-control study.. Sleep. 2017;40",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"J Saini, FB Axelrod, C Maayan, J Stringer, SW Smilen. Urinary incontinence in familial dysautonomia.. Int Urogynecol J Pelvic Floor Dysfunct 2003;14:209-13",
"SA Sands, P Giarraffa, CM Jacobson, FB Axelrod. Familial dysautonomia's impact on quality of life in childhood, adolescence, and adulthood.. Acta Paediatr 2006;95:457-62",
"SA Slaugenhaupt, A Blumenfeld, SP Gill, M Leyne, J Mull, MP Cuajungco, CB Liebert, B Chadwick, M Idelson, L Reznik, C Robbins, I Makalowska, M Brownstein, D Krappmann, C Scheidereit, C Maayan, FB Axelrod, JF Gusella. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.. Am J Hum Genet 2001;68:598-605",
"CL Spalink, E Barnes, JA Palma, L Norcliffe-Kaufmann, H Kaufmann. Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia.. Clin Auton Res. 2017;27:279-82",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"K Verhoeven, P De Jonghe, K Coen, N Verpoorten, M Auer-Grumbach, JM Kwon, D FitzPatrick, E Schmedding, E De Vriendt, A Jacobs, V Van Gerwen, K Wagner, HP Hartung, V Timmerman. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy.. Am J Hum Genet. 2003;72:722-7",
"W Welton, D Clayson, FB Axelrod, DB Levine. Intellectual development and familial dysautonomia.. Pediatrics. 1979;63:708-12"
] |
21/1/2003
|
4/11/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
feingold
|
feingold
|
[
"Oculodigitoesophagoduodenal Syndrome",
"ODED Syndrome",
"Oculodigitoesophagoduodenal Syndrome",
"ODED Syndrome",
"N-myc proto-oncogene protein",
"MYCN",
"Feingold Syndrome 1"
] |
Feingold Syndrome 1
|
Carlo LM Marcelis, Arjan PM de Brouwer
|
Summary Feingold syndrome 1 (referred to as FS1 in this The diagnosis of FS1 is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in FS1 is inherited in an autosomal dominant manner. Approximately 60% of individuals with Feingold syndrome 1 have an affected parent; the proportion of FS1 caused by a
|
## Diagnosis
Feingold syndrome 1 (FS1)
Digital anomalies (brachymesophalangy, thumb hypoplasia, toe syndactyly)
Microcephaly (occipito-frontal circumference <10th centile)
Short palpebral fissures
Gastrointestinal atresias, especially esophageal and duodenal, diagnosed pre- or postnatally by imaging studies (usually ultrasound examination, possibly MRI)
The diagnosis of FS1
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of FS1, molecular genetic testing approaches can include
Note: Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
For an introduction to multigene panels click
When the diagnosis of FS1 is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Feingold Syndrome 1 (FS1)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Larger deletions of
• Digital anomalies (brachymesophalangy, thumb hypoplasia, toe syndactyly)
• Microcephaly (occipito-frontal circumference <10th centile)
• Short palpebral fissures
• Gastrointestinal atresias, especially esophageal and duodenal, diagnosed pre- or postnatally by imaging studies (usually ultrasound examination, possibly MRI)
• Note: Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
• For an introduction to multigene panels click
## Suggestive Findings
Feingold syndrome 1 (FS1)
Digital anomalies (brachymesophalangy, thumb hypoplasia, toe syndactyly)
Microcephaly (occipito-frontal circumference <10th centile)
Short palpebral fissures
Gastrointestinal atresias, especially esophageal and duodenal, diagnosed pre- or postnatally by imaging studies (usually ultrasound examination, possibly MRI)
• Digital anomalies (brachymesophalangy, thumb hypoplasia, toe syndactyly)
• Microcephaly (occipito-frontal circumference <10th centile)
• Short palpebral fissures
• Gastrointestinal atresias, especially esophageal and duodenal, diagnosed pre- or postnatally by imaging studies (usually ultrasound examination, possibly MRI)
## Establishing the Diagnosis
The diagnosis of FS1
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of FS1, molecular genetic testing approaches can include
Note: Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
For an introduction to multigene panels click
When the diagnosis of FS1 is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Feingold Syndrome 1 (FS1)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Larger deletions of
• Note: Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of FS1, molecular genetic testing approaches can include
Note: Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
For an introduction to multigene panels click
• Note: Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
• For an introduction to multigene panels click
## Option 2
When the diagnosis of FS1 is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Feingold Syndrome 1 (FS1)
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Larger deletions of
## Clinical Characteristics
Feingold syndrome 1 (FS1) as described by
Features are summarized in
Features in Feingold Syndrome 1 (FS1)
Digital anomalies include brachymesophalangy (shortening of the 2nd and 5th middle phalanx of the hand with clinodactyly of the 5th finger) and thumb hypoplasia (
Gastrointestinal atresia (esophageal and/or duodenal) is a cause of major medical concern in FS1 and requires immediate surgical intervention (see
Mild learning deficit is frequent in FS1; most affected individuals are able to live an independent life. Clear intellectual disability is rare, but intelligence is below average when compared to the general population and healthy, unaffected family members.
Some reports show that growth is impaired in FS1 [
Associated features that occur in fewer than 50% of affected individuals include the following:
No significant differences are observed among individuals with deletions or missense, nonsense, or frameshift variants.
The penetrance for major features of FS1, especially digital abnormalities, appears to be 100% but clinical expression can vary considerably.
Terms used in the past for Feingold syndrome 1:
Microcephaly-oculo-digito-esophageal-duodenal syndrome
Microcephaly mesobrachyphalangy tracheoesophageal fistula syndrome
Microcephaly-digital anomalies-normal intelligence syndrome
Prevalence is unknown; FS1 is likely rare. To date, 69 families with 116 affected individuals have been reported [
• Microcephaly-oculo-digito-esophageal-duodenal syndrome
• Microcephaly mesobrachyphalangy tracheoesophageal fistula syndrome
• Microcephaly-digital anomalies-normal intelligence syndrome
## Clinical Description
Feingold syndrome 1 (FS1) as described by
Features are summarized in
Features in Feingold Syndrome 1 (FS1)
Digital anomalies include brachymesophalangy (shortening of the 2nd and 5th middle phalanx of the hand with clinodactyly of the 5th finger) and thumb hypoplasia (
Gastrointestinal atresia (esophageal and/or duodenal) is a cause of major medical concern in FS1 and requires immediate surgical intervention (see
Mild learning deficit is frequent in FS1; most affected individuals are able to live an independent life. Clear intellectual disability is rare, but intelligence is below average when compared to the general population and healthy, unaffected family members.
Some reports show that growth is impaired in FS1 [
Associated features that occur in fewer than 50% of affected individuals include the following:
## Genotype-Phenotype Correlations
No significant differences are observed among individuals with deletions or missense, nonsense, or frameshift variants.
## Penetrance
The penetrance for major features of FS1, especially digital abnormalities, appears to be 100% but clinical expression can vary considerably.
## Nomenclature
Terms used in the past for Feingold syndrome 1:
Microcephaly-oculo-digito-esophageal-duodenal syndrome
Microcephaly mesobrachyphalangy tracheoesophageal fistula syndrome
Microcephaly-digital anomalies-normal intelligence syndrome
• Microcephaly-oculo-digito-esophageal-duodenal syndrome
• Microcephaly mesobrachyphalangy tracheoesophageal fistula syndrome
• Microcephaly-digital anomalies-normal intelligence syndrome
## Prevalence
Prevalence is unknown; FS1 is likely rare. To date, 69 families with 116 affected individuals have been reported [
## Genetically Related (Allelic) Disorders
The
Contiguous gene deletions involving
## Differential Diagnosis
Other Genes of Interest in the Differential Diagnosis of Feingold Syndrome 1 (FS1)
Esophageal atresia
Heart defects
Renal abnormalities
Coloboma
Genital abnormalities
Ear anomalies
Microcephaly
Mild growth delay
Brachymesophalangy, toe syndactyly, & thumb hypoplasia
Learning disabilities
Thumb hypoplasia
Microcephaly
Growth restriction
Intestinal/anal atresia
Renal abnormalities
Absence of brachymesophalangy / toe syndactyly
↑ tumor risk (not found in FS1)
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Feingold syndrome 2 is caused by hemizygous deletions of chromosome 13q31.3 including
To date, seven individuals with Feingold syndrome 2 have been described [
The brachymesophalangy observed in FS1 is very similar to brachydactyly type A4 (BDA4). The molecular basis of BDA4 is known. Although no pathogenic variants in
• Esophageal atresia
• Heart defects
• Renal abnormalities
• Coloboma
• Genital abnormalities
• Ear anomalies
• Microcephaly
• Mild growth delay
• Brachymesophalangy, toe syndactyly, & thumb hypoplasia
• Learning disabilities
• Thumb hypoplasia
• Microcephaly
• Growth restriction
• Intestinal/anal atresia
• Renal abnormalities
• Absence of brachymesophalangy / toe syndactyly
• ↑ tumor risk (not found in FS1)
## Management
To establish the extent of disease and needs in an individual diagnosed with Feingold syndrome 1 (FS1), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Feingold Syndrome 1 (FS1)
Hand surgeon
Occupational therapy to assess hand function / need for therapy
Foot specialist to assess for functional needs
See
Appropriate treatment includes a multidisciplinary approach to address the following possible concerns:
Surgical treatment of gastrointestinal atresia
Occupational therapy / surgical intervention for finger/toe anomalies
Treatment of cardiac and/or renal anomalies as per standard practice
Treatment for significant hearing loss (See
Developmental or educational intervention for children with learning difficulties
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
IEP services will be reviewed annually to determine if any changes are needed.
As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Recommended Surveillance for Individuals with Feingold Syndrome 1
GI = gastrointestinal; OT = occupational therapist/therapy
See
Search
• Hand surgeon
• Occupational therapy to assess hand function / need for therapy
• Foot specialist to assess for functional needs
• Surgical treatment of gastrointestinal atresia
• Occupational therapy / surgical intervention for finger/toe anomalies
• Treatment of cardiac and/or renal anomalies as per standard practice
• Treatment for significant hearing loss (See
• Developmental or educational intervention for children with learning difficulties
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• In the US:
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Feingold syndrome 1 (FS1), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Feingold Syndrome 1 (FS1)
Hand surgeon
Occupational therapy to assess hand function / need for therapy
Foot specialist to assess for functional needs
See
• Hand surgeon
• Occupational therapy to assess hand function / need for therapy
• Foot specialist to assess for functional needs
## Treatment of Manifestations
Appropriate treatment includes a multidisciplinary approach to address the following possible concerns:
Surgical treatment of gastrointestinal atresia
Occupational therapy / surgical intervention for finger/toe anomalies
Treatment of cardiac and/or renal anomalies as per standard practice
Treatment for significant hearing loss (See
Developmental or educational intervention for children with learning difficulties
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
IEP services will be reviewed annually to determine if any changes are needed.
As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Surgical treatment of gastrointestinal atresia
• Occupational therapy / surgical intervention for finger/toe anomalies
• Treatment of cardiac and/or renal anomalies as per standard practice
• Treatment for significant hearing loss (See
• Developmental or educational intervention for children with learning difficulties
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• In the US:
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.
IEP services will be reviewed annually to determine if any changes are needed.
As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• In the US:
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restrictive environment at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Surveillance
Recommended Surveillance for Individuals with Feingold Syndrome 1
GI = gastrointestinal; OT = occupational therapist/therapy
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Feingold syndrome 1 (FS1) is inherited in an autosomal dominant manner.
Many individuals (~60%) diagnosed with FS1 have an affected parent.
A proband with FS1 may have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with FS1 may appear to be negative because of failure to recognize the disorder in a family member with a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations and/or molecular genetic testing have been performed.
Note: If the parent is the family member in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
If a parent of the proband is affected and/or known to have the
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents have not been tested for the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Because of the risk for major congenital abnormalities of the gastrointestinal tract, heart, and kidney, high-resolution ultrasound investigations (including fetal echocardiogram) are advised in any pregnancy in which the fetus is known to have an
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Many individuals (~60%) diagnosed with FS1 have an affected parent.
• A proband with FS1 may have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with FS1 may appear to be negative because of failure to recognize the disorder in a family member with a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations and/or molecular genetic testing have been performed.
• Note: If the parent is the family member in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
• If a parent of the proband is affected and/or known to have the
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Feingold syndrome 1 (FS1) is inherited in an autosomal dominant manner.
## Risk to Family Members
Many individuals (~60%) diagnosed with FS1 have an affected parent.
A proband with FS1 may have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with FS1 may appear to be negative because of failure to recognize the disorder in a family member with a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations and/or molecular genetic testing have been performed.
Note: If the parent is the family member in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
If a parent of the proband is affected and/or known to have the
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents have not been tested for the
• Many individuals (~60%) diagnosed with FS1 have an affected parent.
• A proband with FS1 may have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with FS1 may appear to be negative because of failure to recognize the disorder in a family member with a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations and/or molecular genetic testing have been performed.
• Note: If the parent is the family member in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
• If a parent of the proband is affected and/or known to have the
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Because of the risk for major congenital abnormalities of the gastrointestinal tract, heart, and kidney, high-resolution ultrasound investigations (including fetal echocardiogram) are advised in any pregnancy in which the fetus is known to have an
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
United Kingdom
•
•
•
• United Kingdom
•
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Feingold Syndrome 1: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Feingold Syndrome 1 (
The Myc family of proteins is well known for its role in oncogenic processes. Members of this family include c-Myc, N-Myc, and L-Myc. The gene
c-Myc and N-Myc also play a crucial role in development. Mice deficient for either of these Myc genes die before embryonic day 11.5. Inactivation of murine
Notable
Variants listed in the table have been provided by the authors.
Somatic amplification of
## Molecular Pathogenesis
The Myc family of proteins is well known for its role in oncogenic processes. Members of this family include c-Myc, N-Myc, and L-Myc. The gene
c-Myc and N-Myc also play a crucial role in development. Mice deficient for either of these Myc genes die before embryonic day 11.5. Inactivation of murine
Notable
Variants listed in the table have been provided by the authors.
## Cancer and Benign Tumors
Somatic amplification of
## Chapter Notes
4 April 2019 (bp) Comprehensive update posted live
6 September 2012 (me) Comprehensive update posted live
30 June 2009 (me) Review posted live
23 April 2009 (cm) Original submission
• 4 April 2019 (bp) Comprehensive update posted live
• 6 September 2012 (me) Comprehensive update posted live
• 30 June 2009 (me) Review posted live
• 23 April 2009 (cm) Original submission
## Revision History
4 April 2019 (bp) Comprehensive update posted live
6 September 2012 (me) Comprehensive update posted live
30 June 2009 (me) Review posted live
23 April 2009 (cm) Original submission
• 4 April 2019 (bp) Comprehensive update posted live
• 6 September 2012 (me) Comprehensive update posted live
• 30 June 2009 (me) Review posted live
• 23 April 2009 (cm) Original submission
## References
## Literature Cited
Typical brachymesophalangy in an adult with FS1
X-ray showing typical brachymesophalangy (digits 2 and 5) and thumb hypoplasia
Typical syndactyly of 2nd and 3rd or 4th and 5th toe
|
[
"B Blaumeiser, B Oehl-Jaschkowitz, W Borozdin, J Kohlhase. Feingold syndrome associated with two novel MYCN mutations in sporadic and familial cases including monozygotic twins.. Am J Med Genet. 2008;146A:2304-7",
"HG Brunner, RM Winter. Autosomal dominant inheritance of abnormalities of the hands and feet with short palpebral fissures, variable microcephaly with learning disability, and oesophageal/duodenal atresia.. J Med Genet 1991;28:389-94",
"RD Burnside, S Molinari, C Botti, SS Brooks, WK Chung, L Mehta, S Schwartz, P Papenhausen. Features of Feingold syndrome 1 dominate in subjects with 2p deletions including MYCN.. Am J Med Genet A. 2018;176:1956-63",
"J Celli, E van Beusekom, RC Hennekam, ME Gallardo, DF Smeets, SR de Córdoba, JW Innis, M Frydman, R König, H Kingston, J Tolmie, LC Govaerts, H van Bokhoven, HG Brunner. Familial syndromic esophageal atresia maps to 2p23-p24.. Am J Hum Genet 2000;66:436-44",
"J Charron, JF Gagnon, JF Cadrin-Girard. Identification of N-myc regulatory regions involved in embryonic expression.. Pediatr Res 2002;51:48-56",
"CP Chen, SP Lin, SR Chern, PS Wu, SD Chang, SH Ng, YP Liu, JW Su, W Wang. A de novo 4.4-Mb microdeletion in 2p24.3 → p24.2 in a girl with bilateral hearing impairment, microcephaly, digit abnormalities and Feingold syndrome.. Eur J Med Genet. 2012;55:666-9",
"M Cognet, A Nougayrede, V Malan, P Callier, C Cretolle, L Faivre, D Genevieve, A Goldenberg, D Heron, S Mercier, N Philip, S Sigaudy, A Verloes, S Sarnacki, A Munnich, M Vekemans, S Lyonnet, H Etchevers, J Amiel, L de Pontual. Dissection of the MYCN locus in Feingold syndrome and isolated oesophageal atresia.. Eur J Hum Genet 2011;19:602-6",
"L de Pontual, E Yao, P Callier, L Faivre, V Drouin, S Cariou, A van Haeringen, D Genevieve, A Goldenberg, M Oufadem, S Manouvrier, A Munnich, JA Vidigal, M Vekemans, S Lyonnet, A Henrion-Caude, A Ventura, J Amiel. Germline deletion of the miR-17-92 cluster causes growth and skeletal defects in humans.. Nat Genet 2011;43:1026-30",
"M Feingold. Case Report 30.. Synd Ident 1975;3:16-7",
"A Hempel, AT Pagnamenta, M Blyth, S Mansour, V McConnell, I Kou, S Ikegawa, Y Tsurusaki, N Matsumoto, A Lo-Castro, G Plessis, B Albrecht, A Battaglia, JC Taylor, MF Howard, D Keays, AS Sohal, SJ Kühl, U Kini, A McNeill. Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome.. J Med Genet. 2016;53:152-62",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"CL Jopling, AE Willis. N-myc translation is initiated via an internal ribosome entry segment that displays enhanced activity in neuronal cells.. Oncogene 2001;20:2664-70",
"K Kato, F Miya, N Hamada, Y Negishi, Y Narumi-Kishimoto, H Ozawa, H Ito, I Hori, A Hattori, N Okamoto, M Kato, T Tsunoda, Y Kanemura, K Kosaki, Y Takahashi, KI Nagata, S Saitoh. J Med Genet. 2019;56:388-95",
"PS Knoepfler, PF Cheng, RN Eisenman. N-myc is essential during neurogenesis for the rapid expansion of progenitor cell populations and the inhibition of neuronal differentiation.. Genes Dev 2002;16:2699-712",
"CLM Marcelis, FA Hol, GE Graham, PNMA Rieu, R Kellermayer, RPP Meijer, D Lugtenberg, H Scheffer, H van Bokhoven, HG Brunner, APM de Brouwer. Genotype-phenotype correlations in MYCN-related Feingold syndrome.. Hum Mutat 2008;29:1125-32",
"M Muriello, AY Kim, K Sondergaard Schatz, N Beck, M Gunay-Aygun, JE Hoover-Fong. Growth hormone deficiency, aortic dilation, and neurocognitive issues in Feingold syndrome 2.. Am J Med Genet A. 2019;179:410-6",
"S Ota, ZQ Zhou, DR Keene, P Knoepfler, PJ Hurlin. Activities of N-Myc in the developing limb link control of skeletal size with digit separation.. Development 2007;134:1583-92",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"MV Ruiz-Pérez, AB Henley, M Arsenian-Henriksson. The MYCN protein in health and disease.. Genes (Basel) 2017;8",
"C Shaw-Smith, L Willatt, N Thalange. Growth deficiency in oculodigitoesophagoduodenal (Feingold) syndrome--case report and review of the literature.. Clin Dysmorphol 2005;14:155-8",
"E Tassano, M Di Rocco, S Signa, G. Gimelli. De novo 13q31.1-q32.1 interstitial deletion encompassing the miR-17-92 cluster in a patient with Feingold syndrome-2.. Am J Med Genet A. 2013;161A:894-6",
"H van Bokhoven, J Celli, J van Reeuwijk, T Rinne, B Glaudemans, E van Beusekom, P Rieu, RA Newbury-Ecob, C Chiang, HG Brunner. MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.. Nat Genet 2005;37:465-7"
] |
30/6/2009
|
4/4/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
fevr
|
fevr
|
[
"adFEVR",
"adFEVR",
"Frizzled-4",
"Low-density lipoprotein receptor-related protein 5",
"Tetraspanin-12",
"FZD4",
"LRP5",
"TSPAN12",
"Familial Exudative Vitreoretinopathy, Autosomal Dominant"
] |
Familial Exudative Vitreoretinopathy, Autosomal Dominant – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Carmel Toomes, Louise Downey
|
Summary Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is characterized by failure of peripheral retinal vascularization. The visual problems and variable phenotype associated with adFEVR result from secondary complications caused by retinal ischemia. The retinal avascularity is probably present from birth and generates sequelae that stabilize in early adult life or progress in later life. Expressivity may be asymmetric and is highly variable, ranging from mild or asymptomatic to severe (e.g., registered as blind) within the same family. The diagnosis of adFEVR is based on a family history compatible with autosomal dominant inheritance and bilateral peripheral retinal avascularity, seen temporally, by indirect ophthalmoscope and scleral indentation, or by fundus fluorescein angiography. Pathogenic variants in one of three genes are known to be associated with adFEVR: Autosomal dominant FEVR is inherited in an autosomal dominant manner. Offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant, but many individuals with adFEVR can be asymptomatic because of reduced penetrance. Prenatal testing is possible if the pathogenic variant has been identified in the family.
|
## Diagnosis
The diagnosis of autosomal dominant familial exudative vitreoretinopathy (adFEVR) is based on the following:
Family history compatible with autosomal dominant inheritance
Bilateral peripheral retinal avascularity (
Retinal avascularity is usually seen temporally, but may be missed unless an indirect ophthalmoscope and scleral indentation are used.
Retinal vascular changes may be more apparent with fundus fluorescein angiography; one small study has suggested that this method identifies 100% of FEVR cases [
Other retinal abnormalities that support the diagnosis:
Retinal neovascularization and peripheral brush border anastomoses
Peripheral fibrovascular mass
Retinal holes/tears that may be associated with retinal detachment
Retinal traction (with macular ectopia and/or straightening of vessels at the posterior pole, acute-angle vascular branching) that may be associated with retinal detachment
Exudation that may be associated with retinal detachment
Falciform retinal folds
Rare retinal features:
Retinoschisis
Giant retinal tears
No characteristic electrophysiologic features have been identified.
The proportion of adFEVR attributed to pathogenic variants in each of the genes varies by study:
20% (5/24) [
20% (8/40) [
7% (1/13) [
3% (2/56) [
3% (3/53) [
14% (9/63) [
40% (8/20) [
31% (5/16) [
31% (15/48) [
17% (12/68) [
Molecular Genetic Testing Used in Familial Exudative Vitreoretinopathy, Autosomal Dominant
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.For issues to consider in interpretation of sequence analysis results, click
The diagnosis of adFEVR is based on a family history compatible with autosomal dominant inheritance and bilateral peripheral retinal avascularity, seen temporally, by indirect ophthalmoscope and scleral indentation, or by fundus fluorescein angiography.
Molecular genetic testing should begin with sequence analysis of
If a pathogenic variant is not identified, sequence analysis of
If a pathogenic variant is not identified, sequence analysis of
Because not all genes associated with adFEVR are known, failure to identify a pathogenic variant in
• Family history compatible with autosomal dominant inheritance
• Bilateral peripheral retinal avascularity (
• Retinal avascularity is usually seen temporally, but may be missed unless an indirect ophthalmoscope and scleral indentation are used.
• Retinal vascular changes may be more apparent with fundus fluorescein angiography; one small study has suggested that this method identifies 100% of FEVR cases [
• Retinal avascularity is usually seen temporally, but may be missed unless an indirect ophthalmoscope and scleral indentation are used.
• Retinal vascular changes may be more apparent with fundus fluorescein angiography; one small study has suggested that this method identifies 100% of FEVR cases [
• Retinal avascularity is usually seen temporally, but may be missed unless an indirect ophthalmoscope and scleral indentation are used.
• Retinal vascular changes may be more apparent with fundus fluorescein angiography; one small study has suggested that this method identifies 100% of FEVR cases [
• Retinal neovascularization and peripheral brush border anastomoses
• Peripheral fibrovascular mass
• Retinal holes/tears that may be associated with retinal detachment
• Retinal traction (with macular ectopia and/or straightening of vessels at the posterior pole, acute-angle vascular branching) that may be associated with retinal detachment
• Exudation that may be associated with retinal detachment
• Falciform retinal folds
• Retinoschisis
• Giant retinal tears
• 20% (5/24) [
• 20% (8/40) [
• 7% (1/13) [
• 3% (2/56) [
• 3% (3/53) [
• 14% (9/63) [
• 40% (8/20) [
• 31% (5/16) [
• 31% (15/48) [
• 17% (12/68) [
• 20% (5/24) [
• 20% (8/40) [
• 7% (1/13) [
• 3% (2/56) [
• 3% (3/53) [
• 14% (9/63) [
• 40% (8/20) [
• 31% (5/16) [
• 31% (15/48) [
• 17% (12/68) [
• 20% (5/24) [
• 20% (8/40) [
• 7% (1/13) [
• 3% (2/56) [
• 3% (3/53) [
• 14% (9/63) [
• 40% (8/20) [
• 31% (5/16) [
• 31% (15/48) [
• 17% (12/68) [
• The diagnosis of adFEVR is based on a family history compatible with autosomal dominant inheritance and bilateral peripheral retinal avascularity, seen temporally, by indirect ophthalmoscope and scleral indentation, or by fundus fluorescein angiography.
• Molecular genetic testing should begin with sequence analysis of
• If a pathogenic variant is not identified, sequence analysis of
• If a pathogenic variant is not identified, sequence analysis of
• Because not all genes associated with adFEVR are known, failure to identify a pathogenic variant in
## Clinical Diagnosis
The diagnosis of autosomal dominant familial exudative vitreoretinopathy (adFEVR) is based on the following:
Family history compatible with autosomal dominant inheritance
Bilateral peripheral retinal avascularity (
Retinal avascularity is usually seen temporally, but may be missed unless an indirect ophthalmoscope and scleral indentation are used.
Retinal vascular changes may be more apparent with fundus fluorescein angiography; one small study has suggested that this method identifies 100% of FEVR cases [
Other retinal abnormalities that support the diagnosis:
Retinal neovascularization and peripheral brush border anastomoses
Peripheral fibrovascular mass
Retinal holes/tears that may be associated with retinal detachment
Retinal traction (with macular ectopia and/or straightening of vessels at the posterior pole, acute-angle vascular branching) that may be associated with retinal detachment
Exudation that may be associated with retinal detachment
Falciform retinal folds
Rare retinal features:
Retinoschisis
Giant retinal tears
No characteristic electrophysiologic features have been identified.
• Family history compatible with autosomal dominant inheritance
• Bilateral peripheral retinal avascularity (
• Retinal avascularity is usually seen temporally, but may be missed unless an indirect ophthalmoscope and scleral indentation are used.
• Retinal vascular changes may be more apparent with fundus fluorescein angiography; one small study has suggested that this method identifies 100% of FEVR cases [
• Retinal avascularity is usually seen temporally, but may be missed unless an indirect ophthalmoscope and scleral indentation are used.
• Retinal vascular changes may be more apparent with fundus fluorescein angiography; one small study has suggested that this method identifies 100% of FEVR cases [
• Retinal avascularity is usually seen temporally, but may be missed unless an indirect ophthalmoscope and scleral indentation are used.
• Retinal vascular changes may be more apparent with fundus fluorescein angiography; one small study has suggested that this method identifies 100% of FEVR cases [
• Retinal neovascularization and peripheral brush border anastomoses
• Peripheral fibrovascular mass
• Retinal holes/tears that may be associated with retinal detachment
• Retinal traction (with macular ectopia and/or straightening of vessels at the posterior pole, acute-angle vascular branching) that may be associated with retinal detachment
• Exudation that may be associated with retinal detachment
• Falciform retinal folds
• Retinoschisis
• Giant retinal tears
## Molecular Genetic Testing
The proportion of adFEVR attributed to pathogenic variants in each of the genes varies by study:
20% (5/24) [
20% (8/40) [
7% (1/13) [
3% (2/56) [
3% (3/53) [
14% (9/63) [
40% (8/20) [
31% (5/16) [
31% (15/48) [
17% (12/68) [
Molecular Genetic Testing Used in Familial Exudative Vitreoretinopathy, Autosomal Dominant
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.For issues to consider in interpretation of sequence analysis results, click
• 20% (5/24) [
• 20% (8/40) [
• 7% (1/13) [
• 3% (2/56) [
• 3% (3/53) [
• 14% (9/63) [
• 40% (8/20) [
• 31% (5/16) [
• 31% (15/48) [
• 17% (12/68) [
• 20% (5/24) [
• 20% (8/40) [
• 7% (1/13) [
• 3% (2/56) [
• 3% (3/53) [
• 14% (9/63) [
• 40% (8/20) [
• 31% (5/16) [
• 31% (15/48) [
• 17% (12/68) [
• 20% (5/24) [
• 20% (8/40) [
• 7% (1/13) [
• 3% (2/56) [
• 3% (3/53) [
• 14% (9/63) [
• 40% (8/20) [
• 31% (5/16) [
• 31% (15/48) [
• 17% (12/68) [
## Testing Strategy
The diagnosis of adFEVR is based on a family history compatible with autosomal dominant inheritance and bilateral peripheral retinal avascularity, seen temporally, by indirect ophthalmoscope and scleral indentation, or by fundus fluorescein angiography.
Molecular genetic testing should begin with sequence analysis of
If a pathogenic variant is not identified, sequence analysis of
If a pathogenic variant is not identified, sequence analysis of
Because not all genes associated with adFEVR are known, failure to identify a pathogenic variant in
• The diagnosis of adFEVR is based on a family history compatible with autosomal dominant inheritance and bilateral peripheral retinal avascularity, seen temporally, by indirect ophthalmoscope and scleral indentation, or by fundus fluorescein angiography.
• Molecular genetic testing should begin with sequence analysis of
• If a pathogenic variant is not identified, sequence analysis of
• If a pathogenic variant is not identified, sequence analysis of
• Because not all genes associated with adFEVR are known, failure to identify a pathogenic variant in
## Clinical Characteristics
All individuals with autosomal dominant familial exudative vitreoretinopathy (adFEVR) have failure of peripheral retinal vascularization, which by itself usually causes no clinical symptoms. The visual problems and variable phenotype associated with adFEVR result from secondary complications caused by retinal ischemia. This region of retinal avascularity is presumed to be present from birth and initially was thought to generate sequelae that stabilized in early adult life [
Autosomal dominant FEVR shows highly variable expressivity and may be markedly asymmetric. The phenotype ranges from mild to severe even within the same family. At the mild end of the spectrum, individuals are asymptomatic; at the severe end, children are registered as blind shortly after birth.
Forty-one percent of the individuals reported by
Individuals with adFEVR and pathogenic variants in
Although the phenotype has appeared to be indistinguishable by gene involved, research suggests that individuals with adFEVR who have pathogenic variants within
In a family with FEVR with an
Early data suggesting that the
When using fluorescein angiography to determine clinical status, penetrance is reported to be 100% because all affected individuals have a sector of avascular peripheral retina [
Using examination of the retina with an indirect ophthalmoscope through a dilated pupil to determine clinical status, penetrance is considered to be about 90% [
Using reduced vision or other clinical symptoms to determine clinical status, penetrance as low as 10% is reported.
FEVR is often described as a very rare disorder. The prevalence has not been calculated; however, given that molecular testing has shown that as many as 90% of affected individuals may be asymptomatic, it is likely that the frequency of the disorder is underestimated.
FEVR has been described in all ethnic groups.
## Clinical Description
All individuals with autosomal dominant familial exudative vitreoretinopathy (adFEVR) have failure of peripheral retinal vascularization, which by itself usually causes no clinical symptoms. The visual problems and variable phenotype associated with adFEVR result from secondary complications caused by retinal ischemia. This region of retinal avascularity is presumed to be present from birth and initially was thought to generate sequelae that stabilized in early adult life [
Autosomal dominant FEVR shows highly variable expressivity and may be markedly asymmetric. The phenotype ranges from mild to severe even within the same family. At the mild end of the spectrum, individuals are asymptomatic; at the severe end, children are registered as blind shortly after birth.
Forty-one percent of the individuals reported by
Individuals with adFEVR and pathogenic variants in
## Genotype-Phenotype Correlations
Although the phenotype has appeared to be indistinguishable by gene involved, research suggests that individuals with adFEVR who have pathogenic variants within
In a family with FEVR with an
Early data suggesting that the
## Penetrance
When using fluorescein angiography to determine clinical status, penetrance is reported to be 100% because all affected individuals have a sector of avascular peripheral retina [
Using examination of the retina with an indirect ophthalmoscope through a dilated pupil to determine clinical status, penetrance is considered to be about 90% [
Using reduced vision or other clinical symptoms to determine clinical status, penetrance as low as 10% is reported.
## Prevalence
FEVR is often described as a very rare disorder. The prevalence has not been calculated; however, given that molecular testing has shown that as many as 90% of affected individuals may be asymptomatic, it is likely that the frequency of the disorder is underestimated.
FEVR has been described in all ethnic groups.
## Genetically Related (Allelic) Disorders
Mutation of
Autosomal recessive FEVR (arFEVR) [
Osteoporosis-pseudoglioma syndrome (OPPG) (OMIM
Pathogenic missense variants within the first few exons of
High bone mass (OMIM
Endosteal hyperostosis (OMIM
Osteopetrosis (OMIM
• Autosomal recessive FEVR (arFEVR) [
• Osteoporosis-pseudoglioma syndrome (OPPG) (OMIM
• High bone mass (OMIM
• Endosteal hyperostosis (OMIM
• Osteopetrosis (OMIM
## Differential Diagnosis
Familial exudative vitreoretinopathy (FEVR) can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. The mode of inheritance cannot be distinguished by clinical examination alone.
Acquired disorders that resemble adFEVR:
## Management
To establish the extent of disease in an individual diagnosed with autosomal dominant familial exudative vitreoretinopathy (adFEVR), the following evaluations are recommended:
Ophthalmologic examination, including indirect ophthalmoscopy and scleral depression
Fundus fluorescein angiography, which increases the detection rate of peripheral avascularity in asymptomatic affected individuals [
Retinal avascularity per se often requires no treatment; however, it can induce ischemia, leading to neovascularization of the retinal periphery, which can be treated with prophylactic cryotherapy or argon laser photocoagulation to attempt to induce regression of the new vessels. Similar treatments are used to treat retinal holes and areas of retinal exudate to prevent retinal detachment.
Rhegmatogenous retinal detachments produced by retinal traction are repaired surgically using conventional methods, but the prognosis is guarded.
Exudative retinal detachments may be stabilized with cryotherapy, but the prognosis is poor.
The arc of peripheral retinal avascularity, thought to be an aberration of retinal development, is not preventable using current treatments.
Patients with FEVR associated with reduced bone density would be expected to benefit from drugs used to treat osteoporosis, although long-term data demonstrating an increase in bone density in these patients is not yet available [
Children who are at risk based on family history should undergo regular fundus examination to evaluate for the development of retinal neovascularization, traction, or exudate.
Asymptomatic individuals with a small region of peripheral avascularity may require annual review only. Those with active neovascularization or exudate may well require treatment and close observation thereafter.
Individuals with retinal traction require review at intervals depending on the degree of stability of the clinical findings. The frequency of the review varies by individual depending on the assessment of the examining clinician.
Relatives at risk benefit from fundus examination and, ideally, fundus fluorescein angiography to identify any characteristic lesions. Prophylaxis in the form of peripheral retinal ablation with laser photocoagulation or cryotherapy depends on the individual's age and the progression of the lesion.
If the pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk family members may be useful: relatives who do not have the family-specific pathogenic variant do not need regular retinal examinations.
See
Vascular endothelial growth factor (VEGF) inhibitors are currently in widespread use for acquired retinal diseases with a neovascular or exudative component. An as-yet unpublished study presented information on six children with FEVR and sight-threatening retinal neovascularization and exudate who had failed to stabilize with conventional treatments [
Search
• Ophthalmologic examination, including indirect ophthalmoscopy and scleral depression
• Fundus fluorescein angiography, which increases the detection rate of peripheral avascularity in asymptomatic affected individuals [
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with autosomal dominant familial exudative vitreoretinopathy (adFEVR), the following evaluations are recommended:
Ophthalmologic examination, including indirect ophthalmoscopy and scleral depression
Fundus fluorescein angiography, which increases the detection rate of peripheral avascularity in asymptomatic affected individuals [
• Ophthalmologic examination, including indirect ophthalmoscopy and scleral depression
• Fundus fluorescein angiography, which increases the detection rate of peripheral avascularity in asymptomatic affected individuals [
## Treatment of Manifestations
Retinal avascularity per se often requires no treatment; however, it can induce ischemia, leading to neovascularization of the retinal periphery, which can be treated with prophylactic cryotherapy or argon laser photocoagulation to attempt to induce regression of the new vessels. Similar treatments are used to treat retinal holes and areas of retinal exudate to prevent retinal detachment.
Rhegmatogenous retinal detachments produced by retinal traction are repaired surgically using conventional methods, but the prognosis is guarded.
Exudative retinal detachments may be stabilized with cryotherapy, but the prognosis is poor.
## Prevention of Primary Manifestations
The arc of peripheral retinal avascularity, thought to be an aberration of retinal development, is not preventable using current treatments.
## Prevention of Secondary Complications
Patients with FEVR associated with reduced bone density would be expected to benefit from drugs used to treat osteoporosis, although long-term data demonstrating an increase in bone density in these patients is not yet available [
## Surveillance
Children who are at risk based on family history should undergo regular fundus examination to evaluate for the development of retinal neovascularization, traction, or exudate.
Asymptomatic individuals with a small region of peripheral avascularity may require annual review only. Those with active neovascularization or exudate may well require treatment and close observation thereafter.
Individuals with retinal traction require review at intervals depending on the degree of stability of the clinical findings. The frequency of the review varies by individual depending on the assessment of the examining clinician.
## Evaluation of Relatives at Risk
Relatives at risk benefit from fundus examination and, ideally, fundus fluorescein angiography to identify any characteristic lesions. Prophylaxis in the form of peripheral retinal ablation with laser photocoagulation or cryotherapy depends on the individual's age and the progression of the lesion.
If the pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk family members may be useful: relatives who do not have the family-specific pathogenic variant do not need regular retinal examinations.
See
## Therapies Under Investigation
Vascular endothelial growth factor (VEGF) inhibitors are currently in widespread use for acquired retinal diseases with a neovascular or exudative component. An as-yet unpublished study presented information on six children with FEVR and sight-threatening retinal neovascularization and exudate who had failed to stabilize with conventional treatments [
Search
## Genetic Counseling
Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is inherited in an autosomal dominant manner.
Most individuals diagnosed with adFEVR have inherited the pathogenic variant from a parent who may or may not be affected.
Because of reduced penetrance, it is common for such parents to have no visual complications and thus be undiagnosed.
The pathogenic variant may be in an (as-yet) unidentified gene.
A proband with adFEVR may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
If a parent of the proband has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the sib inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity of symptoms.
Initial studies have shown that up to 90% of individuals with adFEVR can be asymptomatic.
If a pathogenic variant has not been identified in the proband and both parents have normal findings on fundus fluorescein angiography, the risk to the sibs of a proband for adFEVR is low.
Although no instances of germline mosaicism have been reported, it remains a possibility.
Each child of an individual with adFEVR has a 50% chance of inheriting the pathogenic variant.
If the offspring inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity.
Up to 90% of individuals with adFEVR can be asymptomatic.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
• Most individuals diagnosed with adFEVR have inherited the pathogenic variant from a parent who may or may not be affected.
• Because of reduced penetrance, it is common for such parents to have no visual complications and thus be undiagnosed.
• The pathogenic variant may be in an (as-yet) unidentified gene.
• Because of reduced penetrance, it is common for such parents to have no visual complications and thus be undiagnosed.
• The pathogenic variant may be in an (as-yet) unidentified gene.
• A proband with adFEVR may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Because of reduced penetrance, it is common for such parents to have no visual complications and thus be undiagnosed.
• The pathogenic variant may be in an (as-yet) unidentified gene.
• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
• If a parent of the proband has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the sib inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity of symptoms.
• Initial studies have shown that up to 90% of individuals with adFEVR can be asymptomatic.
• If the sib inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity of symptoms.
• Initial studies have shown that up to 90% of individuals with adFEVR can be asymptomatic.
• If a pathogenic variant has not been identified in the proband and both parents have normal findings on fundus fluorescein angiography, the risk to the sibs of a proband for adFEVR is low.
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• If the sib inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity of symptoms.
• Initial studies have shown that up to 90% of individuals with adFEVR can be asymptomatic.
• Each child of an individual with adFEVR has a 50% chance of inheriting the pathogenic variant.
• If the offspring inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity.
• Up to 90% of individuals with adFEVR can be asymptomatic.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with adFEVR have inherited the pathogenic variant from a parent who may or may not be affected.
Because of reduced penetrance, it is common for such parents to have no visual complications and thus be undiagnosed.
The pathogenic variant may be in an (as-yet) unidentified gene.
A proband with adFEVR may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
If a parent of the proband has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the sib inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity of symptoms.
Initial studies have shown that up to 90% of individuals with adFEVR can be asymptomatic.
If a pathogenic variant has not been identified in the proband and both parents have normal findings on fundus fluorescein angiography, the risk to the sibs of a proband for adFEVR is low.
Although no instances of germline mosaicism have been reported, it remains a possibility.
Each child of an individual with adFEVR has a 50% chance of inheriting the pathogenic variant.
If the offspring inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity.
Up to 90% of individuals with adFEVR can be asymptomatic.
• Most individuals diagnosed with adFEVR have inherited the pathogenic variant from a parent who may or may not be affected.
• Because of reduced penetrance, it is common for such parents to have no visual complications and thus be undiagnosed.
• The pathogenic variant may be in an (as-yet) unidentified gene.
• Because of reduced penetrance, it is common for such parents to have no visual complications and thus be undiagnosed.
• The pathogenic variant may be in an (as-yet) unidentified gene.
• A proband with adFEVR may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Because of reduced penetrance, it is common for such parents to have no visual complications and thus be undiagnosed.
• The pathogenic variant may be in an (as-yet) unidentified gene.
• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
• If a parent of the proband has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the sib inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity of symptoms.
• Initial studies have shown that up to 90% of individuals with adFEVR can be asymptomatic.
• If the sib inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity of symptoms.
• Initial studies have shown that up to 90% of individuals with adFEVR can be asymptomatic.
• If a pathogenic variant has not been identified in the proband and both parents have normal findings on fundus fluorescein angiography, the risk to the sibs of a proband for adFEVR is low.
• Although no instances of germline mosaicism have been reported, it remains a possibility.
• If the sib inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity of symptoms.
• Initial studies have shown that up to 90% of individuals with adFEVR can be asymptomatic.
• Each child of an individual with adFEVR has a 50% chance of inheriting the pathogenic variant.
• If the offspring inherits the pathogenic variant, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity.
• Up to 90% of individuals with adFEVR can be asymptomatic.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Diagnosis
Once the pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
31 Center Drive
MSC 2510
Bethesda MD 20892-2510
12 Camden Row
Suite 108, Camden Business Centre
Dublin 8
Ireland
Moran Eye Center, University of Utah
65 Medical Drive
Room 6620-C
Salt Lake City UT 84112
•
• 31 Center Drive
• MSC 2510
• Bethesda MD 20892-2510
•
•
• 12 Camden Row
• Suite 108, Camden Business Centre
• Dublin 8
• Ireland
•
•
• Moran Eye Center, University of Utah
• 65 Medical Drive
• Room 6620-C
• Salt Lake City UT 84112
•
•
## Molecular Genetics
Familial Exudative Vitreoretinopathy, Autosomal Dominant: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Familial Exudative Vitreoretinopathy, Autosomal Dominant (
The primary pathologic process in autosomal dominant familial exudative vitreoretinopathy (adFEVR) is believed to be a premature arrest of retinal angiogenesis/vasculogenesis or retinal vascular differentiation, leading to incomplete vascularization of the peripheral retina. To date, pathogenic variants in four genes have been shown to cause FEVR:
Selected
Variants listed in the table have been provided by the authors.
Associated with a more severe phenotype when
Associated with a more severe ocular phenotype when
The majority of the frizzled-4 pathogenic missense variants appear to be in functional sites, suggesting that they knock out the function of the protein. For example, in vitro experiments have shown that missense variants in the CRD domain (p.Met105Val and p.Met157Val) reduce the ability of frizzled-4 to bind norrin and to activate the β-catenin pathway [
Selected
Variants listed in the table have been provided by the authors.
Associated with a more severe phenotype when
Selected
Variants listed in the table have been provided by the authors.
Common in the Netherlands
## Molecular Pathogenesis
The primary pathologic process in autosomal dominant familial exudative vitreoretinopathy (adFEVR) is believed to be a premature arrest of retinal angiogenesis/vasculogenesis or retinal vascular differentiation, leading to incomplete vascularization of the peripheral retina. To date, pathogenic variants in four genes have been shown to cause FEVR:
Selected
Variants listed in the table have been provided by the authors.
Associated with a more severe phenotype when
Associated with a more severe ocular phenotype when
The majority of the frizzled-4 pathogenic missense variants appear to be in functional sites, suggesting that they knock out the function of the protein. For example, in vitro experiments have shown that missense variants in the CRD domain (p.Met105Val and p.Met157Val) reduce the ability of frizzled-4 to bind norrin and to activate the β-catenin pathway [
Selected
Variants listed in the table have been provided by the authors.
Associated with a more severe phenotype when
Selected
Variants listed in the table have been provided by the authors.
Common in the Netherlands
##
Selected
Variants listed in the table have been provided by the authors.
Associated with a more severe phenotype when
Associated with a more severe ocular phenotype when
The majority of the frizzled-4 pathogenic missense variants appear to be in functional sites, suggesting that they knock out the function of the protein. For example, in vitro experiments have shown that missense variants in the CRD domain (p.Met105Val and p.Met157Val) reduce the ability of frizzled-4 to bind norrin and to activate the β-catenin pathway [
##
Selected
Variants listed in the table have been provided by the authors.
Associated with a more severe phenotype when
##
Selected
Variants listed in the table have been provided by the authors.
Common in the Netherlands
## References
## Literature Cited
## Chapter Notes
3 September 2020 (ma) Chapter retired: outdated; qualified authors not available for update
22 September 2011 (cd) Revision: sequence analysis of
14 July 2011 (me) Comprehensive update posted live
11 December 2008 (cd) Revision: clinical and prenatal testing available for mutations in
28 August 2008 (cd) Revision: sequence analysis available clinically
27 August 2007 (me) Comprehensive update posted live
21 March 2005 (me) Review posted live
9 September 2004 (ct) Original submission
• 3 September 2020 (ma) Chapter retired: outdated; qualified authors not available for update
• 22 September 2011 (cd) Revision: sequence analysis of
• 14 July 2011 (me) Comprehensive update posted live
• 11 December 2008 (cd) Revision: clinical and prenatal testing available for mutations in
• 28 August 2008 (cd) Revision: sequence analysis available clinically
• 27 August 2007 (me) Comprehensive update posted live
• 21 March 2005 (me) Review posted live
• 9 September 2004 (ct) Original submission
## Revision History
3 September 2020 (ma) Chapter retired: outdated; qualified authors not available for update
22 September 2011 (cd) Revision: sequence analysis of
14 July 2011 (me) Comprehensive update posted live
11 December 2008 (cd) Revision: clinical and prenatal testing available for mutations in
28 August 2008 (cd) Revision: sequence analysis available clinically
27 August 2007 (me) Comprehensive update posted live
21 March 2005 (me) Review posted live
9 September 2004 (ct) Original submission
• 3 September 2020 (ma) Chapter retired: outdated; qualified authors not available for update
• 22 September 2011 (cd) Revision: sequence analysis of
• 14 July 2011 (me) Comprehensive update posted live
• 11 December 2008 (cd) Revision: clinical and prenatal testing available for mutations in
• 28 August 2008 (cd) Revision: sequence analysis available clinically
• 27 August 2007 (me) Comprehensive update posted live
• 21 March 2005 (me) Review posted live
• 9 September 2004 (ct) Original submission
Classic features of FEVR
1A. Fundus fluorescein angiogram showing the temporal retinal periphery of the right eye of a mildly affected person. Black areas to the left of the photograph represent loss of the normal capillary architecture corresponding to a region of retinal avascularity. Adjacent to this are dilated truncated telangictatic vessels leaking fluorescein dye (white patches). On the right of the photograph preserved retinal vessels are straightened as they approach the avascular zone.
1B. Fundus photograph of the right eye from an individual with more severe disease. Extensive vitreoretinal traction distorts the retinal vessels emerging from the optic disc, producing a retinal fold extending across the posterior pole to the temporal periphery.
|
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"HM Bottomley, LM Downey, CF Inglehearn, C Toomes. Comment on 'cosegregation of two unlinked mutant alleles in some cases of autosomal dominant familial exudative vitreoretinopathy.'. Eur J Hum Genet 2006;14:6-7",
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"ZY Chen, EM Battinelli, A Fielder, S Bundey, K Sims, XO Breakefield, IW Craig. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy.. Nat Genet 1993;5:180-3",
"G de Crecchio, F Simonelli, G Nunziata, S Mazzeo, GM Greco, E Rinaldi, V Ventruto, A Ciccodicola, MG Miano, F Testa, A Curci, M D'Urso, MM Rinaldi, ML Cavaliere, P Castelluccio. Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity.. Clin Genet 1998;54:315-20",
"LM Downey, HM Bottomley, E Sheridan, M Ahmed, DF Gilmour, CF Inglehearn, A Reddy, A Agrawal, J Bradbury, C Toomes. Reduced bone mineral density and hyaloid vasculature remnants in a consanguineous recessive FEVR family with a mutation in LRP5.. Br J Ophthalmol 2006;90:1163-7",
"LM Downey, TJ Keen, E Roberts, DC Mansfield, M Bamashmus, CF Inglehearn. A new locus for autosomal dominant familial exudative vitreoretinopathy maps to chromosome 11p12-13.. Am J Hum Genet 2001;68:778-81",
"KA Drenser, W Dailey, A Vinekar, K Dalal, A Capone, MT Trese. Clinical presentation and genetic correlation of patients with mutations affecting the FZD4 gene.. Arch Ophthalmol. 2009;127:1649-54",
"Y Gong, RB Slee, N Fukai, G Rawadi, S Roman-Roman, AM Reginato, H Wang, T Cundy, FH Glorieux, D Lev, M Zacharin, K Oexle, J Marcelino, W Suwairi, S Heeger, G Sabatakos, S Apte, WN Adkins, J Allgrove, M Arslan-Kirchner, JA Batch, P Beighton, GC Black, RG Boles, LM Boon, C Borrone, HG Brunner, GF Carle, B Dallapiccola, A De Paepe, B Floege, ML Halfhide, B Hall, RC Hennekam, T Hirose, A Jans, H Juppner, CA Kim, K Keppler-Noreuil, A Kohlschuetter, D LaCombe, M Lambert, E Lemyre, T Letteboer, L Peltonen, RS Ramesar, M Romanengo, H Somer, E Steichen-Gersdorf, B Steinmann, B Sullivan, A Superti-Furga, W Swoboda, MJ van den Boogaard, W Van Hul, M Vikkula, M Votruba, B Zabel, T Garcia, R Baron, BR Olsen, ML Warman. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.. Cell 2001;107:513-23",
"X He, M Semenov, K Tamai, X Zeng. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way.. Development 2004;131:1663-77",
"HC Huang, PS Klein. The Frizzled family: receptors for multiple signal transduction pathways.. Genome Biol 2004;5:234",
"LY Jia, XX Li, WZ Yu, WT Zeng, C Liang. Novel frizzled-4 gene mutations in chinese patients with familial exudative vitreoretinopathy.. Arch Ophthalmol. 2010;128:1341-9",
"X Jiao, V Ventruto, MT Trese, BS Shastry, JF Hejtmancik. Autosomal recessive familial exudative vitreoretinopathy is associated with mutations in LRP5.. Am J Hum Genet 2004;75:878-84",
"HJ Junge, S Yang, JB Burton, K Paes, X Shu, DM French, M Costa, DS Rice, W Ye. TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling.. Cell. 2009;139:299-311",
"A Kaykas, J Yang-Snyder, M Heroux, KV Shah, M Bouvier, RT Moon. Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization.. Nat Cell Biol 2004;6:52-8",
"H Kondo, H Hayashi, K Oshima, T Tahira, K Hayashi. Frizzled 4 gene (FZD4) mutations in patients with familial exudative vitreoretinopathy with variable expressivity.. Br J Ophthalmol 2003;87:1291-5",
"H Kondo, S Kusaka, A Yoshinaga, E Uchio, A Tawara, K Hayashi, T Tahira. Mutations in the TSPAN12 gene in Japanese patients with familial exudative vitreoretinopathy.. Am J Ophthalmol. 2011;151:1095-1100",
"RD Little, JP Carulli, RG Del Mastro, J Dupuis, M Osborne, C Folz, SP Manning, PM Swain, SC Zhao, B Eustace, MM Lappe, L Spitzer, S Zweier, K Braunschweiger, Y Benchekroun, X Hu, R Adair, L Chee, MG FitzGerald, C Tulig, A Caruso, N Tzellas, A Bawa, B Franklin, S McGuire, X Nogues, G Gong, KM Allen, A Anisowicz, AJ Morales, PT Lomedico, SM Recker, P Van Eerdewegh, RR Recker, ML Johnson. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.. Am J Hum Genet 2002;70:11-9",
"ML MacDonald, YP Goldberg, J Macfarlane, ME Samuels, MT Trese, BS Shastry. Genetic variants of frizzled-4 gene in familial exudative vitreoretinopathy and advanced retinopathy of prematurity.. Clin Genet 2005;67:363-6",
"H Miyakubo, K Hashimoto, S Miyakubo. Retinal vascular pattern in familial exudative vitreoretinopathy.. Ophthalmology 1984;91:1524-30",
"J Nallathambi, D Shukla, A Rajendran, P Namperumalsamy, R Muthulakshmi, P Sundaresan. Identification of novel FZD4 mutations in Indian patients with familial exudative vitreoretinopathy.. Mol Vis 2006;12:1086-92",
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"K Nikopoulos, H Venselaar, RW Collin, R Riveiro-Alvarez, FN Boonstra, JM Hooymans, A Mukhopadhyay, D Shears, M van Bers, IJ de Wijs, AJ van Essen, RH Sijmons, MA Tilanus, CE van Nouhuys, C Ayuso, LH Hoefsloot, FP Cremers. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP.. Hum Mutat. 2010b;31:656-66",
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"JA Poulter, M Ali, DF Gilmour, A Rice, H Kondo, K Hayashi, DA Mackey, LS Kearns, JB Ruddle, JE Craig, EA Pierce, LM Downey, MD Mohamed, AF Markham, CF Inglehearn, C Toomes. Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy.. Am J Hum Genet. 2010;86:248-53",
"M Qin, H Hayashi, K Oshima, T Tahira, K Hayashi, H Kondo. Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes.. Hum Mutat 2005;26:104-12",
"J Robitaille, ML MacDonald, A Kaykas, LC Sheldahl, J Zeisler, MP Dube, LH Zhang, RR Singaraja, DL Guernsey, B Zheng, LF Siebert, A Hoskin-Mott, MT Trese, SN Pimstone, BS Shastry, RT Moon, MR Hayden, YP Goldberg, ME Samuels. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy.. Nat Genet 2002;32:326-30",
"JM Robitaille, B Zheng, K Wallace, MJ Beis, C Tatlidil, J Yang, TG Sheidow, L Siebert, AV Levin, WC Lam, BW Arthur, CJ Lyons, E Jaakkola, E Tsilou, CA Williams, RG Weaver, CL Shields, DL Guernsey. The role of Frizzled-4 mutations in familial exudative vitreoretinopathy and Coats disease.. Br J Ophthalmol. 2011;95:574-9",
"BS Shastry, MT Trese. Familial exudative vitreoretinopathy: further evidence for genetic heterogeneity.. Am J Med Genet 1997;69:217-8",
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"W Tasman, JJ Augsburger, JA Shields, A Caputo, WH Annesley. Familial exudative vitreoretinopathy.. Trans Am Ophthalmol Soc 1981;79:211-26",
"C Toomes, HM Bottomley, RM Jackson, KV Towns, S Scott, DA Mackey, JE Craig, L Jiang, Z Yang, R Trembath, G Woodruff, CY Gregory-Evans, K Gregory-Evans, MJ Parker, GC Black, LM Downey, K Zhang, CF Inglehearn. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q.. Am J Hum Genet 2004a;74:721-30",
"C Toomes, HM Bottomley, S Scott, DA Mackey, JE Craig, B Appukuttan, JT Stout, CJ Flaxel, K Zhang, GC Black, A Fryer, LM Downey, CF Inglehearn. Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy.. Invest Ophthalmol Vis Sci 2004b;45:2083-90",
"CE van Nouhuys. Dominant exudative vitreoretinopathy and other vascular developmental disorders of the peripheral retina.. Doc Ophthalmol 1982;54:1-414",
"CE van Nouhuys. Signs, complications, and platelet aggregation in familial exudative vitreoretinopathy.. Am J Ophthalmol 1991;111:34-41",
"L Van Wesenbeeck, E Cleiren, J Gram, RK Beals, O Benichou, D Scopelliti, L Key, T Renton, C Bartels, Y Gong, ML Warman, MC De Vernejoul, J Bollerslev, W Van Hul. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density.. Am J Hum Genet 2003;72:763-71",
"Q Xu, Y Wang, A Dabdoub, PM Smallwood, J Williams, C Woods, MW Kelley, L Jiang, W Tasman, K Zhang, J Nathans. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair.. Cell 2004;116:883-95",
"X Ye, Y Wang, J Nathans. The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease.. Trends Mol Med. 2010;16:417-25"
] |
21/3/2005
|
14/7/2011
|
22/9/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
fg
|
fg
|
[
"FG Syndrome Type 1 (FGS1)",
"Lujan Syndrome (LS)",
"X-Linked Ohdo Syndrome (XLOS)",
"MED12-Related Nonspecific Intellectual Disability (MED12-Related NSID)",
"Hardikar Syndrome (HS)",
"Mediator of RNA polymerase II transcription subunit 12",
"MED12",
"MED12-Related Disorders"
] |
Michael J Lyons
|
Summary The diagnosis of an
|
FG syndrome type 1 (FGS1)
Lujan syndrome (LS)
X-linked Ohdo syndrome (XLOS)
Hardikar syndrome (HS)
Nonspecific intellectual disability (NSID)
For synonyms and outdated names see
• FG syndrome type 1 (FGS1)
• Lujan syndrome (LS)
• X-linked Ohdo syndrome (XLOS)
• Hardikar syndrome (HS)
• Nonspecific intellectual disability (NSID)
## Diagnosis
An
Neurodevelopmental delays
Characteristic facial features:
Absolute or relative macrocephaly
Dolichocephaly
Frontal hair upsweep
Tall forehead
Downslanted palpebral fissures
Widely spaced eyes
Fullness of the upper eyelids
Small, simple ears (≤10th percentile)
Open mouth
Long narrow face
Broad thumbs and halluces
Congenital anomaly (corpus callosum, anal, cardiac, skeletal)
Hypotonia, constipation, or feeding problems
Characteristic behavior (affable and eager to please)
A family history consistent with X-linked inheritance
Intellectual disability
Hypotonia
Large head (occipitofrontal circumference >75th percentile)
Tall, thin body habitus (height >75th percentile)
Long, thin face
Prominent nasal bridge
High narrow palate
Short philtrum
Additional clinical features that can assist in recognition of individuals with LS:
Hypernasal speech
Dysphagia
Micrognathia
Long hands
Hyperextensible digits
Abnormalities of the corpus callosum
Family history consistent with X-linked inheritance
Intellectual disability
Blepharophimosis
Ptosis
Epicanthal folds
Facial coarsening at an older age
Additional clinical features that can assist in recognition of individuals with XLOS:
Triangular face
Maxillary hypoplasia
Sparse eyebrows
Hypertelorism
Strabismus
Small low-set ears
Thick alae nasi
Wide nasal bridge
Broad nasal tip
Micrognathia
Small mouth
Dental anomalies
Hypotonia
Family history consistent with X-linked inheritance
Cleft lip and/or cleft palate
Biliary anomalies
Liver disease
Intestinal malrotation
Pigmentary retinopathy
Coarctation of the aorta
Additional clinical features that can assist in recognition of individuals with HS:
Normal cognition
Preauricular pit/tag
Hydronephrosis
Choledochal cyst
Strabismus
Intellectual disability
Behavior issues
Feeding problems
Growth delays
Abnormalities of the corpus callosum
Hypotonia
Blepharophimosis
Low-set, posteriorly rotated ears
Prominent forehead
Palatal anomalies
Constipation
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous
Note: Female carriers of a pathogenic variant in
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Neurodevelopmental delays
• Characteristic facial features:
• Absolute or relative macrocephaly
• Dolichocephaly
• Frontal hair upsweep
• Tall forehead
• Downslanted palpebral fissures
• Widely spaced eyes
• Fullness of the upper eyelids
• Small, simple ears (≤10th percentile)
• Open mouth
• Long narrow face
• Absolute or relative macrocephaly
• Dolichocephaly
• Frontal hair upsweep
• Tall forehead
• Downslanted palpebral fissures
• Widely spaced eyes
• Fullness of the upper eyelids
• Small, simple ears (≤10th percentile)
• Open mouth
• Long narrow face
• Broad thumbs and halluces
• Congenital anomaly (corpus callosum, anal, cardiac, skeletal)
• Hypotonia, constipation, or feeding problems
• Characteristic behavior (affable and eager to please)
• A family history consistent with X-linked inheritance
• Absolute or relative macrocephaly
• Dolichocephaly
• Frontal hair upsweep
• Tall forehead
• Downslanted palpebral fissures
• Widely spaced eyes
• Fullness of the upper eyelids
• Small, simple ears (≤10th percentile)
• Open mouth
• Long narrow face
• Intellectual disability
• Hypotonia
• Large head (occipitofrontal circumference >75th percentile)
• Tall, thin body habitus (height >75th percentile)
• Long, thin face
• Prominent nasal bridge
• High narrow palate
• Short philtrum
• Hypernasal speech
• Dysphagia
• Micrognathia
• Long hands
• Hyperextensible digits
• Abnormalities of the corpus callosum
• Family history consistent with X-linked inheritance
• Intellectual disability
• Blepharophimosis
• Ptosis
• Epicanthal folds
• Facial coarsening at an older age
• Triangular face
• Maxillary hypoplasia
• Sparse eyebrows
• Hypertelorism
• Strabismus
• Small low-set ears
• Thick alae nasi
• Wide nasal bridge
• Broad nasal tip
• Micrognathia
• Small mouth
• Dental anomalies
• Hypotonia
• Family history consistent with X-linked inheritance
• Cleft lip and/or cleft palate
• Biliary anomalies
• Liver disease
• Intestinal malrotation
• Pigmentary retinopathy
• Coarctation of the aorta
• Normal cognition
• Preauricular pit/tag
• Hydronephrosis
• Choledochal cyst
• Strabismus
• Intellectual disability
• Behavior issues
• Feeding problems
• Growth delays
• Abnormalities of the corpus callosum
• Hypotonia
• Blepharophimosis
• Low-set, posteriorly rotated ears
• Prominent forehead
• Palatal anomalies
• Constipation
## Suggestive Findings
An
Neurodevelopmental delays
Characteristic facial features:
Absolute or relative macrocephaly
Dolichocephaly
Frontal hair upsweep
Tall forehead
Downslanted palpebral fissures
Widely spaced eyes
Fullness of the upper eyelids
Small, simple ears (≤10th percentile)
Open mouth
Long narrow face
Broad thumbs and halluces
Congenital anomaly (corpus callosum, anal, cardiac, skeletal)
Hypotonia, constipation, or feeding problems
Characteristic behavior (affable and eager to please)
A family history consistent with X-linked inheritance
Intellectual disability
Hypotonia
Large head (occipitofrontal circumference >75th percentile)
Tall, thin body habitus (height >75th percentile)
Long, thin face
Prominent nasal bridge
High narrow palate
Short philtrum
Additional clinical features that can assist in recognition of individuals with LS:
Hypernasal speech
Dysphagia
Micrognathia
Long hands
Hyperextensible digits
Abnormalities of the corpus callosum
Family history consistent with X-linked inheritance
Intellectual disability
Blepharophimosis
Ptosis
Epicanthal folds
Facial coarsening at an older age
Additional clinical features that can assist in recognition of individuals with XLOS:
Triangular face
Maxillary hypoplasia
Sparse eyebrows
Hypertelorism
Strabismus
Small low-set ears
Thick alae nasi
Wide nasal bridge
Broad nasal tip
Micrognathia
Small mouth
Dental anomalies
Hypotonia
Family history consistent with X-linked inheritance
Cleft lip and/or cleft palate
Biliary anomalies
Liver disease
Intestinal malrotation
Pigmentary retinopathy
Coarctation of the aorta
Additional clinical features that can assist in recognition of individuals with HS:
Normal cognition
Preauricular pit/tag
Hydronephrosis
Choledochal cyst
Strabismus
Intellectual disability
Behavior issues
Feeding problems
Growth delays
Abnormalities of the corpus callosum
Hypotonia
Blepharophimosis
Low-set, posteriorly rotated ears
Prominent forehead
Palatal anomalies
Constipation
• Neurodevelopmental delays
• Characteristic facial features:
• Absolute or relative macrocephaly
• Dolichocephaly
• Frontal hair upsweep
• Tall forehead
• Downslanted palpebral fissures
• Widely spaced eyes
• Fullness of the upper eyelids
• Small, simple ears (≤10th percentile)
• Open mouth
• Long narrow face
• Absolute or relative macrocephaly
• Dolichocephaly
• Frontal hair upsweep
• Tall forehead
• Downslanted palpebral fissures
• Widely spaced eyes
• Fullness of the upper eyelids
• Small, simple ears (≤10th percentile)
• Open mouth
• Long narrow face
• Broad thumbs and halluces
• Congenital anomaly (corpus callosum, anal, cardiac, skeletal)
• Hypotonia, constipation, or feeding problems
• Characteristic behavior (affable and eager to please)
• A family history consistent with X-linked inheritance
• Absolute or relative macrocephaly
• Dolichocephaly
• Frontal hair upsweep
• Tall forehead
• Downslanted palpebral fissures
• Widely spaced eyes
• Fullness of the upper eyelids
• Small, simple ears (≤10th percentile)
• Open mouth
• Long narrow face
• Intellectual disability
• Hypotonia
• Large head (occipitofrontal circumference >75th percentile)
• Tall, thin body habitus (height >75th percentile)
• Long, thin face
• Prominent nasal bridge
• High narrow palate
• Short philtrum
• Hypernasal speech
• Dysphagia
• Micrognathia
• Long hands
• Hyperextensible digits
• Abnormalities of the corpus callosum
• Family history consistent with X-linked inheritance
• Intellectual disability
• Blepharophimosis
• Ptosis
• Epicanthal folds
• Facial coarsening at an older age
• Triangular face
• Maxillary hypoplasia
• Sparse eyebrows
• Hypertelorism
• Strabismus
• Small low-set ears
• Thick alae nasi
• Wide nasal bridge
• Broad nasal tip
• Micrognathia
• Small mouth
• Dental anomalies
• Hypotonia
• Family history consistent with X-linked inheritance
• Cleft lip and/or cleft palate
• Biliary anomalies
• Liver disease
• Intestinal malrotation
• Pigmentary retinopathy
• Coarctation of the aorta
• Normal cognition
• Preauricular pit/tag
• Hydronephrosis
• Choledochal cyst
• Strabismus
• Intellectual disability
• Behavior issues
• Feeding problems
• Growth delays
• Abnormalities of the corpus callosum
• Hypotonia
• Blepharophimosis
• Low-set, posteriorly rotated ears
• Prominent forehead
• Palatal anomalies
• Constipation
## Establishing the Diagnosis
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous
Note: Female carriers of a pathogenic variant in
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
FGS1 is an X-linked disorder associated with intellectual disability, hypotonia, relative macrocephaly, broad and flat thumbs, and imperforate anus. The clinical phenotype attributed to FGS1 has widened since the initial description. Many of the clinical features in individuals reported to have FGS1 are nonspecific and may lead to overdiagnosis [
Other musculoskeletal features described in individuals with FGS1 include: cutaneous syndactyly, oligodactyly, joint hypermobility, joint contractures, limited elbow supination, ectrodactyly, clinodactyly, duplicated thumbs and halluces, spinal curvature, pectus excavatum, rib anomalies, and hip dysplasia [
A pathogenic
XLOS is characterized by blepharophimosis, intellectual disability, and coarse facial features [
HS is characterized by cleft lip and/or cleft palate, biliary anomalies, pigmentary retinopathy, intestinal malrotation, coarctation of the aorta, and normal cognition [
Both males and females have been reported with
Penetrance is presumed to be 100% in males with
Females with
The name FG syndrome represents two surname initials in the originally reported family. FGS1 is also referred to as Opitz-Kaveggia syndrome [
Lujan syndrome is also referred to as Lujan-Fryns syndrome or intellectual disability, X-linked, with marfanoid habitus [
X-linked Ohdo syndrome has been referred to as blepharophimosis and mental retardation syndrome, Maat-Kievit-Brunner type [
The prevalence of
The prevalence of
The prevalence of
The prevalence of
The overall prevalence of
## Clinical Description
FGS1 is an X-linked disorder associated with intellectual disability, hypotonia, relative macrocephaly, broad and flat thumbs, and imperforate anus. The clinical phenotype attributed to FGS1 has widened since the initial description. Many of the clinical features in individuals reported to have FGS1 are nonspecific and may lead to overdiagnosis [
Other musculoskeletal features described in individuals with FGS1 include: cutaneous syndactyly, oligodactyly, joint hypermobility, joint contractures, limited elbow supination, ectrodactyly, clinodactyly, duplicated thumbs and halluces, spinal curvature, pectus excavatum, rib anomalies, and hip dysplasia [
A pathogenic
XLOS is characterized by blepharophimosis, intellectual disability, and coarse facial features [
HS is characterized by cleft lip and/or cleft palate, biliary anomalies, pigmentary retinopathy, intestinal malrotation, coarctation of the aorta, and normal cognition [
Both males and females have been reported with
## FG Syndrome Type 1 (FGS1)
FGS1 is an X-linked disorder associated with intellectual disability, hypotonia, relative macrocephaly, broad and flat thumbs, and imperforate anus. The clinical phenotype attributed to FGS1 has widened since the initial description. Many of the clinical features in individuals reported to have FGS1 are nonspecific and may lead to overdiagnosis [
Other musculoskeletal features described in individuals with FGS1 include: cutaneous syndactyly, oligodactyly, joint hypermobility, joint contractures, limited elbow supination, ectrodactyly, clinodactyly, duplicated thumbs and halluces, spinal curvature, pectus excavatum, rib anomalies, and hip dysplasia [
## Lujan Syndrome (LS)
A pathogenic
## X-Linked Ohdo Syndrome (XLOS)
XLOS is characterized by blepharophimosis, intellectual disability, and coarse facial features [
## Hardikar Syndrome (HS)
HS is characterized by cleft lip and/or cleft palate, biliary anomalies, pigmentary retinopathy, intestinal malrotation, coarctation of the aorta, and normal cognition [
## Nonspecific Intellectual Disability (NSID)
Both males and females have been reported with
## Genotype-Phenotype Correlations
## Penetrance
Penetrance is presumed to be 100% in males with
Females with
## Nomenclature
The name FG syndrome represents two surname initials in the originally reported family. FGS1 is also referred to as Opitz-Kaveggia syndrome [
Lujan syndrome is also referred to as Lujan-Fryns syndrome or intellectual disability, X-linked, with marfanoid habitus [
X-linked Ohdo syndrome has been referred to as blepharophimosis and mental retardation syndrome, Maat-Kievit-Brunner type [
## Prevalence
The prevalence of
The prevalence of
The prevalence of
The prevalence of
The overall prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders with features overlapping those of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS) and/or Hardikar syndrome (HS) are summarized in
Disorders to Consider in the Differential Diagnosis of FG Syndrome Type 1, Lujan Syndrome, X-Linked Ohdo Syndrome, and Hardikar Syndrome
AD = autosomal dominant; AR = autosomal recessive; FGS1 = FG syndrome type 1; HS = Hardikar syndrome; ID = intellectual disability; LS = Lujan syndrome; MOI = mode of inheritance; XL = X-linked; XLOS = X-linked Ohdo syndrome
## Management
To establish the extent of disease and needs in an individual diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Neurologic eval for evidence of seizures & hypotonia
Consider EEG if seizures are a concern.
Consider brain imaging studies in persons w/seizures.
Assessment for feeding problems, constipation & gastroesophageal reflux
Exam for evidence of anal anomalies
Gastroenterology eval for liver disease & intestinal malrotation
Liver function testing, clotting studies, & liver ultrasound
Community or
Social work involvement for parental support;
Home nursing referral.
HS = Hardikar syndrome; MOI = mode of inheritance; NSID = nonspecific intellectual disability
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; HS = Hardikar syndrome; ID = intellectual disability; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures & changes in tone.
HS = Hardikar syndrome
See
Search
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Neurologic eval for evidence of seizures & hypotonia
• Consider EEG if seizures are a concern.
• Consider brain imaging studies in persons w/seizures.
• Assessment for feeding problems, constipation & gastroesophageal reflux
• Exam for evidence of anal anomalies
• Gastroenterology eval for liver disease & intestinal malrotation
• Liver function testing, clotting studies, & liver ultrasound
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures & changes in tone.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Neurologic eval for evidence of seizures & hypotonia
Consider EEG if seizures are a concern.
Consider brain imaging studies in persons w/seizures.
Assessment for feeding problems, constipation & gastroesophageal reflux
Exam for evidence of anal anomalies
Gastroenterology eval for liver disease & intestinal malrotation
Liver function testing, clotting studies, & liver ultrasound
Community or
Social work involvement for parental support;
Home nursing referral.
HS = Hardikar syndrome; MOI = mode of inheritance; NSID = nonspecific intellectual disability
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Neurologic eval for evidence of seizures & hypotonia
• Consider EEG if seizures are a concern.
• Consider brain imaging studies in persons w/seizures.
• Assessment for feeding problems, constipation & gastroesophageal reflux
• Exam for evidence of anal anomalies
• Gastroenterology eval for liver disease & intestinal malrotation
• Liver function testing, clotting studies, & liver ultrasound
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; HS = Hardikar syndrome; ID = intellectual disability; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures & changes in tone.
HS = Hardikar syndrome
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures & changes in tone.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
Because there have been no instances reported to date of a male with a pathogenic
A female proband may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
The risk to sibs of a male proband depends on the genetic status of the mother; the risk to sibs of a female proband is also expected to depend on the genetic status of the mother as there are no reports to date of a male with a pathogenic
If the mother of the proband has a
Males who inherit a
Females who inherit a pathogenic variant associated with FG syndrome type 1 (FGS1) or Lujan syndrome (LS) will be heterozygotes and will typically be unaffected but may have clinical manifestations (see
Both males and females have been reported with X-linked Ohdo syndrome (XLOS) [
Hardikar syndrome (HS) has only been reported in females [
Females with specific pathogenic variants associated with NSID may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Females with a
Female probands with NSID due to specific
Note: Molecular genetic testing may be able to identify the family member in whom a
Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the
Females who are heterozygous for an
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or are at risk of being heterozygotes.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• Because there have been no instances reported to date of a male with a pathogenic
• A female proband may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• The risk to sibs of a male proband depends on the genetic status of the mother; the risk to sibs of a female proband is also expected to depend on the genetic status of the mother as there are no reports to date of a male with a pathogenic
• If the mother of the proband has a
• Males who inherit a
• Females who inherit a pathogenic variant associated with FG syndrome type 1 (FGS1) or Lujan syndrome (LS) will be heterozygotes and will typically be unaffected but may have clinical manifestations (see
• Both males and females have been reported with X-linked Ohdo syndrome (XLOS) [
• Hardikar syndrome (HS) has only been reported in females [
• Females with specific pathogenic variants associated with NSID may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
• Males who inherit a
• Females who inherit a pathogenic variant associated with FG syndrome type 1 (FGS1) or Lujan syndrome (LS) will be heterozygotes and will typically be unaffected but may have clinical manifestations (see
• Both males and females have been reported with X-linked Ohdo syndrome (XLOS) [
• Hardikar syndrome (HS) has only been reported in females [
• Females with specific pathogenic variants associated with NSID may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit a
• Females who inherit a pathogenic variant associated with FG syndrome type 1 (FGS1) or Lujan syndrome (LS) will be heterozygotes and will typically be unaffected but may have clinical manifestations (see
• Both males and females have been reported with X-linked Ohdo syndrome (XLOS) [
• Hardikar syndrome (HS) has only been reported in females [
• Females with specific pathogenic variants associated with NSID may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
• Females with a
• Female probands with NSID due to specific
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or are at risk of being heterozygotes.
## Mode of Inheritance
## Risk to Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
Because there have been no instances reported to date of a male with a pathogenic
A female proband may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
The risk to sibs of a male proband depends on the genetic status of the mother; the risk to sibs of a female proband is also expected to depend on the genetic status of the mother as there are no reports to date of a male with a pathogenic
If the mother of the proband has a
Males who inherit a
Females who inherit a pathogenic variant associated with FG syndrome type 1 (FGS1) or Lujan syndrome (LS) will be heterozygotes and will typically be unaffected but may have clinical manifestations (see
Both males and females have been reported with X-linked Ohdo syndrome (XLOS) [
Hardikar syndrome (HS) has only been reported in females [
Females with specific pathogenic variants associated with NSID may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Females with a
Female probands with NSID due to specific
Note: Molecular genetic testing may be able to identify the family member in whom a
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• Because there have been no instances reported to date of a male with a pathogenic
• A female proband may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• The risk to sibs of a male proband depends on the genetic status of the mother; the risk to sibs of a female proband is also expected to depend on the genetic status of the mother as there are no reports to date of a male with a pathogenic
• If the mother of the proband has a
• Males who inherit a
• Females who inherit a pathogenic variant associated with FG syndrome type 1 (FGS1) or Lujan syndrome (LS) will be heterozygotes and will typically be unaffected but may have clinical manifestations (see
• Both males and females have been reported with X-linked Ohdo syndrome (XLOS) [
• Hardikar syndrome (HS) has only been reported in females [
• Females with specific pathogenic variants associated with NSID may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
• Males who inherit a
• Females who inherit a pathogenic variant associated with FG syndrome type 1 (FGS1) or Lujan syndrome (LS) will be heterozygotes and will typically be unaffected but may have clinical manifestations (see
• Both males and females have been reported with X-linked Ohdo syndrome (XLOS) [
• Hardikar syndrome (HS) has only been reported in females [
• Females with specific pathogenic variants associated with NSID may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit a
• Females who inherit a pathogenic variant associated with FG syndrome type 1 (FGS1) or Lujan syndrome (LS) will be heterozygotes and will typically be unaffected but may have clinical manifestations (see
• Both males and females have been reported with X-linked Ohdo syndrome (XLOS) [
• Hardikar syndrome (HS) has only been reported in females [
• Females with specific pathogenic variants associated with NSID may have clinical features with variable expression based on the pathogenic variant and X-chromosome inactivation.
• Females with a
• Female probands with NSID due to specific
## Heterozygote Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the
Females who are heterozygous for an
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or are at risk of being heterozygotes.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygotes or are at risk of being heterozygotes.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
## Molecular Genetics
MED12-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MED12-Related Disorders (
The MED12 protein contains an N-terminal MED12 domain involved in Cdk8 activation and a C-terminal Pro-, Gln-, and Leu-rich (PQL) domain which plays an important role in gene regulation through interaction with the Wnt, sonic hedgehog, REST, and SOX9 pathways [
Notable
FGS1 = FG syndrome type 1; HS = Hardikar syndrome; LS = Lujan syndrome; NSID = nonspecific intellectual disability; XLOS = X-linked Ohdo syndrome
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
The MED12 protein contains an N-terminal MED12 domain involved in Cdk8 activation and a C-terminal Pro-, Gln-, and Leu-rich (PQL) domain which plays an important role in gene regulation through interaction with the Wnt, sonic hedgehog, REST, and SOX9 pathways [
Notable
FGS1 = FG syndrome type 1; HS = Hardikar syndrome; LS = Lujan syndrome; NSID = nonspecific intellectual disability; XLOS = X-linked Ohdo syndrome
Variants listed in the table have been provided by the author.
## Chapter Notes
The author would like to thank Drs Roger Stevenson and Michael Friez for their critical review of the manuscript.
12 August 2021 (sw) Comprehensive update posted live
11 August 2016 (sw) Comprehensive update posted live
6 June 2013 (me) Comprehensive update posted live
14 July 2009 (cd) Revision: targeted mutation analysis for p.Arg961Trp mutation available clinically
23 June 2008 (me) Review posted live
25 April 2008 (mjl) Original submission
• 12 August 2021 (sw) Comprehensive update posted live
• 11 August 2016 (sw) Comprehensive update posted live
• 6 June 2013 (me) Comprehensive update posted live
• 14 July 2009 (cd) Revision: targeted mutation analysis for p.Arg961Trp mutation available clinically
• 23 June 2008 (me) Review posted live
• 25 April 2008 (mjl) Original submission
## Author Notes
## Acknowledgments
The author would like to thank Drs Roger Stevenson and Michael Friez for their critical review of the manuscript.
## Revision History
12 August 2021 (sw) Comprehensive update posted live
11 August 2016 (sw) Comprehensive update posted live
6 June 2013 (me) Comprehensive update posted live
14 July 2009 (cd) Revision: targeted mutation analysis for p.Arg961Trp mutation available clinically
23 June 2008 (me) Review posted live
25 April 2008 (mjl) Original submission
• 12 August 2021 (sw) Comprehensive update posted live
• 11 August 2016 (sw) Comprehensive update posted live
• 6 June 2013 (me) Comprehensive update posted live
• 14 July 2009 (cd) Revision: targeted mutation analysis for p.Arg961Trp mutation available clinically
• 23 June 2008 (me) Review posted live
• 25 April 2008 (mjl) Original submission
## References
## Literature Cited
|
[
"S Amodeo, G Vitrano, M Guardino, G Paci, F Corselli, V Antona, G Barrano, M Magliozzi, A Novelli, R Venezia, G Corsello. What is the impact of a novel MED12 variant on syndromic conotruncal heart defects? Analysis of case report on two male sibs.. Ital J Pediatr. 2020;46:98",
"H Bouazzi, G Lesca, C Trujillo, MK Alwasiyah, A Munnich. Nonsyndromic X-linked intellectual disability in three brothers with a novel MED12 missense mutation. Clin Case Rep. 2015;3:604-9",
"A Charzewska, R Maiwald, K Kahrizi, B Oehl-Jaschkowitz, A Dufke, JR Lemke, H Enders, H Najmabadi, A Tzschach, W Hachmann, C Jensen, M Bienek, J Poznanski, M Nawara, T Chilarska, E Obersztyn, D Hoffman-Zacharska, M Gos, J Bal, VM Kalscheuer. The power of the Mediator complex – expanding the genetic architecture and phenotypic spectrum of MED12-related disorders.. Clin Genet. 2018;94:450-6",
"RD Clark, JM Graham, MJ Friez, JJ Hoo, KL Jones, C McKeown, JB Moeschler, FL Raymond, RC Rogers, CE Schwartz, A Battaglia, MJ Lyons, RE Stevenson. FG syndrome, an X-linked multiple congenital anomaly syndrome: the clinical phenotype and an algorithm for diagnostic testing.. Genet Med. 2009;11:769-75",
"LM Donnio, B Bidon, S Hashimoto, M May, A Epanchintsev, C Ryan, W Allen, A Hackett, J Gecz, C Skinner, RE Stevenson, APM de Brouwer, C Coutton, C Francannet, PS Jouk, CE Schwartz, JM Egly. MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression.. Hum Mol Genet. 2017;26:2062-75",
"A Gonzalez, S Kapur, M Walsh, J Vengoechea. Two females with distinct de novo missense pathogenic variants in MED12 and vastly differing phenotypes.. Am J Med Genet A. 2021;185:2582-5",
"B Isidor, T Lefebvre, C Le Vaillant, G Caillaud, L Faivre, F Jossic, M Joubert, N Winer, C Le Caignec, G Borck, A Pelet, J Amiel, A Toutain, N Ronce, M Raynaud, A Verloes, A David. Blepharophimosis, short humeri, developmental delay and Hirschsprung disease: expanding the phenotypic spectrum of MED12 mutations.. Am J Med Genet A. 2014;164A:1821-5",
"A Khan, M Humayun, I Haider, M. Ayub. Lujan-Fryns Syndrome (LFS): A unique combination of hypernasality, Marfanoid body habitus, and neuropsychiatric issues, presenting as acute-onset dysphagia.. Clin Med Insights Case Rep. 2016;9:115-8",
"S Lahbib, M Trabelsi, H Dallali, R Sakka, R Bourourou, R Kefi, R Mrad, S Abdelhak. Gaddour. Novel MED12 variant in a multiplex Fragile X syndrome family: dual molecular etiology of two X-linked intellectual disabilities with autism in the same family.. Mol Biol Rep. 2019;46:4185-93",
"KG Langley, J Brown, RJ Gerber, J Fox, MJ Friez, M Lyons, SA Schrier Vergano. Beyond Ohdo syndrome: A familial missense mutation broadens the MED12 spectrum.. Am J Med Genet A. 2015;167A:3180-5",
"G Lesca, MP Moizard, G Bussy, D Boggio, H Hu, SA Haas, HH Ropers, VM Klascheuer, V Des Portes, A Labalme, D Sanlaville, P Edery, M Raynaud, J Lespinasse. Clinical and neurocognitive characterization of a family with a novel MED12 gene frameshift mutation.. Am J Med Genet A. 2013;161A:3063-71",
"D Li, A Strong, KM Shen, D Cassiman, M Van Dyck, ND Linhares, ER Valadares, T Wang, SDJ Pena, J Jaeken, S Vergano, E Zackai, A Hing, P Chow, A Ganguly, T Scholz, T Bierhals, D Philipp, H Hakonarson, E Bhoj. De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females.. Genet Med. 2021;23:637-44",
"H Murakami, Y Enomoto, Y Tsurusaki, Y Sugio, K. Kurosawa. A female patient with X-linked Ohdo syndrome of the Maat-Kievit-Brunner phenotype caused by a novel variant of MED12.. Congenit Anom (Kyoto) 2020;60:91-3",
"DL Narayanan, SR Phadke. A novel variant in MED12 gene: Further delineation of phenotype.. Am J Med Genet A. 2017;173:2257-60",
"SJ Patil, PH Somashekar, A Shukla, S Siddaiah, V Bhat, KM Girisha, PN Rao. Clinical variability in familial X-linke Ohdo syndrome Maat-Kievit-Brunner type with MED12 mutation.. J Pediatr Genet. 2017;6:198-204",
"SV Plassche, AP Brouwer. MED12-related (neuro)developmental disorders: a question of causality.. Genes (Basel) 2021;12:663",
"DL Polla, EJ Bhoj, JBGM Verheij, JSK Wassink-Ruiter, A Reis, C Deshpande, A Gregor, K Hill-Karfe, ATV Silfhout, R Pfundt, EMHF Bongers, H Hakonarson, S Berland, G Gradek, S Banka, K Chandler, L Gompertz, SC Huffels, CTRM Stumpel, R Wennekes, APA Stegmann, W Reardon, EKSM Leenders, BBA de Vries, D Li, E Zackai, N Ragge, SA Lynch, S Cuddapah, H van Bokhoven, C Zweier, APM de Brouwer. De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females.. Genet Med. 2021;23:645-52",
"TE Prescott, MA Kulseth, KR Heimdal, B Stadheim, E Hopp, T Gambin, ZH Coban Akdemir, SN Jhangiani, DM Muzny, RA Gibbs, JR Lupski, A Stray-Pedersen. Two male sibs with severe micrognathia and a missense variant in MED12.. Eur J Med Genet. 2016;59:367-72",
"P Prontera, V Ottaviani, D Rogaia, I Isidori, A Mencarelli, N Malerba, D Cocciadiferro, P Rolph, G Stangoni, A Vulto-van Silfhout, G. Merla. A novel MED12 mutation: evidence for a fourth phenotype.. Am J Med Genet A. 2016;170:2377-82",
"F Riccardi, A Astier, M Grisval, A Maillard, V Michaud, C Badens, CT Gordon, A Trimouille, L Faivre, J Amiel, S Sigaudy, S Gorokhova. Correspondence on “De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females” by Polla et al.. Genet Med. 2021;23:2003-4",
"H Risheg, JM Graham, RD Clark, RC Rogers, JM Opitz, JB Moeschler, AP Peiffer, M May, SM Joseph, JR Jones, RE Stevenson, CE Schwartz, MF Freiz. A recurrent mutation in MED12 leading to R961W causes Optiz-Kaveggia syndrome.. Nat Genet. 2007;39:451-3",
"Z Rubin, DK Grange, MA Cooper. Siblings with a novel MED12 variant and Ohdo syndrome with immune defects.. Clin Genet. 2020;98:308-10",
"E Rubinato, S Rondeau, F Giuliano, M Kossorotoff, M Parodi, S Gherbi, J Steffan, L Jonard, S. Marlin. MED12 missense mutation in a three-generation family. Clinical characterization of MED12-related disorders and literature review.. Eur J Med Genet. 2020;63",
"P Rump, RC Niessen, KT Verbruggen, OF Brouwer, M de Raad, R Hordijk. A novel mutation in MED12 causes FG syndrome (Opitz-Kaveggia syndrome).. Clin Genet. 2011;79:183-8",
"CE Schwartz, PS Tarpey, HA Lubs, A Verloes, MM May, H Risheg, MJ Friez, PA Futreal, S Edkins, J Teague, S Briault, C Skinner, A Bauer-Carlin, RJ Simensen, SM Joseph, JR Jones, J Gecz, MR Stratton, FL Raymond, RE Stevenson. The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene.. J Med Genet. 2007;44:472-7",
"S Srivastava, T Niranjan, MM May, P Tarpey, W Allen, A Hackett, PS Jouk, L Raymond, S Briault, C Skinner, A Toutain, J Gecz, W Heath, RE Stevenson, CE Schwartz, T Wang. Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders.. Mol Genet Genomic Med. 2019;7",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"AT Vulto-van Silfhout, BB de Vries, BW van Bon, A Hoischen, M Ruiterkamp-Versteeg, C Gilissen, F Gao, M van Zwam, CL Harteveld, AJ van Essen, BC Hamel, T Kleefstra, MA Willemsen, HG Yntema, H van Bokhoven, HG Brunner, TG Boyer, AP de Brouwer. Mutations in MED12 cause X-linked Ohdo syndrome.. Am J Hum Genet. 2013;92:401-6",
"C Wang, L Lin, Y Xue, Y Wang, Z Liu, Z Ou, S Wu, X Lan, Y Zhang, F Yuan, X Luo, C Wang, J Xi, X Sun, Y. Chen. MED12-related disease in a Chinese girl: clinical characteristics and underlying mechanism.. Front Genet. 2020;11:129",
"T Yamamoto, K. Shimojima. A novel MED12 mutation associated with nonspecific X-linked intellectual disability.. Hum Genome Var. 2015;2:15018"
] |
23/6/2008
|
12/8/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
fgf14-ataxia
|
fgf14-ataxia
|
[
"Spinocerebellar Ataxia 27B (SCA27B)",
"FGF14 (GAA)n-Mediated Ataxia",
"GAA-FGF14 Ataxia",
"GAA-FGF14 Disease",
"GAA-FGF14-Related Disease",
"SCA27B/ATX-FGF14",
"Spinocerebellar Ataxia 27B (SCA27B)",
"FGF14 (GAA)n-Mediated Ataxia",
"GAA-FGF14 Ataxia",
"GAA-FGF14 Disease",
"GAA-FGF14-Related Disease",
"SCA27B/ATX-FGF14",
"Fibroblast growth factor 14",
"FGF14",
"GAA-FGF14-Related Ataxia"
] |
GAA-
|
David Pellerin, Matt Danzi, Mathilde Renaud, Henry Houlden, Matthis Synofzik, Stephan Zuchner, Bernard Brais
|
Summary GAA- The diagnosis of GAA- GAA-
|
## Diagnosis
GAA-
Commonly associated neurologic findings include the following:
Episodic ataxia, commonly triggered by exercise / physically demanding tasks or alcohol intake; may manifest with diplopia, vertigo, dysarthria, and ataxia
Cerebellar oculomotor signs, such as saccadic pursuit, dysmetric saccades, rebound nystagmus, gaze-evoked nystagmus, impaired visual fixation suppression of the vestibuloocular reflex, and downbeat nystagmus. Note that early in the disease course, downbeat nystagmus may occur with other cerebellar oculomotor signs in the absence of other neurologic findings.
Visual symptoms, such as diplopia, oscillopsia, and visual blurring
Vertigo and/or dizziness
Vestibular hypofunction that can present with dizziness and loss of balance
Decreased vibration sense in distal lower extremities
Less commonly associated neurologic findings include the following:
Mild spasticity
Postural tremor
Autonomic dysfunction, mostly urinary urgency
Mild sensory or sensorimotor axonal polyneuropathy
The diagnosis of GAA-
Due to reduced penetrance of
Individuals whose phenotype differs significantly from GAA-
Note: (1) To date, pathogenic GAA repeat expansions in
Note (1) Short-read genome sequencing (GS)-based tools for the detection of triplet repeat expansions have been developed [
Molecular Genetic Testing Used in GAA-
See
See
To date, standard sequence-based multigene panels, exome sequencing, and short-read genome sequencing cannot reliably detect pathogenic repeat expansions in this gene.
• Episodic ataxia, commonly triggered by exercise / physically demanding tasks or alcohol intake; may manifest with diplopia, vertigo, dysarthria, and ataxia
• Cerebellar oculomotor signs, such as saccadic pursuit, dysmetric saccades, rebound nystagmus, gaze-evoked nystagmus, impaired visual fixation suppression of the vestibuloocular reflex, and downbeat nystagmus. Note that early in the disease course, downbeat nystagmus may occur with other cerebellar oculomotor signs in the absence of other neurologic findings.
• Visual symptoms, such as diplopia, oscillopsia, and visual blurring
• Vertigo and/or dizziness
• Vestibular hypofunction that can present with dizziness and loss of balance
• Decreased vibration sense in distal lower extremities
• Mild spasticity
• Postural tremor
• Autonomic dysfunction, mostly urinary urgency
• Mild sensory or sensorimotor axonal polyneuropathy
## Suggestive Findings
GAA-
Commonly associated neurologic findings include the following:
Episodic ataxia, commonly triggered by exercise / physically demanding tasks or alcohol intake; may manifest with diplopia, vertigo, dysarthria, and ataxia
Cerebellar oculomotor signs, such as saccadic pursuit, dysmetric saccades, rebound nystagmus, gaze-evoked nystagmus, impaired visual fixation suppression of the vestibuloocular reflex, and downbeat nystagmus. Note that early in the disease course, downbeat nystagmus may occur with other cerebellar oculomotor signs in the absence of other neurologic findings.
Visual symptoms, such as diplopia, oscillopsia, and visual blurring
Vertigo and/or dizziness
Vestibular hypofunction that can present with dizziness and loss of balance
Decreased vibration sense in distal lower extremities
Less commonly associated neurologic findings include the following:
Mild spasticity
Postural tremor
Autonomic dysfunction, mostly urinary urgency
Mild sensory or sensorimotor axonal polyneuropathy
• Episodic ataxia, commonly triggered by exercise / physically demanding tasks or alcohol intake; may manifest with diplopia, vertigo, dysarthria, and ataxia
• Cerebellar oculomotor signs, such as saccadic pursuit, dysmetric saccades, rebound nystagmus, gaze-evoked nystagmus, impaired visual fixation suppression of the vestibuloocular reflex, and downbeat nystagmus. Note that early in the disease course, downbeat nystagmus may occur with other cerebellar oculomotor signs in the absence of other neurologic findings.
• Visual symptoms, such as diplopia, oscillopsia, and visual blurring
• Vertigo and/or dizziness
• Vestibular hypofunction that can present with dizziness and loss of balance
• Decreased vibration sense in distal lower extremities
• Mild spasticity
• Postural tremor
• Autonomic dysfunction, mostly urinary urgency
• Mild sensory or sensorimotor axonal polyneuropathy
## Establishing the Diagnosis
The diagnosis of GAA-
Due to reduced penetrance of
Individuals whose phenotype differs significantly from GAA-
Note: (1) To date, pathogenic GAA repeat expansions in
Note (1) Short-read genome sequencing (GS)-based tools for the detection of triplet repeat expansions have been developed [
Molecular Genetic Testing Used in GAA-
See
See
To date, standard sequence-based multigene panels, exome sequencing, and short-read genome sequencing cannot reliably detect pathogenic repeat expansions in this gene.
## Clinical Characteristics
To date, more than 400 individuals with GAA-
GAA-
Based on
GAA-
The median age at onset is 60 years (range: 21 to 87 years) [
Although some individuals eventually require assistance with mobility, the use of a wheelchair is uncommon even after protracted disease duration.
Frank autonomic dysfunction manifested by orthostatic hypotension is rare in GAA-
Of note, age-related mechanisms as well as other additional diseases (age related or not age related; acquired or inherited) can contribute to or aggravate the clinical features of GAA-
The possibility of
Of note, one study found no association between disease progression or severity and the length of the GAA repeat expansion [
Reduced penetrance has been reported in persons heterozygous for 250-300
The
The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission [
The instability of the GAA repeat locus upon maternal transmission, which is at high risk of further expansion, partly accounts for the high incidence of simplex cases of GAA-
In contrast, contraction of the size of the GAA repeat upon male transmission may lead to transmission of reduced-penetrance alleles to the offspring, resulting in "generation skipping" of the disease [
The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract. GAA repeat expansions may be pure (GAA)
Prior to establishing the molecular diagnosis, individuals with phenotypes consistent with GAA-
The current alphanumeric designation for GAA-
The prevalence of GAA-
Excluding French Canadian cohorts, we have estimated the prevalence of GAA-
It is important to note that although the frequency of
## Clinical Description
To date, more than 400 individuals with GAA-
GAA-
Based on
GAA-
The median age at onset is 60 years (range: 21 to 87 years) [
Although some individuals eventually require assistance with mobility, the use of a wheelchair is uncommon even after protracted disease duration.
Frank autonomic dysfunction manifested by orthostatic hypotension is rare in GAA-
Of note, age-related mechanisms as well as other additional diseases (age related or not age related; acquired or inherited) can contribute to or aggravate the clinical features of GAA-
The possibility of
## Genotype-Phenotype Correlations
Of note, one study found no association between disease progression or severity and the length of the GAA repeat expansion [
## Penetrance
Reduced penetrance has been reported in persons heterozygous for 250-300
## Intergenerational Instability
The
The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission [
The instability of the GAA repeat locus upon maternal transmission, which is at high risk of further expansion, partly accounts for the high incidence of simplex cases of GAA-
In contrast, contraction of the size of the GAA repeat upon male transmission may lead to transmission of reduced-penetrance alleles to the offspring, resulting in "generation skipping" of the disease [
The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract. GAA repeat expansions may be pure (GAA)
## Nomenclature
Prior to establishing the molecular diagnosis, individuals with phenotypes consistent with GAA-
The current alphanumeric designation for GAA-
## Prevalence
The prevalence of GAA-
Excluding French Canadian cohorts, we have estimated the prevalence of GAA-
It is important to note that although the frequency of
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
GAA-
The differential diagnosis of adult-onset ataxia is broad and encompasses acquired, hereditary, and neurodegenerative ataxias.
Episodic ataxia type 2 (EA2) – caused by pathogenic missense, nonsense, splice site, or frameshift variants or exon/multiexon deletion in
Genes of particular interest are summarized in
Selected Genes of Interest in the Differential Diagnosis of GAA-
Adult-onset progressive cerebellar ataxia
Cerebellar dysarthria
Nystagmus
Vestibular hypofunction possible
Autonomic dysfunction
Lid retraction
Dystonia / extrapyramidal syndrome
Peripheral amyotrophy
Muscle cramp & fasciculation
Generalized areflexia
Action-induced facial & lingual fasciculations
Parkinsonism
Progressive external ophthalmoplegia
Sleep disturbances
MRI: pontine atrophy
Adult-onset slowly progressive cerebellar ataxia (typical onset in 3rd-5th decade)
Cerebellar dysarthria
Nystagmus
Tremor
Adult-onset slowly progressive cerebellar ataxia
Cerebellar dysarthria
Nystagmus (horizontal gaze-evoked, downbeat)
Visual disturbances such as diplopia
Vestibular hypofunction possible
MRI: isolated cerebellar atrophy
Less common episodic symptoms at disease onset (<15%)
In some, additional clinical signs incl dystonia, blepharospasm, extensor plantar responses
Episodic ataxia w/paroxysmal attacks of ataxia, dysarthria, diplopia, vertigo
May be triggered by alcohol intake & physical activity
May eventually develop interictal progressive ataxia & downbeat nystagmus
MRI: cerebellar atrophy
Typical onset in childhood / early adolescence (range: 2-32 yrs)
Attacks of ataxia may be assoc w/dystonia, hemiplegia, & tonic upward gaze
Progressive cerebellar ataxia
Cerebellar dysarthria
Vestibular hypofunction possible
Autonomic dysfunction
Typical onset <25 yrs (but late-onset presentation possible).
Sensory neuronopathy
Muscle weakness
Hypertrophic cardiomyopathy
Diabetes
Optic atrophy
Skeletal deformities (pes cavus, scoliosis)
Episodic ataxia w/paroxysmal attacks of ataxia, dysarthria, diplopia, vertigo
May be triggered by alcohol intake & physical activity
Typical onset in childhood / early adolescence (range: 2-15 yrs)
Attacks of brief duration (seconds to minutes)
Attacks of ataxia may be assoc w/choreoathetosis, carpal spasm, hyperthermia, & stiffening of body
Interictal myokymia
Neuromyotonia
Cognitive dysfunction
In some, seizures & skeletal deformities (scoliosis, high-arched palate)
Adult-onset ataxia
Cerebellar dysarthria
Nystagmus (horizontal gaze-evoked, downbeat)
Vestibular hypofunction
Autonomic dysfunction
Sensory neuronopathy
Frequent chronic cough
No episodic ataxia
Rare postural tremor
Adult-onset slowly progressive cerebellar ataxia (mean onset in 3rd decade)
Cerebellar dysarthria
Nystagmus (gaze-evoked & downbeat)
In some, impaired vibration sense
MRI: isolated cerebellar atrophy
In some, facial myokymia, horizontal gaze palsy
No episodic ataxia
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SCA = spinocerebellar ataxia
MSA is a rapidly progressive disorder. Approximately 60% of affected individuals become wheelchair bound after five years, and the mean survival is six to ten years from symptom onset [
Persons with MSA-C typically exhibit cerebellar features, extrapyramidal features, pyramidal features, rapid eye movement sleep behavior disorder, significant dysphagia, and debilitating autonomic failure [
In contrast to GAA-
Certain imaging findings favor a diagnosis of MSA-C: atrophy of the putamen, middle cerebellar peduncles, pons, and cerebellum; cruciform T
• Adult-onset progressive cerebellar ataxia
• Cerebellar dysarthria
• Nystagmus
• Vestibular hypofunction possible
• Autonomic dysfunction
• Lid retraction
• Dystonia / extrapyramidal syndrome
• Peripheral amyotrophy
• Muscle cramp & fasciculation
• Generalized areflexia
• Action-induced facial & lingual fasciculations
• Parkinsonism
• Progressive external ophthalmoplegia
• Sleep disturbances
• MRI: pontine atrophy
• Adult-onset slowly progressive cerebellar ataxia (typical onset in 3rd-5th decade)
• Cerebellar dysarthria
• Nystagmus
• Tremor
• Adult-onset slowly progressive cerebellar ataxia
• Cerebellar dysarthria
• Nystagmus (horizontal gaze-evoked, downbeat)
• Visual disturbances such as diplopia
• Vestibular hypofunction possible
• MRI: isolated cerebellar atrophy
• Less common episodic symptoms at disease onset (<15%)
• In some, additional clinical signs incl dystonia, blepharospasm, extensor plantar responses
• Episodic ataxia w/paroxysmal attacks of ataxia, dysarthria, diplopia, vertigo
• May be triggered by alcohol intake & physical activity
• May eventually develop interictal progressive ataxia & downbeat nystagmus
• MRI: cerebellar atrophy
• Typical onset in childhood / early adolescence (range: 2-32 yrs)
• Attacks of ataxia may be assoc w/dystonia, hemiplegia, & tonic upward gaze
• Progressive cerebellar ataxia
• Cerebellar dysarthria
• Vestibular hypofunction possible
• Autonomic dysfunction
• Typical onset <25 yrs (but late-onset presentation possible).
• Sensory neuronopathy
• Muscle weakness
• Hypertrophic cardiomyopathy
• Diabetes
• Optic atrophy
• Skeletal deformities (pes cavus, scoliosis)
• Episodic ataxia w/paroxysmal attacks of ataxia, dysarthria, diplopia, vertigo
• May be triggered by alcohol intake & physical activity
• Typical onset in childhood / early adolescence (range: 2-15 yrs)
• Attacks of brief duration (seconds to minutes)
• Attacks of ataxia may be assoc w/choreoathetosis, carpal spasm, hyperthermia, & stiffening of body
• Interictal myokymia
• Neuromyotonia
• Cognitive dysfunction
• In some, seizures & skeletal deformities (scoliosis, high-arched palate)
• Adult-onset ataxia
• Cerebellar dysarthria
• Nystagmus (horizontal gaze-evoked, downbeat)
• Vestibular hypofunction
• Autonomic dysfunction
• Sensory neuronopathy
• Frequent chronic cough
• No episodic ataxia
• Rare postural tremor
• Adult-onset slowly progressive cerebellar ataxia (mean onset in 3rd decade)
• Cerebellar dysarthria
• Nystagmus (gaze-evoked & downbeat)
• In some, impaired vibration sense
• MRI: isolated cerebellar atrophy
• In some, facial myokymia, horizontal gaze palsy
• No episodic ataxia
• MSA is a rapidly progressive disorder. Approximately 60% of affected individuals become wheelchair bound after five years, and the mean survival is six to ten years from symptom onset [
• Persons with MSA-C typically exhibit cerebellar features, extrapyramidal features, pyramidal features, rapid eye movement sleep behavior disorder, significant dysphagia, and debilitating autonomic failure [
• In contrast to GAA-
• Certain imaging findings favor a diagnosis of MSA-C: atrophy of the putamen, middle cerebellar peduncles, pons, and cerebellum; cruciform T
## Management
No clinical practice guidelines for GAA-
To establish the extent of disease and needs in an individual diagnosed with GAA-
GAA-
Assess for postural change in blood pressure to assess for orthostatic hypotension.
Consider autonomic testing in persons who are symptomatic.
Assess need for balance exercises, gait training to maintain mobility, & exercises to help prevent falls & maintain function.
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
Speech-language therapy;
Alternative means of communication.
Assess nystagmus, saccades, & smooth pursuit & vertical & horizontal gaze limitation.
Consider referral for corrective measures incl prisms &/or surgery.
Consider video fluoroscopic swallowing study to assess risk of aspiration.
Referral to nutritionist & OT
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; INAS = Inventory of Non-Ataxia Signs; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for GAA-
GAA-
PT to maintain mobility & function
Self-directed exercise as prescribed by PT
OT to optimize ADL
Avoid alcohol intake & strenuous physical activity that may precipitate episodes of ataxia.
Consider adaptive devices to maintain/improve mobility (e.g., canes, walking sticks, walker).
Inpatient rehab w/PT & OT may improve ataxia & functional abilities in persons w/degenerative ataxias.
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Downbeat nystagmus may respond to 4-aminopyridine.
Prisms may be used to obviate diplopia.
Consider nutritional & vitamin supplementation to meet dietary needs.
Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
Feeding recommendations per nutritional therapy / OT
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADL = activities of daily living; ENT = ears, nose, and throat; OT = occupational therapy; PT = physical therapy
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
GAA-
Neurologic eval to assess progression & need for pharmacotherapy
Monitor ataxia progression w/standardized scale (SARA).
OT = occupational therapy/therapist; PT = physical therapy/therapist; SARA = Scale for the Assessment and Rating of Ataxia
Inform affected individuals that alcohol intake and strenuous physical activity may precipitate episodes of ataxia and may exacerbate incoordination.
Avoid medications with known toxicity to the cerebellum and the vestibular system.
See
Although GAA-
Search
• Assess for postural change in blood pressure to assess for orthostatic hypotension.
• Consider autonomic testing in persons who are symptomatic.
• Assess need for balance exercises, gait training to maintain mobility, & exercises to help prevent falls & maintain function.
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
• Speech-language therapy;
• Alternative means of communication.
• Assess nystagmus, saccades, & smooth pursuit & vertical & horizontal gaze limitation.
• Consider referral for corrective measures incl prisms &/or surgery.
• Consider video fluoroscopic swallowing study to assess risk of aspiration.
• Referral to nutritionist & OT
• Community or
• Social work involvement for parental support
• Home nursing referral
• PT to maintain mobility & function
• Self-directed exercise as prescribed by PT
• OT to optimize ADL
• Avoid alcohol intake & strenuous physical activity that may precipitate episodes of ataxia.
• Consider adaptive devices to maintain/improve mobility (e.g., canes, walking sticks, walker).
• Inpatient rehab w/PT & OT may improve ataxia & functional abilities in persons w/degenerative ataxias.
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Downbeat nystagmus may respond to 4-aminopyridine.
• Prisms may be used to obviate diplopia.
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
• Feeding recommendations per nutritional therapy / OT
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Neurologic eval to assess progression & need for pharmacotherapy
• Monitor ataxia progression w/standardized scale (SARA).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with GAA-
GAA-
Assess for postural change in blood pressure to assess for orthostatic hypotension.
Consider autonomic testing in persons who are symptomatic.
Assess need for balance exercises, gait training to maintain mobility, & exercises to help prevent falls & maintain function.
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
Speech-language therapy;
Alternative means of communication.
Assess nystagmus, saccades, & smooth pursuit & vertical & horizontal gaze limitation.
Consider referral for corrective measures incl prisms &/or surgery.
Consider video fluoroscopic swallowing study to assess risk of aspiration.
Referral to nutritionist & OT
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; INAS = Inventory of Non-Ataxia Signs; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assess for postural change in blood pressure to assess for orthostatic hypotension.
• Consider autonomic testing in persons who are symptomatic.
• Assess need for balance exercises, gait training to maintain mobility, & exercises to help prevent falls & maintain function.
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
• Speech-language therapy;
• Alternative means of communication.
• Assess nystagmus, saccades, & smooth pursuit & vertical & horizontal gaze limitation.
• Consider referral for corrective measures incl prisms &/or surgery.
• Consider video fluoroscopic swallowing study to assess risk of aspiration.
• Referral to nutritionist & OT
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for GAA-
GAA-
PT to maintain mobility & function
Self-directed exercise as prescribed by PT
OT to optimize ADL
Avoid alcohol intake & strenuous physical activity that may precipitate episodes of ataxia.
Consider adaptive devices to maintain/improve mobility (e.g., canes, walking sticks, walker).
Inpatient rehab w/PT & OT may improve ataxia & functional abilities in persons w/degenerative ataxias.
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Downbeat nystagmus may respond to 4-aminopyridine.
Prisms may be used to obviate diplopia.
Consider nutritional & vitamin supplementation to meet dietary needs.
Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
Feeding recommendations per nutritional therapy / OT
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADL = activities of daily living; ENT = ears, nose, and throat; OT = occupational therapy; PT = physical therapy
• PT to maintain mobility & function
• Self-directed exercise as prescribed by PT
• OT to optimize ADL
• Avoid alcohol intake & strenuous physical activity that may precipitate episodes of ataxia.
• Consider adaptive devices to maintain/improve mobility (e.g., canes, walking sticks, walker).
• Inpatient rehab w/PT & OT may improve ataxia & functional abilities in persons w/degenerative ataxias.
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Downbeat nystagmus may respond to 4-aminopyridine.
• Prisms may be used to obviate diplopia.
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
• Feeding recommendations per nutritional therapy / OT
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
GAA-
Neurologic eval to assess progression & need for pharmacotherapy
Monitor ataxia progression w/standardized scale (SARA).
OT = occupational therapy/therapist; PT = physical therapy/therapist; SARA = Scale for the Assessment and Rating of Ataxia
• Neurologic eval to assess progression & need for pharmacotherapy
• Monitor ataxia progression w/standardized scale (SARA).
## Agents/Circumstances to Avoid
Inform affected individuals that alcohol intake and strenuous physical activity may precipitate episodes of ataxia and may exacerbate incoordination.
Avoid medications with known toxicity to the cerebellum and the vestibular system.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Although GAA-
## Therapies Under Investigation
Search
## Genetic Counseling
GAA-
Note: Although GAA-
Most individuals diagnosed with GAA-
Fifteen to 50% of individuals diagnosed with GAA-
The
The family history of some individuals diagnosed with GAA-
If a parent of the proband has an
The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract [
Sibs who inherit an expansion of 250-300 GAA repeats may or may not develop GAA-
Sibs who inherit an
If the parents have not been tested for the
Each child of an individual with GAA-
The size of the GAA repeat is more likely to expand in transmission to offspring if the proband is female and to contract in transmission if the proband is male (see Clinical Characteristics,
Predictive testing for at-risk relatives is possible once a pathogenic or likely pathogenic GAA repeat expansion in intron 1 of
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Of note:
It is difficult to predict the age of onset, severity, clinical features, and rate of progression in an asymptomatic individual with >300 GAA repeats. While age of onset was found to inversely correlate with the size of the GAA repeat expansion in some cohorts, some studies found no such association (see Clinical Characteristics,
An asymptomatic individual with an expansion of 250-300 GAA repeats may or may not develop GAA-
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of GAA-
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once a GAA repeat expansion in intron 1 of
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors
• Most individuals diagnosed with GAA-
• Fifteen to 50% of individuals diagnosed with GAA-
• The
• The family history of some individuals diagnosed with GAA-
• If a parent of the proband has an
• The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
• The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract [
• The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
• The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract [
• Sibs who inherit an expansion of 250-300 GAA repeats may or may not develop GAA-
• Sibs who inherit an
• If the parents have not been tested for the
• The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
• The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract [
• Each child of an individual with GAA-
• The size of the GAA repeat is more likely to expand in transmission to offspring if the proband is female and to contract in transmission if the proband is male (see Clinical Characteristics,
• Predictive testing for at-risk relatives is possible once a pathogenic or likely pathogenic GAA repeat expansion in intron 1 of
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Of note:
• It is difficult to predict the age of onset, severity, clinical features, and rate of progression in an asymptomatic individual with >300 GAA repeats. While age of onset was found to inversely correlate with the size of the GAA repeat expansion in some cohorts, some studies found no such association (see Clinical Characteristics,
• An asymptomatic individual with an expansion of 250-300 GAA repeats may or may not develop GAA-
• It is difficult to predict the age of onset, severity, clinical features, and rate of progression in an asymptomatic individual with >300 GAA repeats. While age of onset was found to inversely correlate with the size of the GAA repeat expansion in some cohorts, some studies found no such association (see Clinical Characteristics,
• An asymptomatic individual with an expansion of 250-300 GAA repeats may or may not develop GAA-
• It is difficult to predict the age of onset, severity, clinical features, and rate of progression in an asymptomatic individual with >300 GAA repeats. While age of onset was found to inversely correlate with the size of the GAA repeat expansion in some cohorts, some studies found no such association (see Clinical Characteristics,
• An asymptomatic individual with an expansion of 250-300 GAA repeats may or may not develop GAA-
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
GAA-
Note: Although GAA-
## Risk to Family Members
Most individuals diagnosed with GAA-
Fifteen to 50% of individuals diagnosed with GAA-
The
The family history of some individuals diagnosed with GAA-
If a parent of the proband has an
The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract [
Sibs who inherit an expansion of 250-300 GAA repeats may or may not develop GAA-
Sibs who inherit an
If the parents have not been tested for the
Each child of an individual with GAA-
The size of the GAA repeat is more likely to expand in transmission to offspring if the proband is female and to contract in transmission if the proband is male (see Clinical Characteristics,
• Most individuals diagnosed with GAA-
• Fifteen to 50% of individuals diagnosed with GAA-
• The
• The family history of some individuals diagnosed with GAA-
• If a parent of the proband has an
• The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
• The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract [
• The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
• The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract [
• Sibs who inherit an expansion of 250-300 GAA repeats may or may not develop GAA-
• Sibs who inherit an
• If the parents have not been tested for the
• The size of the GAA repeat is more likely to expand with maternal transmission and to contract with paternal transmission.
• The degree of intergenerational instability is proportional to the size of the GAA repeat of the transmitted allele and dependent on the purity of the repeat tract [
• Each child of an individual with GAA-
• The size of the GAA repeat is more likely to expand in transmission to offspring if the proband is female and to contract in transmission if the proband is male (see Clinical Characteristics,
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once a pathogenic or likely pathogenic GAA repeat expansion in intron 1 of
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Of note:
It is difficult to predict the age of onset, severity, clinical features, and rate of progression in an asymptomatic individual with >300 GAA repeats. While age of onset was found to inversely correlate with the size of the GAA repeat expansion in some cohorts, some studies found no such association (see Clinical Characteristics,
An asymptomatic individual with an expansion of 250-300 GAA repeats may or may not develop GAA-
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of GAA-
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once a pathogenic or likely pathogenic GAA repeat expansion in intron 1 of
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. Of note:
• It is difficult to predict the age of onset, severity, clinical features, and rate of progression in an asymptomatic individual with >300 GAA repeats. While age of onset was found to inversely correlate with the size of the GAA repeat expansion in some cohorts, some studies found no such association (see Clinical Characteristics,
• An asymptomatic individual with an expansion of 250-300 GAA repeats may or may not develop GAA-
• It is difficult to predict the age of onset, severity, clinical features, and rate of progression in an asymptomatic individual with >300 GAA repeats. While age of onset was found to inversely correlate with the size of the GAA repeat expansion in some cohorts, some studies found no such association (see Clinical Characteristics,
• An asymptomatic individual with an expansion of 250-300 GAA repeats may or may not develop GAA-
• It is difficult to predict the age of onset, severity, clinical features, and rate of progression in an asymptomatic individual with >300 GAA repeats. While age of onset was found to inversely correlate with the size of the GAA repeat expansion in some cohorts, some studies found no such association (see Clinical Characteristics,
• An asymptomatic individual with an expansion of 250-300 GAA repeats may or may not develop GAA-
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once a GAA repeat expansion in intron 1 of
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors
## Resources
Canada
United Kingdom
United Kingdom
•
•
•
• Canada
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
## Molecular Genetics
GAA-FGF14-Related Ataxia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GAA-FGF14-Related Ataxia (
Note: Expansion of non-GAA-pure repeats appears to be
GAA (expanded pathogenic); however, interrupted repeats are also possible.
Expansions consisting of an alternative non-GAA motif, such as GAAGGA or (GAA)
Long-range PCR (LR-PCR)
Repeat-primed PCR (RP-PCR)
Long-read sequencing
GAA repeat expansions may be pure – (GAA)
The GAA repeat is more likely to expand when maternally transmitted.
The GAA repeat is more likely to contract when paternally transmitted, and may result in smaller repeats that may fall into the decreased penetrance size range or non-pathogenic range.
Methods to Characterize
GAA and TTC refer to the reverse and forward sequences, respectively.
The design of a repeat-primed PCR (RP-PCR) assay may include conventional PCR primers to size normal repeats and detect expanded repeats in a single assay. The RP-PCR assay itself does not determine repeat size, even for alleles in the normal range.
Methods to detect and approximate the size of expanded repeats include long-range PCR sized by capillary electrophoresis or agarose gel electrophoresis [
Detection of an apparently homozygous repeat does not rule out the presence of an expanded GAA repeat; thus, testing by RP-PCR or expanded repeat analysis is required to detect a repeat expansion.
Long-read sequencing may be used to detect and measure the size of repeat expansions [
Alleles in the 250-300 repeat range are likely to be pathogenic, albeit with reduced penetrance.
RP-PCR for the GAA repeat expansion has been described [
Non-GAA-pure repeats do not show the characteristic stutter/sawtooth pattern that indicates an expanded GAA repeat [
Variants listed in the table have been provided by the authors.
• GAA (expanded pathogenic); however, interrupted repeats are also possible.
• Expansions consisting of an alternative non-GAA motif, such as GAAGGA or (GAA)
• Long-range PCR (LR-PCR)
• Repeat-primed PCR (RP-PCR)
• Long-read sequencing
• GAA repeat expansions may be pure – (GAA)
• The GAA repeat is more likely to expand when maternally transmitted.
• The GAA repeat is more likely to contract when paternally transmitted, and may result in smaller repeats that may fall into the decreased penetrance size range or non-pathogenic range.
## Molecular Pathogenesis
Note: Expansion of non-GAA-pure repeats appears to be
GAA (expanded pathogenic); however, interrupted repeats are also possible.
Expansions consisting of an alternative non-GAA motif, such as GAAGGA or (GAA)
Long-range PCR (LR-PCR)
Repeat-primed PCR (RP-PCR)
Long-read sequencing
GAA repeat expansions may be pure – (GAA)
The GAA repeat is more likely to expand when maternally transmitted.
The GAA repeat is more likely to contract when paternally transmitted, and may result in smaller repeats that may fall into the decreased penetrance size range or non-pathogenic range.
Methods to Characterize
GAA and TTC refer to the reverse and forward sequences, respectively.
The design of a repeat-primed PCR (RP-PCR) assay may include conventional PCR primers to size normal repeats and detect expanded repeats in a single assay. The RP-PCR assay itself does not determine repeat size, even for alleles in the normal range.
Methods to detect and approximate the size of expanded repeats include long-range PCR sized by capillary electrophoresis or agarose gel electrophoresis [
Detection of an apparently homozygous repeat does not rule out the presence of an expanded GAA repeat; thus, testing by RP-PCR or expanded repeat analysis is required to detect a repeat expansion.
Long-read sequencing may be used to detect and measure the size of repeat expansions [
Alleles in the 250-300 repeat range are likely to be pathogenic, albeit with reduced penetrance.
RP-PCR for the GAA repeat expansion has been described [
Non-GAA-pure repeats do not show the characteristic stutter/sawtooth pattern that indicates an expanded GAA repeat [
Variants listed in the table have been provided by the authors.
• GAA (expanded pathogenic); however, interrupted repeats are also possible.
• Expansions consisting of an alternative non-GAA motif, such as GAAGGA or (GAA)
• Long-range PCR (LR-PCR)
• Repeat-primed PCR (RP-PCR)
• Long-read sequencing
• GAA repeat expansions may be pure – (GAA)
• The GAA repeat is more likely to expand when maternally transmitted.
• The GAA repeat is more likely to contract when paternally transmitted, and may result in smaller repeats that may fall into the decreased penetrance size range or non-pathogenic range.
## Chapter Notes
David Pellerin (
Drs Pellerin, Danzi, Zuchner, Synofzik, and Brais are also interested in hearing from clinicians treating families affected by adult-onset ataxia in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Drs Pellerin, Danzi, Zuchner, or Brais to inquire about review of
This work has been supported, in part, by the Canadian Institutes of Health Research (CIHR) grant no. 189963 (to B.B.), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) no. 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP no. 825575 (to M.S., B.B., and – as an associated partner – S.Z.).
25 January 2024 (bp) Review posted live
30 June 2023 (dp) Original submission
• 25 January 2024 (bp) Review posted live
• 30 June 2023 (dp) Original submission
## Author Notes
David Pellerin (
Drs Pellerin, Danzi, Zuchner, Synofzik, and Brais are also interested in hearing from clinicians treating families affected by adult-onset ataxia in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Drs Pellerin, Danzi, Zuchner, or Brais to inquire about review of
## Acknowledgments
This work has been supported, in part, by the Canadian Institutes of Health Research (CIHR) grant no. 189963 (to B.B.), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) no. 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP no. 825575 (to M.S., B.B., and – as an associated partner – S.Z.).
## Revision History
25 January 2024 (bp) Review posted live
30 June 2023 (dp) Original submission
• 25 January 2024 (bp) Review posted live
• 30 June 2023 (dp) Original submission
## References
## Literature Cited
|
[] |
25/1/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
fhm
|
fhm
|
[
"Sodium channel protein type 1 subunit alpha",
"Sodium/potassium-transporting ATPase subunit alpha-2",
"Voltage-dependent P/Q-type calcium channel subunit alpha-1A",
"ATP1A2",
"CACNA1A",
"SCN1A",
"Familial Hemiplegic Migraine"
] |
Familial Hemiplegic Migraine
|
Joanna C Jen
|
Summary Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with The clinical diagnosis of FHM can be established in a proband: (1) who fulfills criteria for migraine with aura; (2) in whom the aura includes fully reversible motor weakness and visual, sensory, or language symptoms; and (3) who has at least one first- or second-degree relative with similar attacks that fulfill the diagnostic criteria for hemiplegic migraine. The molecular diagnosis can be established in a proband by identification of a heterozygous pathogenic variant in FHM and simplex hemiplegic migraine caused by a heterozygous
|
## Diagnosis
Consensus clinical diagnostic criteria for familial hemiplegic migraine (FHM) have been published by the
FHM is a category of migraine with aura.
Note: Migraine with aura is a recurring disorder of neurologic symptoms unequivocally localizable to the cerebral cortex or brain stem. The aura usually develops over a period of five to 20 minutes and lasts less than 60 minutes. Headache, nausea, and/or photophobia usually follow neurologic aura symptoms, either immediately or after a symptom-free interval of less than an hour. The headache usually lasts four to 72 hours but may be completely absent (acephalgic migraine).
Headaches that fulfill criteria for migraine with aura
Aura consisting of
Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness
Fully reversible visual, sensory, and/or speech/language symptoms
HM is categorized as
Note: HM is sporadic if no first- or second-degree relative meets criteria for HM.
At least two episodes fulfilling criteria for migraine
Migraine with at least one of the following fully reversible aura symptoms:
Visual
Sensory
Speech and/or language
Motor
Brain stem
Retinal
At least three of the following characteristics:
At least one aura symptom spreads gradually over five minutes.
Two or more aura symptoms occur in succession.
Each individual aura symptom lasts five to 60 minutes.
At least one aura symptom is unilateral.
At least one aura symptom is positive.
The aura is accompanied – or followed within 60 minutes – by headache.
Absence of other causes of headache (e.g., head trauma, vascular disorders, nonvascular intracranial disorders, substance use or their withdrawal, non-cephalic infection, metabolic disorder, pain associated with other facial or cranial disorders)
The clinical diagnosis of FHM can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Note: (1) In the majority of persons with adult-onset hemiplegic migraine without nystagmus, seizures, or other unusual associated neurologic features, the yield for genetic testing is low. (2) Multiple studies have shown that pathogenic variants in the genes listed in
In individuals with
In individuals with
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Hemiplegic Migraine
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
An intragenic duplication involving exon 21 was reported in one individual with hemiplegic migraine [
A 39.5-kb
A heterozygous
• Headaches that fulfill criteria for migraine with aura
• Aura consisting of
• Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness
• Fully reversible visual, sensory, and/or speech/language symptoms
• Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness
• Fully reversible visual, sensory, and/or speech/language symptoms
• Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness
• Fully reversible visual, sensory, and/or speech/language symptoms
• At least two episodes fulfilling criteria for migraine
• Migraine with at least one of the following fully reversible aura symptoms:
• Visual
• Sensory
• Speech and/or language
• Motor
• Brain stem
• Retinal
• Visual
• Sensory
• Speech and/or language
• Motor
• Brain stem
• Retinal
• At least three of the following characteristics:
• At least one aura symptom spreads gradually over five minutes.
• Two or more aura symptoms occur in succession.
• Each individual aura symptom lasts five to 60 minutes.
• At least one aura symptom is unilateral.
• At least one aura symptom is positive.
• The aura is accompanied – or followed within 60 minutes – by headache.
• At least one aura symptom spreads gradually over five minutes.
• Two or more aura symptoms occur in succession.
• Each individual aura symptom lasts five to 60 minutes.
• At least one aura symptom is unilateral.
• At least one aura symptom is positive.
• The aura is accompanied – or followed within 60 minutes – by headache.
• Absence of other causes of headache (e.g., head trauma, vascular disorders, nonvascular intracranial disorders, substance use or their withdrawal, non-cephalic infection, metabolic disorder, pain associated with other facial or cranial disorders)
• Visual
• Sensory
• Speech and/or language
• Motor
• Brain stem
• Retinal
• At least one aura symptom spreads gradually over five minutes.
• Two or more aura symptoms occur in succession.
• Each individual aura symptom lasts five to 60 minutes.
• At least one aura symptom is unilateral.
• At least one aura symptom is positive.
• The aura is accompanied – or followed within 60 minutes – by headache.
•
• In individuals with
• In individuals with
• In individuals with
• In individuals with
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• In individuals with
• In individuals with
## Suggestive Findings
FHM is a category of migraine with aura.
Note: Migraine with aura is a recurring disorder of neurologic symptoms unequivocally localizable to the cerebral cortex or brain stem. The aura usually develops over a period of five to 20 minutes and lasts less than 60 minutes. Headache, nausea, and/or photophobia usually follow neurologic aura symptoms, either immediately or after a symptom-free interval of less than an hour. The headache usually lasts four to 72 hours but may be completely absent (acephalgic migraine).
Headaches that fulfill criteria for migraine with aura
Aura consisting of
Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness
Fully reversible visual, sensory, and/or speech/language symptoms
HM is categorized as
Note: HM is sporadic if no first- or second-degree relative meets criteria for HM.
At least two episodes fulfilling criteria for migraine
Migraine with at least one of the following fully reversible aura symptoms:
Visual
Sensory
Speech and/or language
Motor
Brain stem
Retinal
At least three of the following characteristics:
At least one aura symptom spreads gradually over five minutes.
Two or more aura symptoms occur in succession.
Each individual aura symptom lasts five to 60 minutes.
At least one aura symptom is unilateral.
At least one aura symptom is positive.
The aura is accompanied – or followed within 60 minutes – by headache.
Absence of other causes of headache (e.g., head trauma, vascular disorders, nonvascular intracranial disorders, substance use or their withdrawal, non-cephalic infection, metabolic disorder, pain associated with other facial or cranial disorders)
• Headaches that fulfill criteria for migraine with aura
• Aura consisting of
• Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness
• Fully reversible visual, sensory, and/or speech/language symptoms
• Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness
• Fully reversible visual, sensory, and/or speech/language symptoms
• Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness
• Fully reversible visual, sensory, and/or speech/language symptoms
• At least two episodes fulfilling criteria for migraine
• Migraine with at least one of the following fully reversible aura symptoms:
• Visual
• Sensory
• Speech and/or language
• Motor
• Brain stem
• Retinal
• Visual
• Sensory
• Speech and/or language
• Motor
• Brain stem
• Retinal
• At least three of the following characteristics:
• At least one aura symptom spreads gradually over five minutes.
• Two or more aura symptoms occur in succession.
• Each individual aura symptom lasts five to 60 minutes.
• At least one aura symptom is unilateral.
• At least one aura symptom is positive.
• The aura is accompanied – or followed within 60 minutes – by headache.
• At least one aura symptom spreads gradually over five minutes.
• Two or more aura symptoms occur in succession.
• Each individual aura symptom lasts five to 60 minutes.
• At least one aura symptom is unilateral.
• At least one aura symptom is positive.
• The aura is accompanied – or followed within 60 minutes – by headache.
• Absence of other causes of headache (e.g., head trauma, vascular disorders, nonvascular intracranial disorders, substance use or their withdrawal, non-cephalic infection, metabolic disorder, pain associated with other facial or cranial disorders)
• Visual
• Sensory
• Speech and/or language
• Motor
• Brain stem
• Retinal
• At least one aura symptom spreads gradually over five minutes.
• Two or more aura symptoms occur in succession.
• Each individual aura symptom lasts five to 60 minutes.
• At least one aura symptom is unilateral.
• At least one aura symptom is positive.
• The aura is accompanied – or followed within 60 minutes – by headache.
## Establishing the Diagnosis
The clinical diagnosis of FHM can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Note: (1) In the majority of persons with adult-onset hemiplegic migraine without nystagmus, seizures, or other unusual associated neurologic features, the yield for genetic testing is low. (2) Multiple studies have shown that pathogenic variants in the genes listed in
In individuals with
In individuals with
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Familial Hemiplegic Migraine
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
An intragenic duplication involving exon 21 was reported in one individual with hemiplegic migraine [
A 39.5-kb
A heterozygous
•
• In individuals with
• In individuals with
• In individuals with
• In individuals with
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• In individuals with
• In individuals with
## Clinical Characteristics
In migraine with aura, including familial hemiplegic migraine (FHM), the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include fully reversible
Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision).
Dysphasia usually occurs when hemiplegia is right-sided.
Hemiparesis (unilateral weakness), not necessarily hemiplegia (unilateral paralysis), occurs with at least one other symptom during FHM aura.
Some confusion and/or drowsiness may be present even without dysphasia. Impaired consciousness ranging from drowsiness to coma is well described in FHM [
Neurologic deficits with hemiplegic migraine attacks can be prolonged for hours to days and may outlast the associated migrainous headache. Persistent attention and memory loss can last weeks to months [
FHM is a rare and extreme phenotype of migraine with aura. The frequency of attacks ranges from one per day to fewer than five in a lifetime (mean: 2-3/year). Long attack-free intervals are often reported (range: 2-37 years). The frequency of FHM attacks tends to decrease with age. FHM attacks may be provoked by typical migraine triggers (e.g., foods, odors, exertion, stress), cerebral angiography, and minor head trauma.
The eventual neurologic outcome is often benign in the pure FHM group without interictal deficits (e.g., seizures/epilepsy, ataxia, nystagmus, cognitive impairment / learning disability).
Note: Cerebral infarction and death have rarely been associated with hemiplegic migraine and should instead raise the possibility of other disorders associated with migraine and stroke (see
Abnormalities in the cerebellum on magnetic resonance spectroscopy have been reported [
Those with identified FHM-related pathogenic variants tend to present with earlier age of onset, more severe symptoms, and associated interictal symptoms and signs (nystagmus, episodic or progressive ataxia, learning disability, epilepsy). In the report of
A severe phenotype with seizures, coma, and elevated temperature has been reported with the
A severe phenotype with seizures and intellectual disability has been reported with the pathogenic variants
Penetrance appears to be high and is estimated at 80% [
Although families with FHM in which attacks are strikingly identical do exist, the term FHM is often used inconsistently to describe families in which different forms of migraine occur, as most individuals with hemiplegic attacks have these attacks intermingled with more frequent attacks of migraine without hemiparesis.
In Denmark,
• Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision).
• Dysphasia usually occurs when hemiplegia is right-sided.
• Hemiparesis (unilateral weakness), not necessarily hemiplegia (unilateral paralysis), occurs with at least one other symptom during FHM aura.
• A severe phenotype with seizures, coma, and elevated temperature has been reported with the
• A severe phenotype with seizures and intellectual disability has been reported with the pathogenic variants
## Clinical Description
In migraine with aura, including familial hemiplegic migraine (FHM), the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include fully reversible
Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision).
Dysphasia usually occurs when hemiplegia is right-sided.
Hemiparesis (unilateral weakness), not necessarily hemiplegia (unilateral paralysis), occurs with at least one other symptom during FHM aura.
Some confusion and/or drowsiness may be present even without dysphasia. Impaired consciousness ranging from drowsiness to coma is well described in FHM [
Neurologic deficits with hemiplegic migraine attacks can be prolonged for hours to days and may outlast the associated migrainous headache. Persistent attention and memory loss can last weeks to months [
FHM is a rare and extreme phenotype of migraine with aura. The frequency of attacks ranges from one per day to fewer than five in a lifetime (mean: 2-3/year). Long attack-free intervals are often reported (range: 2-37 years). The frequency of FHM attacks tends to decrease with age. FHM attacks may be provoked by typical migraine triggers (e.g., foods, odors, exertion, stress), cerebral angiography, and minor head trauma.
The eventual neurologic outcome is often benign in the pure FHM group without interictal deficits (e.g., seizures/epilepsy, ataxia, nystagmus, cognitive impairment / learning disability).
Note: Cerebral infarction and death have rarely been associated with hemiplegic migraine and should instead raise the possibility of other disorders associated with migraine and stroke (see
Abnormalities in the cerebellum on magnetic resonance spectroscopy have been reported [
• Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision).
• Dysphasia usually occurs when hemiplegia is right-sided.
• Hemiparesis (unilateral weakness), not necessarily hemiplegia (unilateral paralysis), occurs with at least one other symptom during FHM aura.
## Phenotype Correlations by Gene
Those with identified FHM-related pathogenic variants tend to present with earlier age of onset, more severe symptoms, and associated interictal symptoms and signs (nystagmus, episodic or progressive ataxia, learning disability, epilepsy). In the report of
## Genotype-Phenotype Correlations
A severe phenotype with seizures, coma, and elevated temperature has been reported with the
A severe phenotype with seizures and intellectual disability has been reported with the pathogenic variants
• A severe phenotype with seizures, coma, and elevated temperature has been reported with the
• A severe phenotype with seizures and intellectual disability has been reported with the pathogenic variants
## Penetrance
Penetrance appears to be high and is estimated at 80% [
## Nomenclature
Although families with FHM in which attacks are strikingly identical do exist, the term FHM is often used inconsistently to describe families in which different forms of migraine occur, as most individuals with hemiplegic attacks have these attacks intermingled with more frequent attacks of migraine without hemiparesis.
## Prevalence
In Denmark,
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
Note: In one large family with pathogenic variants in
## Differential Diagnosis
Caution: Even with normal imaging studies and description of spreading aura, an age-appropriate stroke evaluation should be considered at presentation. Overlap in clinical features, inaccuracies of historical family information, rarity of FHM, and the seriousness of stroke-related disorders warrant this cautious approach. Stroke or other CNS-related disorders should be strongly considered if family history is negative for hemiplegic migraine.
Hereditary Disorders with Migrainous Headache That May Include Hemiplegic Aura in the Differential Diagnosis of Familial Hemiplegic Migraine
Dutch form of hereditary cerebral amyloid angiopathy (OMIM
AD = autosomal dominant; AVM = arteriovenous malformation; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CCM = cerebral cavernous malformation; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA
The most common mtDNA pathogenic variant, present in more than 80% of individuals with typical clinical findings of MELAS, is an A-to-G transition at nucleotide 3243 in the tRNALeu(UUR) of mtDNA.
Other
## Management
To establish the extent of disease and needs in an individual diagnosed with familial hemiplegic migraine (FHM) or simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history), the evaluations summarized in this
Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Hemiplegic Migraine
Quantitative eye movement exam in persons w/nystagmus or complaints of incoordination or imbalance to look for additional clues of cerebellar involvement
EEG & neuroimaging studies if seizures are present in order to further characterize seizure disorder
Neuroimaging studies in those w/impaired responsiveness to assess for cerebral edema
Community or
Social work involvement for parental support;
Home nursing referral.
FHM = familial hemiplegic migraine; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Symptomatic support during an episode of hemiplegic migraine is the only therapy available.
Treatment of Manifestations in Individuals with Familial Hemiplegic Migraine
Trial of acetazolamide for persons w/
Trial of standard migraine prophylactic drugs (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, ASMs)
ASM = anti-seizure medication
Recommended Surveillance for Individuals with Familial Hemiplegic Migraine
In general, vasoconstricting agents should be avoided because of the risk of stroke.
Cerebral angiography is hazardous as it may precipitate a severe attack [
See
Search
• Quantitative eye movement exam in persons w/nystagmus or complaints of incoordination or imbalance to look for additional clues of cerebellar involvement
• EEG & neuroimaging studies if seizures are present in order to further characterize seizure disorder
• Neuroimaging studies in those w/impaired responsiveness to assess for cerebral edema
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Trial of acetazolamide for persons w/
• Trial of standard migraine prophylactic drugs (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, ASMs)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with familial hemiplegic migraine (FHM) or simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history), the evaluations summarized in this
Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Hemiplegic Migraine
Quantitative eye movement exam in persons w/nystagmus or complaints of incoordination or imbalance to look for additional clues of cerebellar involvement
EEG & neuroimaging studies if seizures are present in order to further characterize seizure disorder
Neuroimaging studies in those w/impaired responsiveness to assess for cerebral edema
Community or
Social work involvement for parental support;
Home nursing referral.
FHM = familial hemiplegic migraine; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Quantitative eye movement exam in persons w/nystagmus or complaints of incoordination or imbalance to look for additional clues of cerebellar involvement
• EEG & neuroimaging studies if seizures are present in order to further characterize seizure disorder
• Neuroimaging studies in those w/impaired responsiveness to assess for cerebral edema
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Symptomatic support during an episode of hemiplegic migraine is the only therapy available.
Treatment of Manifestations in Individuals with Familial Hemiplegic Migraine
Trial of acetazolamide for persons w/
Trial of standard migraine prophylactic drugs (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, ASMs)
ASM = anti-seizure medication
• Trial of acetazolamide for persons w/
• Trial of standard migraine prophylactic drugs (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, ASMs)
## Surveillance
Recommended Surveillance for Individuals with Familial Hemiplegic Migraine
## Agents/Circumstances to Avoid
In general, vasoconstricting agents should be avoided because of the risk of stroke.
Cerebral angiography is hazardous as it may precipitate a severe attack [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Familial hemiplegic migraine (FHM) and simplex hemiplegic migraine caused by a heterozygous
Note: The term "simplex hemiplegic migraine" is used in this section to refer to individuals with hemiplegic migraine and a heterozygous pathogenic variant in
Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with FHM have an affected parent.
Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a
Recommendations for the evaluation of the parents of an individual who appears to be the only affected family member include clinical interview, neurologic examination, and molecular genetic testing if a molecular diagnosis has been established in the proband.
If a pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have an FHM-causing pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. There is a high likelihood that a sib who inherits an FHM-causing pathogenic variant will have clinical manifestations of the disorder. Intrafamilial clinical variability has been observed in age at onset and severity of manifestations, including attack frequency, severity, and associated features.
Of note, the core
If the proband has a known
If the proband does not have a known FHM-related pathogenic variant and both of the proband's parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
Once an FHM-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with FHM have an affected parent.
• Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a
• Recommendations for the evaluation of the parents of an individual who appears to be the only affected family member include clinical interview, neurologic examination, and molecular genetic testing if a molecular diagnosis has been established in the proband.
• If a pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have an FHM-causing pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. There is a high likelihood that a sib who inherits an FHM-causing pathogenic variant will have clinical manifestations of the disorder. Intrafamilial clinical variability has been observed in age at onset and severity of manifestations, including attack frequency, severity, and associated features.
• Of note, the core
• Of note, the core
• If the proband has a known
• If the proband does not have a known FHM-related pathogenic variant and both of the proband's parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• Of note, the core
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
## Mode of Inheritance
Familial hemiplegic migraine (FHM) and simplex hemiplegic migraine caused by a heterozygous
Note: The term "simplex hemiplegic migraine" is used in this section to refer to individuals with hemiplegic migraine and a heterozygous pathogenic variant in
## Risk to Family Members
Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with FHM have an affected parent.
Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a
Recommendations for the evaluation of the parents of an individual who appears to be the only affected family member include clinical interview, neurologic examination, and molecular genetic testing if a molecular diagnosis has been established in the proband.
If a pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have an FHM-causing pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. There is a high likelihood that a sib who inherits an FHM-causing pathogenic variant will have clinical manifestations of the disorder. Intrafamilial clinical variability has been observed in age at onset and severity of manifestations, including attack frequency, severity, and associated features.
Of note, the core
If the proband has a known
If the proband does not have a known FHM-related pathogenic variant and both of the proband's parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with FHM have an affected parent.
• Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a
• Recommendations for the evaluation of the parents of an individual who appears to be the only affected family member include clinical interview, neurologic examination, and molecular genetic testing if a molecular diagnosis has been established in the proband.
• If a pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have an FHM-causing pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. There is a high likelihood that a sib who inherits an FHM-causing pathogenic variant will have clinical manifestations of the disorder. Intrafamilial clinical variability has been observed in age at onset and severity of manifestations, including attack frequency, severity, and associated features.
• Of note, the core
• Of note, the core
• If the proband has a known
• If the proband does not have a known FHM-related pathogenic variant and both of the proband's parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• Of note, the core
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once an FHM-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
## Molecular Genetics
Familial Hemiplegic Migraine: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Familial Hemiplegic Migraine (
The three FHM-related genes identified to date encode ion channels and transporters important in regulating neuronal excitability and cortical synaptic transmission. The observation of seizures and epilepsy in individuals with FHM-causing variants further emphasizes the mechanistic overlap between migraine and epilepsy from dysregulation of cortical excitation/inhibition balance.
Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying migraine aura is cortical spreading depolarization (CSD) of Leão, which is characterized by a slowly propagating wave 2-6 mm/min of hyperexcitation followed by sustained depression. Mouse models generated from
Familial Hemiplegic Migraine: Gene-Specific Laboratory Considerations
Familial Hemiplegic Migraine: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the author.
Genes from
Variant designations are given for an alternate reference sequence. X99897 is an alternate cDNA commonly used in the literature. Compared to NM_001127221.2, it has an extra three nucleotides (AAG) at nucleotide 3623_3625, resulting in an additional Glu residue.
## Molecular Pathogenesis
The three FHM-related genes identified to date encode ion channels and transporters important in regulating neuronal excitability and cortical synaptic transmission. The observation of seizures and epilepsy in individuals with FHM-causing variants further emphasizes the mechanistic overlap between migraine and epilepsy from dysregulation of cortical excitation/inhibition balance.
Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying migraine aura is cortical spreading depolarization (CSD) of Leão, which is characterized by a slowly propagating wave 2-6 mm/min of hyperexcitation followed by sustained depression. Mouse models generated from
Familial Hemiplegic Migraine: Gene-Specific Laboratory Considerations
Familial Hemiplegic Migraine: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the author.
Genes from
Variant designations are given for an alternate reference sequence. X99897 is an alternate cDNA commonly used in the literature. Compared to NM_001127221.2, it has an extra three nucleotides (AAG) at nucleotide 3623_3625, resulting in an additional Glu residue.
## Chapter Notes
Kathy Lou Gardner, MD; University of Pittsburgh (2001-2009)Joanna C Jen, MD, PhD (2009-present)
4 July 2024 (sw) Revision: information regarding
29 April 2021 (sw) Comprehensive update posted live
14 May 2015 (me) Comprehensive update posted live
8 September 2009 (me) Comprehensive update posted live
15 March 2004 (me) Comprehensive update posted live
17 July 2001 (me) Review posted live
October 2000 (kg) Original submission
• 4 July 2024 (sw) Revision: information regarding
• 29 April 2021 (sw) Comprehensive update posted live
• 14 May 2015 (me) Comprehensive update posted live
• 8 September 2009 (me) Comprehensive update posted live
• 15 March 2004 (me) Comprehensive update posted live
• 17 July 2001 (me) Review posted live
• October 2000 (kg) Original submission
## Author History
Kathy Lou Gardner, MD; University of Pittsburgh (2001-2009)Joanna C Jen, MD, PhD (2009-present)
## Revision History
4 July 2024 (sw) Revision: information regarding
29 April 2021 (sw) Comprehensive update posted live
14 May 2015 (me) Comprehensive update posted live
8 September 2009 (me) Comprehensive update posted live
15 March 2004 (me) Comprehensive update posted live
17 July 2001 (me) Review posted live
October 2000 (kg) Original submission
• 4 July 2024 (sw) Revision: information regarding
• 29 April 2021 (sw) Comprehensive update posted live
• 14 May 2015 (me) Comprehensive update posted live
• 8 September 2009 (me) Comprehensive update posted live
• 15 March 2004 (me) Comprehensive update posted live
• 17 July 2001 (me) Review posted live
• October 2000 (kg) Original submission
## References
## Literature Cited
|
[] |
17/7/2001
|
29/4/2021
|
4/7/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
fhs
|
fhs
|
[
"Helicase SRCAP",
"SRCAP",
"SRCAP-Related Floating-Harbor Syndrome"
] |
Malgorzata JM Nowaczyk, Sarah M Nikkel, Susan M White
|
Summary The diagnosis is established in a proband with suggestive findings and a heterozygous
|
## Diagnosis
No consensus clinical diagnostic criteria for
Triangular face
Deep-set eyes
Short philtrum
Wide mouth with thin vermilion of the upper lip
Long nose with narrow bridge, broad base, broad tip, and low-hanging columella
Low-set ears
Proportionate short stature (see
Significant delay in bone age early in childhood (≥2 standard deviations below the mean for age and sex) with normalization between ages six and 12 years
Skeletal anomalies. Brachydactyly, broad fingertips that give the appearance of clubbing, clinodactyly, short thumbs, prominent joints (see
Dysarthria and verbal dyspraxia with phoneme imprecision
Hypernasality
High-pitched voice
Severe receptive and expressive language impairment across all domains of function
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by short stature,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, large deletions that encompass
• Triangular face
• Deep-set eyes
• Short philtrum
• Wide mouth with thin vermilion of the upper lip
• Long nose with narrow bridge, broad base, broad tip, and low-hanging columella
• Low-set ears
• Proportionate short stature (see
• Significant delay in bone age early in childhood (≥2 standard deviations below the mean for age and sex) with normalization between ages six and 12 years
• Skeletal anomalies. Brachydactyly, broad fingertips that give the appearance of clubbing, clinodactyly, short thumbs, prominent joints (see
• Dysarthria and verbal dyspraxia with phoneme imprecision
• Hypernasality
• High-pitched voice
• Severe receptive and expressive language impairment across all domains of function
• For an introduction to multigene panels click
## Suggestive Findings
Triangular face
Deep-set eyes
Short philtrum
Wide mouth with thin vermilion of the upper lip
Long nose with narrow bridge, broad base, broad tip, and low-hanging columella
Low-set ears
Proportionate short stature (see
Significant delay in bone age early in childhood (≥2 standard deviations below the mean for age and sex) with normalization between ages six and 12 years
Skeletal anomalies. Brachydactyly, broad fingertips that give the appearance of clubbing, clinodactyly, short thumbs, prominent joints (see
Dysarthria and verbal dyspraxia with phoneme imprecision
Hypernasality
High-pitched voice
Severe receptive and expressive language impairment across all domains of function
• Triangular face
• Deep-set eyes
• Short philtrum
• Wide mouth with thin vermilion of the upper lip
• Long nose with narrow bridge, broad base, broad tip, and low-hanging columella
• Low-set ears
• Proportionate short stature (see
• Significant delay in bone age early in childhood (≥2 standard deviations below the mean for age and sex) with normalization between ages six and 12 years
• Skeletal anomalies. Brachydactyly, broad fingertips that give the appearance of clubbing, clinodactyly, short thumbs, prominent joints (see
• Dysarthria and verbal dyspraxia with phoneme imprecision
• Hypernasality
• High-pitched voice
• Severe receptive and expressive language impairment across all domains of function
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic findings suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by short stature,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, large deletions that encompass
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by short stature,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, large deletions that encompass
## Clinical Characteristics
Based on
Pathogenic variants in exons 33 and 34 of
The prevalence of
## Clinical Description
Based on
## Genotype-Phenotype Correlations
Pathogenic variants in exons 33 and 34 of
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
Heterozygous
The Cancer Genome Atlas summarizes somatic pathogenic variants in genes (including
## Differential Diagnosis
The distinctive facial features, bone age delay, and characteristic speech disability that make the diagnosis of
Other Genes of Interest in the Differential Diagnosis of
Triangular face
Short 5th fingers
Bone age may be slightly delayed.
Males may have hypospadias.
Severe pre- & postnatal growth restriction (final height 5-6 SD below mean; i.e., 120-130 cm)
Relatively large head, hypoplastic midface, thick eyebrows, fleshy nasal tip, long philtrum, prominent mouth & lips, pointed chin
Normal intelligence
Absence of language impairment
Characteristic radiologic findings
Short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, prominent heels, loose joints
Hypogonadism in males
Facial features (e.g., low-hanging columella)
Broad or angulated thumbs
Short stature
Arched brows, downslanted palpebral fissures, grimacing smile
Average IQ range is 35-50; however, developmental outcome varies considerably (some persons w/
Normal bone age
Cardiac malformations
Pre- & postnatal growth restriction
Expressive language impairment (much more severe in
Body asymmetry
Café au lait macules
Blue sclera
Absence of
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SD = standard deviations;
Hypomethylation of the imprinting control region 1 (ICR1) at 11p15.5 causes SRS in 35%-67% of individuals, and maternal uniparental disomy of chromosome 7 (upd(7)mat) causes SRS in 7%-10% of individuals. See Silver-Russell Syndrome,
• Triangular face
• Short 5th fingers
• Bone age may be slightly delayed.
• Males may have hypospadias.
• Severe pre- & postnatal growth restriction (final height 5-6 SD below mean; i.e., 120-130 cm)
• Relatively large head, hypoplastic midface, thick eyebrows, fleshy nasal tip, long philtrum, prominent mouth & lips, pointed chin
• Normal intelligence
• Absence of language impairment
• Characteristic radiologic findings
• Short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, prominent heels, loose joints
• Hypogonadism in males
• Facial features (e.g., low-hanging columella)
• Broad or angulated thumbs
• Short stature
• Arched brows, downslanted palpebral fissures, grimacing smile
• Average IQ range is 35-50; however, developmental outcome varies considerably (some persons w/
• Normal bone age
• Cardiac malformations
• Pre- & postnatal growth restriction
• Expressive language impairment (much more severe in
• Body asymmetry
• Café au lait macules
• Blue sclera
• Absence of
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment for clinical manifestations of seizures
EEG if seizures are suspected
Assessment of feeding
Assessment for manifestations of gastroesophageal reflux & constipation
Assessment for celiac disease as indicated
Renal ultrasound exam
Blood pressure assessment
Assessment for cryptorchidism in males
Assessment for signs/symptoms of cardiac malformations
Echocardiogram in those w/suggestive signs/symptoms of cardiac disease
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance; OCD = obsessive-compulsive disorder;
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
HGH therapy w/modest response has been reported in 24 children w/
It is unknown if persons w/
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy as needed for poor weight gain
Gastrostomy tube placement may be required for persistent feeding issues.
Standard treatments for gastroesophageal reflux, constipation, & celiac disease
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; HGH = human growth hormone;
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Bone age exam
Eval for signs of early puberty
Blood pressure measurement
Assessment of kidney function incl plasma BUN & creatinine
ADHD = attention-deficit/hyperactivity disorder; BUN = blood urea nitrogen; HGH = human growth hormone; OCD = obsessive-compulsive disorder
See
No specific pregnancy complications for the mother or the fetus have been observed in the two women with
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assessment for clinical manifestations of seizures
• EEG if seizures are suspected
• Assessment of feeding
• Assessment for manifestations of gastroesophageal reflux & constipation
• Assessment for celiac disease as indicated
• Renal ultrasound exam
• Blood pressure assessment
• Assessment for cryptorchidism in males
• Assessment for signs/symptoms of cardiac malformations
• Echocardiogram in those w/suggestive signs/symptoms of cardiac disease
• HGH therapy w/modest response has been reported in 24 children w/
• It is unknown if persons w/
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy as needed for poor weight gain
• Gastrostomy tube placement may be required for persistent feeding issues.
• Standard treatments for gastroesophageal reflux, constipation, & celiac disease
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Bone age exam
• Eval for signs of early puberty
• Blood pressure measurement
• Assessment of kidney function incl plasma BUN & creatinine
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment for clinical manifestations of seizures
EEG if seizures are suspected
Assessment of feeding
Assessment for manifestations of gastroesophageal reflux & constipation
Assessment for celiac disease as indicated
Renal ultrasound exam
Blood pressure assessment
Assessment for cryptorchidism in males
Assessment for signs/symptoms of cardiac malformations
Echocardiogram in those w/suggestive signs/symptoms of cardiac disease
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance; OCD = obsessive-compulsive disorder;
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assessment for clinical manifestations of seizures
• EEG if seizures are suspected
• Assessment of feeding
• Assessment for manifestations of gastroesophageal reflux & constipation
• Assessment for celiac disease as indicated
• Renal ultrasound exam
• Blood pressure assessment
• Assessment for cryptorchidism in males
• Assessment for signs/symptoms of cardiac malformations
• Echocardiogram in those w/suggestive signs/symptoms of cardiac disease
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
HGH therapy w/modest response has been reported in 24 children w/
It is unknown if persons w/
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy as needed for poor weight gain
Gastrostomy tube placement may be required for persistent feeding issues.
Standard treatments for gastroesophageal reflux, constipation, & celiac disease
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; HGH = human growth hormone;
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• HGH therapy w/modest response has been reported in 24 children w/
• It is unknown if persons w/
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy as needed for poor weight gain
• Gastrostomy tube placement may be required for persistent feeding issues.
• Standard treatments for gastroesophageal reflux, constipation, & celiac disease
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Bone age exam
Eval for signs of early puberty
Blood pressure measurement
Assessment of kidney function incl plasma BUN & creatinine
ADHD = attention-deficit/hyperactivity disorder; BUN = blood urea nitrogen; HGH = human growth hormone; OCD = obsessive-compulsive disorder
• Bone age exam
• Eval for signs of early puberty
• Blood pressure measurement
• Assessment of kidney function incl plasma BUN & creatinine
## Evaluation of Relatives at Risk
See
## Pregnancy Management
No specific pregnancy complications for the mother or the fetus have been observed in the two women with
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals with
Transmission of an
Molecular genetic testing and clinical evaluation for signs of
If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in a family member with a milder phenotype. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
An advanced paternal age effect is suggested. In their series of 13 individuals with a heterozygous
In the rare instance of a parent being affected and/or known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected child and to young adults who are affected.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals with
• Transmission of an
• Molecular genetic testing and clinical evaluation for signs of
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in a family member with a milder phenotype. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• An advanced paternal age effect is suggested. In their series of 13 individuals with a heterozygous
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• In the rare instance of a parent being affected and/or known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected child and to young adults who are affected.
## Mode of Inheritance
## Risk to Family Members
Most individuals with
Transmission of an
Molecular genetic testing and clinical evaluation for signs of
If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in a family member with a milder phenotype. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
An advanced paternal age effect is suggested. In their series of 13 individuals with a heterozygous
In the rare instance of a parent being affected and/or known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.
If the
• Most individuals with
• Transmission of an
• Molecular genetic testing and clinical evaluation for signs of
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in a family member with a milder phenotype. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• An advanced paternal age effect is suggested. In their series of 13 individuals with a heterozygous
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• In the rare instance of a parent being affected and/or known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected child and to young adults who are affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected child and to young adults who are affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
Floating-Harbor Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Floating-Harbor Syndrome (
SRCAP functions as a transcriptional activator for CREB- and CBP-mediated transcription, along with Notch-mediated and steroid receptor-mediated transcription [
## Molecular Pathogenesis
SRCAP functions as a transcriptional activator for CREB- and CBP-mediated transcription, along with Notch-mediated and steroid receptor-mediated transcription [
## Chapter Notes
10 April 2025 (sw) Comprehensive update posted live
23 May 2019 (sw) Comprehensive update posted live
29 November 2012 (me) Review posted live
26 June 2012 (mjmn) Original submission
• 10 April 2025 (sw) Comprehensive update posted live
• 23 May 2019 (sw) Comprehensive update posted live
• 29 November 2012 (me) Review posted live
• 26 June 2012 (mjmn) Original submission
## Revision History
10 April 2025 (sw) Comprehensive update posted live
23 May 2019 (sw) Comprehensive update posted live
29 November 2012 (me) Review posted live
26 June 2012 (mjmn) Original submission
• 10 April 2025 (sw) Comprehensive update posted live
• 23 May 2019 (sw) Comprehensive update posted live
• 29 November 2012 (me) Review posted live
• 26 June 2012 (mjmn) Original submission
## References
## Literature Cited
Facial appearance of a girl age 11 years with
A. Note triangular face with deep-set eyes; short philtrum; long nose with narrow nasal bridge and broad nasal base with low-hanging columella; and thin vermilion of the upper lip.
B. Profile view shows low-set ears and low-hanging columella.
Dorsal (A) and palmar (B) view of the hands of the girl in
Frontal view of the girl in
|
[] |
29/11/2012
|
10/4/2025
|
24/1/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
fkbp14-keds
|
fkbp14-keds
|
[
"kEDS-FKBP14",
"kEDS-FKBP14",
"Peptidyl-prolyl cis-trans isomerase FKBP14",
"FKBP14",
"FKBP14-Kyphoscoliotic Ehlers-Danlos Syndrome"
] |
Cecilia Giunta, Marianne Rohrbach, Christine Fauth, Matthias Baumann
|
Summary Clinical diagnostic criteria rely on the finding of congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis in addition to generalized joint hypermobility or further gene-specific and/or supportive clinical features. The diagnosis of
|
## Diagnosis
Formal clinical diagnostic criteria for
Major and minor clinical features of
Congenital muscular hypotonia
Congenital or early-onset kyphoscoliosis
Generalized joint hypermobility
Early-onset sensorineural, conductive, or mixed hearing impairment (See
Muscle atrophy
Follicular hyperkeratosis
Bladder diverticula
Marfanoid habitus
Pectus deformity
Talipes equinovarus
Skin hyperextensibility
Easily bruisable skin
Hernia (umbilical or inguinal)
Rupture/aneurysm of a medium-sized artery
Blue sclerae
Refractive errors (myopia, hypermetropia)
Osteopenia/osteoporosis
Normal or only slightly elevated serum creatine kinase (CK) level
Histopathology of muscle biopsies showing nonspecific mild myopathic changes with increased variation in muscle fiber diameter to more pronounced changes with profound fiber atrophy and proliferation of fatty tissue
Note: At the time of writing, muscle biopsy is not required to make the diagnosis of
Proposed minimal clinical diagnostic criteria for
Congenital muscular hypotonia
Either or both of the following:
Generalized joint hypermobility
Three minor criteria (from either
However, the diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic findings suggest the diagnosis of
Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited connective tissue disorders,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
A common pathogenic variant (c.362dupC) has been reported; see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Congenital muscular hypotonia
• Congenital or early-onset kyphoscoliosis
• Generalized joint hypermobility
• Early-onset sensorineural, conductive, or mixed hearing impairment (See
• Muscle atrophy
• Follicular hyperkeratosis
• Bladder diverticula
• Marfanoid habitus
• Pectus deformity
• Talipes equinovarus
• Skin hyperextensibility
• Easily bruisable skin
• Hernia (umbilical or inguinal)
• Rupture/aneurysm of a medium-sized artery
• Blue sclerae
• Refractive errors (myopia, hypermetropia)
• Osteopenia/osteoporosis
• Normal or only slightly elevated serum creatine kinase (CK) level
• Histopathology of muscle biopsies showing nonspecific mild myopathic changes with increased variation in muscle fiber diameter to more pronounced changes with profound fiber atrophy and proliferation of fatty tissue
• Congenital muscular hypotonia
• Either or both of the following:
• Generalized joint hypermobility
• Three minor criteria (from either
• Generalized joint hypermobility
• Three minor criteria (from either
• Generalized joint hypermobility
• Three minor criteria (from either
• Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• For an introduction to multigene panels click
## Suggestive Findings
Major and minor clinical features of
Congenital muscular hypotonia
Congenital or early-onset kyphoscoliosis
Generalized joint hypermobility
Early-onset sensorineural, conductive, or mixed hearing impairment (See
Muscle atrophy
Follicular hyperkeratosis
Bladder diverticula
Marfanoid habitus
Pectus deformity
Talipes equinovarus
Skin hyperextensibility
Easily bruisable skin
Hernia (umbilical or inguinal)
Rupture/aneurysm of a medium-sized artery
Blue sclerae
Refractive errors (myopia, hypermetropia)
Osteopenia/osteoporosis
Normal or only slightly elevated serum creatine kinase (CK) level
Histopathology of muscle biopsies showing nonspecific mild myopathic changes with increased variation in muscle fiber diameter to more pronounced changes with profound fiber atrophy and proliferation of fatty tissue
Note: At the time of writing, muscle biopsy is not required to make the diagnosis of
• Congenital muscular hypotonia
• Congenital or early-onset kyphoscoliosis
• Generalized joint hypermobility
• Early-onset sensorineural, conductive, or mixed hearing impairment (See
• Muscle atrophy
• Follicular hyperkeratosis
• Bladder diverticula
• Marfanoid habitus
• Pectus deformity
• Talipes equinovarus
• Skin hyperextensibility
• Easily bruisable skin
• Hernia (umbilical or inguinal)
• Rupture/aneurysm of a medium-sized artery
• Blue sclerae
• Refractive errors (myopia, hypermetropia)
• Osteopenia/osteoporosis
• Normal or only slightly elevated serum creatine kinase (CK) level
• Histopathology of muscle biopsies showing nonspecific mild myopathic changes with increased variation in muscle fiber diameter to more pronounced changes with profound fiber atrophy and proliferation of fatty tissue
## Establishing the Diagnosis
Proposed minimal clinical diagnostic criteria for
Congenital muscular hypotonia
Either or both of the following:
Generalized joint hypermobility
Three minor criteria (from either
However, the diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic findings suggest the diagnosis of
Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited connective tissue disorders,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
A common pathogenic variant (c.362dupC) has been reported; see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Congenital muscular hypotonia
• Either or both of the following:
• Generalized joint hypermobility
• Three minor criteria (from either
• Generalized joint hypermobility
• Three minor criteria (from either
• Generalized joint hypermobility
• Three minor criteria (from either
• Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of
Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
For an introduction to multigene panels click
• Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited connective tissue disorders,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
A common pathogenic variant (c.362dupC) has been reported; see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
A range of clinical severity is observed in individuals with
Wider phenotypic variability of the muscular features may exist, as suggested by the presence of early-onset muscle disease with severe involvement of the lower-limb muscles in one recently described affected individual [
Kyphoscoliosis is a hallmark of
Pronounced joint hypermobility (mean value of Beighton score 8/9) is seen in 23/23 affected individuals [
Hypermobility may result in recurrent joint dislocations/sprains or chronic pain (5/23 affected individuals reported).
Foot deformities that include congenital or postural talipes and pes planus / planovalgus have been found in 23/23 of affected individuals.
Despite significant joint hypermobility, congenital contractures are present in up to one third of affected individuals and may impact the fingers, wrist, elbows, or knees (7/23). Congenital hip dislocation is present in 4/17 of affected individuals.
Fractures probably due to osteopenia/osteoporosis from immobility occurred in 3/23.
Atlantoaxial subluxation/instability has been reported in three individuals [
Additionally, artery dissections occurred in two adult individuals (internal carotid artery and celiac artery) [
Inguinal and/or umbilical hernia in about half of affected individuals (11/23), sometimes with redundant umbilical skin.
Bifid uvula with submucous cleft palate or frank cleft palate (7/23)
Speech or language delay (7/20); true intellectual disability is rare and may be unrelated in children of consanguineous relationships.
Visceral complications, including large bladder diverticula (3/19) and (rarely) rectal prolapse.
Genotype-phenotype correlations that predict risk for specific complications or clinical severity have not been reported to date.
The pathomechanism of
Normal collagen biosynthesis and secretion of collagen types I, III, and V
Disarray of the main components of the extracellular matrix (i.e., collagen type I, III, and VI; fibronectin; tenascins; thrombospondin) by indirect immunofluorescence on skin fibroblast from affected individuals
Type V collagen is organized in an extracellular network that is similar to control fibroblasts.
Loss of the main receptors of collagens and fibronectin, α2β1 and α5β1 integrins.
Marked enlargement of the ER cisterns with accumulation of flocculent material in skin cells of affected individuals by transmission electron microscopy
See also
• Kyphoscoliosis is a hallmark of
• Pronounced joint hypermobility (mean value of Beighton score 8/9) is seen in 23/23 affected individuals [
• Hypermobility may result in recurrent joint dislocations/sprains or chronic pain (5/23 affected individuals reported).
• Foot deformities that include congenital or postural talipes and pes planus / planovalgus have been found in 23/23 of affected individuals.
• Hypermobility may result in recurrent joint dislocations/sprains or chronic pain (5/23 affected individuals reported).
• Foot deformities that include congenital or postural talipes and pes planus / planovalgus have been found in 23/23 of affected individuals.
• Despite significant joint hypermobility, congenital contractures are present in up to one third of affected individuals and may impact the fingers, wrist, elbows, or knees (7/23). Congenital hip dislocation is present in 4/17 of affected individuals.
• Fractures probably due to osteopenia/osteoporosis from immobility occurred in 3/23.
• Atlantoaxial subluxation/instability has been reported in three individuals [
• Hypermobility may result in recurrent joint dislocations/sprains or chronic pain (5/23 affected individuals reported).
• Foot deformities that include congenital or postural talipes and pes planus / planovalgus have been found in 23/23 of affected individuals.
• Inguinal and/or umbilical hernia in about half of affected individuals (11/23), sometimes with redundant umbilical skin.
• Bifid uvula with submucous cleft palate or frank cleft palate (7/23)
• Speech or language delay (7/20); true intellectual disability is rare and may be unrelated in children of consanguineous relationships.
• Visceral complications, including large bladder diverticula (3/19) and (rarely) rectal prolapse.
• Normal collagen biosynthesis and secretion of collagen types I, III, and V
• Disarray of the main components of the extracellular matrix (i.e., collagen type I, III, and VI; fibronectin; tenascins; thrombospondin) by indirect immunofluorescence on skin fibroblast from affected individuals
• Type V collagen is organized in an extracellular network that is similar to control fibroblasts.
• Loss of the main receptors of collagens and fibronectin, α2β1 and α5β1 integrins.
• Marked enlargement of the ER cisterns with accumulation of flocculent material in skin cells of affected individuals by transmission electron microscopy
## Clinical Description
A range of clinical severity is observed in individuals with
Wider phenotypic variability of the muscular features may exist, as suggested by the presence of early-onset muscle disease with severe involvement of the lower-limb muscles in one recently described affected individual [
Kyphoscoliosis is a hallmark of
Pronounced joint hypermobility (mean value of Beighton score 8/9) is seen in 23/23 affected individuals [
Hypermobility may result in recurrent joint dislocations/sprains or chronic pain (5/23 affected individuals reported).
Foot deformities that include congenital or postural talipes and pes planus / planovalgus have been found in 23/23 of affected individuals.
Despite significant joint hypermobility, congenital contractures are present in up to one third of affected individuals and may impact the fingers, wrist, elbows, or knees (7/23). Congenital hip dislocation is present in 4/17 of affected individuals.
Fractures probably due to osteopenia/osteoporosis from immobility occurred in 3/23.
Atlantoaxial subluxation/instability has been reported in three individuals [
Additionally, artery dissections occurred in two adult individuals (internal carotid artery and celiac artery) [
Inguinal and/or umbilical hernia in about half of affected individuals (11/23), sometimes with redundant umbilical skin.
Bifid uvula with submucous cleft palate or frank cleft palate (7/23)
Speech or language delay (7/20); true intellectual disability is rare and may be unrelated in children of consanguineous relationships.
Visceral complications, including large bladder diverticula (3/19) and (rarely) rectal prolapse.
• Kyphoscoliosis is a hallmark of
• Pronounced joint hypermobility (mean value of Beighton score 8/9) is seen in 23/23 affected individuals [
• Hypermobility may result in recurrent joint dislocations/sprains or chronic pain (5/23 affected individuals reported).
• Foot deformities that include congenital or postural talipes and pes planus / planovalgus have been found in 23/23 of affected individuals.
• Hypermobility may result in recurrent joint dislocations/sprains or chronic pain (5/23 affected individuals reported).
• Foot deformities that include congenital or postural talipes and pes planus / planovalgus have been found in 23/23 of affected individuals.
• Despite significant joint hypermobility, congenital contractures are present in up to one third of affected individuals and may impact the fingers, wrist, elbows, or knees (7/23). Congenital hip dislocation is present in 4/17 of affected individuals.
• Fractures probably due to osteopenia/osteoporosis from immobility occurred in 3/23.
• Atlantoaxial subluxation/instability has been reported in three individuals [
• Hypermobility may result in recurrent joint dislocations/sprains or chronic pain (5/23 affected individuals reported).
• Foot deformities that include congenital or postural talipes and pes planus / planovalgus have been found in 23/23 of affected individuals.
• Inguinal and/or umbilical hernia in about half of affected individuals (11/23), sometimes with redundant umbilical skin.
• Bifid uvula with submucous cleft palate or frank cleft palate (7/23)
• Speech or language delay (7/20); true intellectual disability is rare and may be unrelated in children of consanguineous relationships.
• Visceral complications, including large bladder diverticula (3/19) and (rarely) rectal prolapse.
## Genotype-Phenotype Correlations
Genotype-phenotype correlations that predict risk for specific complications or clinical severity have not been reported to date.
## Pathophysiology
The pathomechanism of
Normal collagen biosynthesis and secretion of collagen types I, III, and V
Disarray of the main components of the extracellular matrix (i.e., collagen type I, III, and VI; fibronectin; tenascins; thrombospondin) by indirect immunofluorescence on skin fibroblast from affected individuals
Type V collagen is organized in an extracellular network that is similar to control fibroblasts.
Loss of the main receptors of collagens and fibronectin, α2β1 and α5β1 integrins.
Marked enlargement of the ER cisterns with accumulation of flocculent material in skin cells of affected individuals by transmission electron microscopy
See also
• Normal collagen biosynthesis and secretion of collagen types I, III, and V
• Disarray of the main components of the extracellular matrix (i.e., collagen type I, III, and VI; fibronectin; tenascins; thrombospondin) by indirect immunofluorescence on skin fibroblast from affected individuals
• Type V collagen is organized in an extracellular network that is similar to control fibroblasts.
• Loss of the main receptors of collagens and fibronectin, α2β1 and α5β1 integrins.
• Marked enlargement of the ER cisterns with accumulation of flocculent material in skin cells of affected individuals by transmission electron microscopy
## Nomenclature
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of
Congenital muscular hypotonia
Congenital/early-onset kyphoscoliosis
Generalized joint hypermobility
Absence of hearing impairment
↑ ratio of urinary pyridinolines
Characteristic craniofacial features
Peculiar fingers (tapering, slender, cylindric)
Congenital muscular hypotonia
Progressive kyphoscoliosis
Joint hypermobility
Follicular hyperkeratosis
Myopathy on muscle biopsy
Respiratory muscle failure
Absence of skin hyperelasticity & easy bruising
Absence of hearing impairment & cardiovascular problems
Congenital muscular hypotonia
Kyphoscoliosis (
Joint hypermobility
Pectus deformities
Progressive short stature
Primary skeletal involvement
Dysplastic teeth
Congenital muscular hypotonia
Motor developmental delay
Soft, doughy skin
Muscular atrophy
Myopathy on muscle biopsy
Severe progressive scoliosis
AD = autosomal dominant; AR = autosomal recessive; EDS = Ehlers-Danlos syndrome; MOI = mode of inheritance
In Bethlem myopathy, muscle biopsies reveal myopathic or dystrophic changes. Collagen VI immunolabeling is often normal or shows only subtle alterations. Conversely, in Ulrich congenital muscular dystrophy muscle biopsies more commonly show dystrophic features with degeneration and regeneration and replacement of muscle with fat and fibrous connective tissue. Collagen VI immunolabeling from the endomysium and basal lamina ranges from absent to moderately or markedly reduced, but may be normal around the capillaries (see
• Congenital muscular hypotonia
• Congenital/early-onset kyphoscoliosis
• Generalized joint hypermobility
• Absence of hearing impairment
• ↑ ratio of urinary pyridinolines
• Characteristic craniofacial features
• Peculiar fingers (tapering, slender, cylindric)
• Congenital muscular hypotonia
• Progressive kyphoscoliosis
• Joint hypermobility
• Follicular hyperkeratosis
• Myopathy on muscle biopsy
• Respiratory muscle failure
• Absence of skin hyperelasticity & easy bruising
• Absence of hearing impairment & cardiovascular problems
• Congenital muscular hypotonia
• Kyphoscoliosis (
• Joint hypermobility
• Pectus deformities
• Progressive short stature
• Primary skeletal involvement
• Dysplastic teeth
• Congenital muscular hypotonia
• Motor developmental delay
• Soft, doughy skin
• Muscular atrophy
• Myopathy on muscle biopsy
• Severe progressive scoliosis
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Clinical & radiologic documentation of kyphoscoliosis & measurement of curvature
Eval for joint contractures & other skeletal features
To incl measurement of aortic root size & assessment of heart valves
Cardiac & abdominal ultrasound/MRI may also be considered to monitor for aortic dilatation.
DXA = dual-energy x-ray absorptiometry; PT = physical therapy
Care providers should be made aware of the possibility of atlantoaxial instability; however, proactive assessment for this finding is not typically done.
Treatment of Manifestations in Individuals with
Surgery may be indicated for severe scoliosis.
At surgery caution should be taken due to risk for vascular complications, atlantoaxial instability, & primary muscle disease.
Orthopedists, rehab medicine, & PTs/OTs can assist in recommending appropriate devices to improve joint stability.
Walker or wheelchair may be necessary for mobility.
Use of beta-blockers (e.g., celiprolol) may be considered based on their efficiency in vascular EDS.
Vascular surgery is extremely risky because of vascular fragility in EDS.
OT = occupational therapist; PT = physical therapist/therapy
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Standardized medical surveillance guidelines for individuals with
Recommended Surveillance for Individuals with
Echocardiography w/consideration of cardiac MRI
Vascular ultrasonography to evaluate abdominal & peripheral arteries & veins
DXA = dual-energy x-ray absorptiometry
Maintenance of blood pressure in the normal range for age is recommended to reduce the risk of arterial rupture.
Avoid the following:
For children with severe joint hypermobility, sports that place stress on the joints
High blood pressure
For individuals with aortic aneurysm, contact sports
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance measures. Molecular genetic testing can be used if the pathogenic variants in the family are known.
See
No pregnancies in women with
Search
• Clinical & radiologic documentation of kyphoscoliosis & measurement of curvature
• Eval for joint contractures & other skeletal features
• To incl measurement of aortic root size & assessment of heart valves
• Cardiac & abdominal ultrasound/MRI may also be considered to monitor for aortic dilatation.
• Surgery may be indicated for severe scoliosis.
• At surgery caution should be taken due to risk for vascular complications, atlantoaxial instability, & primary muscle disease.
• Orthopedists, rehab medicine, & PTs/OTs can assist in recommending appropriate devices to improve joint stability.
• Walker or wheelchair may be necessary for mobility.
• Use of beta-blockers (e.g., celiprolol) may be considered based on their efficiency in vascular EDS.
• Vascular surgery is extremely risky because of vascular fragility in EDS.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Echocardiography w/consideration of cardiac MRI
• Vascular ultrasonography to evaluate abdominal & peripheral arteries & veins
• For children with severe joint hypermobility, sports that place stress on the joints
• High blood pressure
• For individuals with aortic aneurysm, contact sports
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Clinical & radiologic documentation of kyphoscoliosis & measurement of curvature
Eval for joint contractures & other skeletal features
To incl measurement of aortic root size & assessment of heart valves
Cardiac & abdominal ultrasound/MRI may also be considered to monitor for aortic dilatation.
DXA = dual-energy x-ray absorptiometry; PT = physical therapy
Care providers should be made aware of the possibility of atlantoaxial instability; however, proactive assessment for this finding is not typically done.
• Clinical & radiologic documentation of kyphoscoliosis & measurement of curvature
• Eval for joint contractures & other skeletal features
• To incl measurement of aortic root size & assessment of heart valves
• Cardiac & abdominal ultrasound/MRI may also be considered to monitor for aortic dilatation.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Surgery may be indicated for severe scoliosis.
At surgery caution should be taken due to risk for vascular complications, atlantoaxial instability, & primary muscle disease.
Orthopedists, rehab medicine, & PTs/OTs can assist in recommending appropriate devices to improve joint stability.
Walker or wheelchair may be necessary for mobility.
Use of beta-blockers (e.g., celiprolol) may be considered based on their efficiency in vascular EDS.
Vascular surgery is extremely risky because of vascular fragility in EDS.
OT = occupational therapist; PT = physical therapist/therapy
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Surgery may be indicated for severe scoliosis.
• At surgery caution should be taken due to risk for vascular complications, atlantoaxial instability, & primary muscle disease.
• Orthopedists, rehab medicine, & PTs/OTs can assist in recommending appropriate devices to improve joint stability.
• Walker or wheelchair may be necessary for mobility.
• Use of beta-blockers (e.g., celiprolol) may be considered based on their efficiency in vascular EDS.
• Vascular surgery is extremely risky because of vascular fragility in EDS.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Surveillance
Standardized medical surveillance guidelines for individuals with
Recommended Surveillance for Individuals with
Echocardiography w/consideration of cardiac MRI
Vascular ultrasonography to evaluate abdominal & peripheral arteries & veins
DXA = dual-energy x-ray absorptiometry
Maintenance of blood pressure in the normal range for age is recommended to reduce the risk of arterial rupture.
• Echocardiography w/consideration of cardiac MRI
• Vascular ultrasonography to evaluate abdominal & peripheral arteries & veins
## Agents/Circumstances to Avoid
Avoid the following:
For children with severe joint hypermobility, sports that place stress on the joints
High blood pressure
For individuals with aortic aneurysm, contact sports
• For children with severe joint hypermobility, sports that place stress on the joints
• High blood pressure
• For individuals with aortic aneurysm, contact sports
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and surveillance measures. Molecular genetic testing can be used if the pathogenic variants in the family are known.
See
## Pregnancy Management
No pregnancies in women with
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
United Kingdom
•
• United Kingdom
•
• United Kingdom
•
•
•
•
•
•
•
## Molecular Genetics
FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FKBP14 Kyphoscoliotic Ehlers-Danlos Syndrome (
The PPIase catalytic domain (aa 45-135)
The first EF-hand1 domain (aa 135-170)
The second EF-hand2 domain (aa 179-211)
FKBP22 is an ER resident protein that belongs to the FK506-binding protein (FKBP) class of immunophilins, which have been implicated in catalyzing cis-trans-isomerization of peptidyl-prolyl peptide bonds and are supposed to accelerate protein folding. FKBP22 catalyzes the folding of type III collagen and interacts with type III collagen, type VI collagen, and type X collagen, but not with type I collagen, type II collagen, or type V collagen [
A missense variant, p.Met48Lys [
Western blot analysis using a FKBP14 mouse polyclonal antibody showed deficiency of FKBP14 in two individuals with
Notable
Variants listed in the table have been provided by the authors.
• The PPIase catalytic domain (aa 45-135)
• The first EF-hand1 domain (aa 135-170)
• The second EF-hand2 domain (aa 179-211)
## Molecular Pathogenesis
The PPIase catalytic domain (aa 45-135)
The first EF-hand1 domain (aa 135-170)
The second EF-hand2 domain (aa 179-211)
FKBP22 is an ER resident protein that belongs to the FK506-binding protein (FKBP) class of immunophilins, which have been implicated in catalyzing cis-trans-isomerization of peptidyl-prolyl peptide bonds and are supposed to accelerate protein folding. FKBP22 catalyzes the folding of type III collagen and interacts with type III collagen, type VI collagen, and type X collagen, but not with type I collagen, type II collagen, or type V collagen [
A missense variant, p.Met48Lys [
Western blot analysis using a FKBP14 mouse polyclonal antibody showed deficiency of FKBP14 in two individuals with
Notable
Variants listed in the table have been provided by the authors.
• The PPIase catalytic domain (aa 45-135)
• The first EF-hand1 domain (aa 135-170)
• The second EF-hand2 domain (aa 179-211)
## References
## Literature Cited
## Chapter Notes
23 May 2019 (ma) Review posted live
5 October 2018 (cg) Original submission
• 23 May 2019 (ma) Review posted live
• 5 October 2018 (cg) Original submission
## Revision History
23 May 2019 (ma) Review posted live
5 October 2018 (cg) Original submission
• 23 May 2019 (ma) Review posted live
• 5 October 2018 (cg) Original submission
|
[] |
23/5/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
flnb-dis
|
flnb-dis
|
[
"Atelosteogenesis Type I (AOI)",
"Atelosteogenesis Type III (AOIII)",
"Larsen Syndrome",
"Spondylocarpotarsal Synostosis (SCT) Syndrome",
"Boomerang Dysplasia",
"Piepkorn Osteochondrodysplasia",
"Filamin-B",
"FLNB",
"FLNB Disorders"
] |
Stephen Robertson
|
Summary The SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic. The diagnosis of SCT is established in a proband by identification of biallelic pathogenic variants in AOI, AOIII, Piepkorn osteochondrodysplasia, and Larsen syndrome are inherited in an autosomal dominant manner. The proportion of autosomal dominant SCT syndrome is inherited in an autosomal recessive manner. At conception, each sib of an individual with SCT syndrome has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for SCT syndrome are possible once the pathogenic variants have been identified in the family.
|
Atelosteogenesis type I (AOI) (includes Boomerang dysplasia)
Atelosteogenesis type III (AOIII)
Larsen syndrome
Piepkorn osteochondrodysplasia
Spondylocarpotarsal synostosis (SCT) syndrome
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• Atelosteogenesis type I (AOI) (includes Boomerang dysplasia)
• Atelosteogenesis type III (AOIII)
• Larsen syndrome
• Piepkorn osteochondrodysplasia
• Spondylocarpotarsal synostosis (SCT) syndrome
## Diagnosis
Formal diagnostic criteria for
The
Spondylocarpotarsal synostosis (SCT) syndrome
Postnatal disproportionate short stature
Scoliosis, lordosis
Clubfeet
Other manifestations: midline cleft palate, conductive and sensorineural hearing loss, joint stiffness, dental enamel hypoplasia
Fusion of adjacent vertebrae and posterior elements that can involve noncontiguous areas of the cervical, thoracic, and lumbar spine
Note: (1) Asymmetric fusion of the posterior elements can result in "a unilateral unsegmented vertebral bar." (2) More complex bilateral and midline-fused structures have also been reported. (3) Although frequently referred to as "segmentation defects," the process of segmentation is normal in SCT syndrome and the fusion of adjacent vertebral elements relates to a defect in a separate morphologic process that occurs later in development. (4) Basilar impression with or without foramen magnum stenosis have been recurrently observed.
Carpal and tarsal synostosis. Carpal synostosis is usually capitate-hamate and lunate-triquetrum [
Delayed ossification of epiphyses (especially of carpal bones) and bilateral epiphyseal dysplasia of the femur; reported in two individuals [
Larsen syndrome should be suspected in individuals with the following clinical and radiographic features [
Congenital dislocations of the hip, knee, elbow, and (occasionally) shoulder
Clubfeet (equinovarus or equinovalgus foot deformities). This may be the only clinically apparent sign in some individuals [
Scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy
Short, broad, spatulate distal phalanges, particularly of the thumb
Craniofacial anomalies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes)
Other manifestations: midline cleft palate, hearing loss (often resulting from malformations of the ossicles)
Vertebral anomalies: hypoplasic vertebrae, hemivertebrae, spondylolysthesis, bifid posterior processes
Supernumerary (accessory) carpal and tarsal bone ossification centers; possibly a universal finding [
Atelosteogenesis type I (AOI)
Perinatal lethal short-limbed dwarfism
Severe, dislocated hips, knees, and elbows; clubfeet
Marked platyspondyly
Hypoplastic pelvis
Thoracic hypoplasia
Incomplete or absent, shortened, or distally tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae
Unossified or partially ossified metacarpals and middle and proximal phalanges
Occasionally, extraskeletal manifestations including encephalocele and omphalocele [
Note: Individuals with a diagnosis of
Piepkorn osteochondrodysplasia (POCD)
Perinatal-lethal micromelic dwarfism with flipper-like limbs
Polysyndactyly. Complete syndactyly of all fingers and toes with missing or hypoplastic thumbs and halluces. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly.
Pronounced cranofacial dysmorphism including macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos
Other manifestations: Cleft palate, omphalocele, cardiac and genitourinary defects
Milder than AOI; survival beyond the neonatal period is possible with intensive and invasive respiratory support [
Laryngotracheobronchomalacia
Dislocated hips, knees, and elbows; clubfeet
Mild vertebral hypoplasia
Distal tapering of the humeri and femora
Short and broad tubular bones of the hands and feet
The diagnosis of
The diagnosis of other
Note: Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of
Note: To date, such variants have not been identified as a cause of Larsen syndrome, AOI, POCD or AOIII. Multiexon
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other skeletal dysplasias,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
Note: To date such variants have not been identified as a cause of Larsen syndrome, AOI, POCD, or AOIII. Multiexon
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date deletions/duplications have not been identified as a cause of
• Postnatal disproportionate short stature
• Scoliosis, lordosis
• Clubfeet
• Other manifestations: midline cleft palate, conductive and sensorineural hearing loss, joint stiffness, dental enamel hypoplasia
• Fusion of adjacent vertebrae and posterior elements that can involve noncontiguous areas of the cervical, thoracic, and lumbar spine
• Note: (1) Asymmetric fusion of the posterior elements can result in "a unilateral unsegmented vertebral bar." (2) More complex bilateral and midline-fused structures have also been reported. (3) Although frequently referred to as "segmentation defects," the process of segmentation is normal in SCT syndrome and the fusion of adjacent vertebral elements relates to a defect in a separate morphologic process that occurs later in development. (4) Basilar impression with or without foramen magnum stenosis have been recurrently observed.
• Carpal and tarsal synostosis. Carpal synostosis is usually capitate-hamate and lunate-triquetrum [
• Delayed ossification of epiphyses (especially of carpal bones) and bilateral epiphyseal dysplasia of the femur; reported in two individuals [
• Congenital dislocations of the hip, knee, elbow, and (occasionally) shoulder
• Clubfeet (equinovarus or equinovalgus foot deformities). This may be the only clinically apparent sign in some individuals [
• Scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy
• Short, broad, spatulate distal phalanges, particularly of the thumb
• Craniofacial anomalies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes)
• Other manifestations: midline cleft palate, hearing loss (often resulting from malformations of the ossicles)
• Vertebral anomalies: hypoplasic vertebrae, hemivertebrae, spondylolysthesis, bifid posterior processes
• Supernumerary (accessory) carpal and tarsal bone ossification centers; possibly a universal finding [
• Perinatal lethal short-limbed dwarfism
• Severe, dislocated hips, knees, and elbows; clubfeet
• Marked platyspondyly
• Hypoplastic pelvis
• Thoracic hypoplasia
• Incomplete or absent, shortened, or distally tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae
• Unossified or partially ossified metacarpals and middle and proximal phalanges
• Occasionally, extraskeletal manifestations including encephalocele and omphalocele [
• Perinatal-lethal micromelic dwarfism with flipper-like limbs
• Polysyndactyly. Complete syndactyly of all fingers and toes with missing or hypoplastic thumbs and halluces. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly.
• Pronounced cranofacial dysmorphism including macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos
• Other manifestations: Cleft palate, omphalocele, cardiac and genitourinary defects
• Milder than AOI; survival beyond the neonatal period is possible with intensive and invasive respiratory support [
• Laryngotracheobronchomalacia
• Dislocated hips, knees, and elbows; clubfeet
• Mild vertebral hypoplasia
• Distal tapering of the humeri and femora
• Short and broad tubular bones of the hands and feet
• Note: To date, such variants have not been identified as a cause of Larsen syndrome, AOI, POCD or AOIII. Multiexon
• For an introduction to multigene panels click
## Suggestive Findings
The
Spondylocarpotarsal synostosis (SCT) syndrome
Postnatal disproportionate short stature
Scoliosis, lordosis
Clubfeet
Other manifestations: midline cleft palate, conductive and sensorineural hearing loss, joint stiffness, dental enamel hypoplasia
Fusion of adjacent vertebrae and posterior elements that can involve noncontiguous areas of the cervical, thoracic, and lumbar spine
Note: (1) Asymmetric fusion of the posterior elements can result in "a unilateral unsegmented vertebral bar." (2) More complex bilateral and midline-fused structures have also been reported. (3) Although frequently referred to as "segmentation defects," the process of segmentation is normal in SCT syndrome and the fusion of adjacent vertebral elements relates to a defect in a separate morphologic process that occurs later in development. (4) Basilar impression with or without foramen magnum stenosis have been recurrently observed.
Carpal and tarsal synostosis. Carpal synostosis is usually capitate-hamate and lunate-triquetrum [
Delayed ossification of epiphyses (especially of carpal bones) and bilateral epiphyseal dysplasia of the femur; reported in two individuals [
Larsen syndrome should be suspected in individuals with the following clinical and radiographic features [
Congenital dislocations of the hip, knee, elbow, and (occasionally) shoulder
Clubfeet (equinovarus or equinovalgus foot deformities). This may be the only clinically apparent sign in some individuals [
Scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy
Short, broad, spatulate distal phalanges, particularly of the thumb
Craniofacial anomalies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes)
Other manifestations: midline cleft palate, hearing loss (often resulting from malformations of the ossicles)
Vertebral anomalies: hypoplasic vertebrae, hemivertebrae, spondylolysthesis, bifid posterior processes
Supernumerary (accessory) carpal and tarsal bone ossification centers; possibly a universal finding [
Atelosteogenesis type I (AOI)
Perinatal lethal short-limbed dwarfism
Severe, dislocated hips, knees, and elbows; clubfeet
Marked platyspondyly
Hypoplastic pelvis
Thoracic hypoplasia
Incomplete or absent, shortened, or distally tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae
Unossified or partially ossified metacarpals and middle and proximal phalanges
Occasionally, extraskeletal manifestations including encephalocele and omphalocele [
Note: Individuals with a diagnosis of
Piepkorn osteochondrodysplasia (POCD)
Perinatal-lethal micromelic dwarfism with flipper-like limbs
Polysyndactyly. Complete syndactyly of all fingers and toes with missing or hypoplastic thumbs and halluces. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly.
Pronounced cranofacial dysmorphism including macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos
Other manifestations: Cleft palate, omphalocele, cardiac and genitourinary defects
Milder than AOI; survival beyond the neonatal period is possible with intensive and invasive respiratory support [
Laryngotracheobronchomalacia
Dislocated hips, knees, and elbows; clubfeet
Mild vertebral hypoplasia
Distal tapering of the humeri and femora
Short and broad tubular bones of the hands and feet
• Postnatal disproportionate short stature
• Scoliosis, lordosis
• Clubfeet
• Other manifestations: midline cleft palate, conductive and sensorineural hearing loss, joint stiffness, dental enamel hypoplasia
• Fusion of adjacent vertebrae and posterior elements that can involve noncontiguous areas of the cervical, thoracic, and lumbar spine
• Note: (1) Asymmetric fusion of the posterior elements can result in "a unilateral unsegmented vertebral bar." (2) More complex bilateral and midline-fused structures have also been reported. (3) Although frequently referred to as "segmentation defects," the process of segmentation is normal in SCT syndrome and the fusion of adjacent vertebral elements relates to a defect in a separate morphologic process that occurs later in development. (4) Basilar impression with or without foramen magnum stenosis have been recurrently observed.
• Carpal and tarsal synostosis. Carpal synostosis is usually capitate-hamate and lunate-triquetrum [
• Delayed ossification of epiphyses (especially of carpal bones) and bilateral epiphyseal dysplasia of the femur; reported in two individuals [
• Congenital dislocations of the hip, knee, elbow, and (occasionally) shoulder
• Clubfeet (equinovarus or equinovalgus foot deformities). This may be the only clinically apparent sign in some individuals [
• Scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy
• Short, broad, spatulate distal phalanges, particularly of the thumb
• Craniofacial anomalies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes)
• Other manifestations: midline cleft palate, hearing loss (often resulting from malformations of the ossicles)
• Vertebral anomalies: hypoplasic vertebrae, hemivertebrae, spondylolysthesis, bifid posterior processes
• Supernumerary (accessory) carpal and tarsal bone ossification centers; possibly a universal finding [
• Perinatal lethal short-limbed dwarfism
• Severe, dislocated hips, knees, and elbows; clubfeet
• Marked platyspondyly
• Hypoplastic pelvis
• Thoracic hypoplasia
• Incomplete or absent, shortened, or distally tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae
• Unossified or partially ossified metacarpals and middle and proximal phalanges
• Occasionally, extraskeletal manifestations including encephalocele and omphalocele [
• Perinatal-lethal micromelic dwarfism with flipper-like limbs
• Polysyndactyly. Complete syndactyly of all fingers and toes with missing or hypoplastic thumbs and halluces. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly.
• Pronounced cranofacial dysmorphism including macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos
• Other manifestations: Cleft palate, omphalocele, cardiac and genitourinary defects
• Milder than AOI; survival beyond the neonatal period is possible with intensive and invasive respiratory support [
• Laryngotracheobronchomalacia
• Dislocated hips, knees, and elbows; clubfeet
• Mild vertebral hypoplasia
• Distal tapering of the humeri and femora
• Short and broad tubular bones of the hands and feet
## Spondylocarpotarsal Synostosis Syndrome
Spondylocarpotarsal synostosis (SCT) syndrome
Postnatal disproportionate short stature
Scoliosis, lordosis
Clubfeet
Other manifestations: midline cleft palate, conductive and sensorineural hearing loss, joint stiffness, dental enamel hypoplasia
Fusion of adjacent vertebrae and posterior elements that can involve noncontiguous areas of the cervical, thoracic, and lumbar spine
Note: (1) Asymmetric fusion of the posterior elements can result in "a unilateral unsegmented vertebral bar." (2) More complex bilateral and midline-fused structures have also been reported. (3) Although frequently referred to as "segmentation defects," the process of segmentation is normal in SCT syndrome and the fusion of adjacent vertebral elements relates to a defect in a separate morphologic process that occurs later in development. (4) Basilar impression with or without foramen magnum stenosis have been recurrently observed.
Carpal and tarsal synostosis. Carpal synostosis is usually capitate-hamate and lunate-triquetrum [
Delayed ossification of epiphyses (especially of carpal bones) and bilateral epiphyseal dysplasia of the femur; reported in two individuals [
• Postnatal disproportionate short stature
• Scoliosis, lordosis
• Clubfeet
• Other manifestations: midline cleft palate, conductive and sensorineural hearing loss, joint stiffness, dental enamel hypoplasia
• Fusion of adjacent vertebrae and posterior elements that can involve noncontiguous areas of the cervical, thoracic, and lumbar spine
• Note: (1) Asymmetric fusion of the posterior elements can result in "a unilateral unsegmented vertebral bar." (2) More complex bilateral and midline-fused structures have also been reported. (3) Although frequently referred to as "segmentation defects," the process of segmentation is normal in SCT syndrome and the fusion of adjacent vertebral elements relates to a defect in a separate morphologic process that occurs later in development. (4) Basilar impression with or without foramen magnum stenosis have been recurrently observed.
• Carpal and tarsal synostosis. Carpal synostosis is usually capitate-hamate and lunate-triquetrum [
• Delayed ossification of epiphyses (especially of carpal bones) and bilateral epiphyseal dysplasia of the femur; reported in two individuals [
## Larsen Syndrome
Larsen syndrome should be suspected in individuals with the following clinical and radiographic features [
Congenital dislocations of the hip, knee, elbow, and (occasionally) shoulder
Clubfeet (equinovarus or equinovalgus foot deformities). This may be the only clinically apparent sign in some individuals [
Scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy
Short, broad, spatulate distal phalanges, particularly of the thumb
Craniofacial anomalies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes)
Other manifestations: midline cleft palate, hearing loss (often resulting from malformations of the ossicles)
Vertebral anomalies: hypoplasic vertebrae, hemivertebrae, spondylolysthesis, bifid posterior processes
Supernumerary (accessory) carpal and tarsal bone ossification centers; possibly a universal finding [
• Congenital dislocations of the hip, knee, elbow, and (occasionally) shoulder
• Clubfeet (equinovarus or equinovalgus foot deformities). This may be the only clinically apparent sign in some individuals [
• Scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy
• Short, broad, spatulate distal phalanges, particularly of the thumb
• Craniofacial anomalies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes)
• Other manifestations: midline cleft palate, hearing loss (often resulting from malformations of the ossicles)
• Vertebral anomalies: hypoplasic vertebrae, hemivertebrae, spondylolysthesis, bifid posterior processes
• Supernumerary (accessory) carpal and tarsal bone ossification centers; possibly a universal finding [
## Atelosteogenesis Type I
Atelosteogenesis type I (AOI)
Perinatal lethal short-limbed dwarfism
Severe, dislocated hips, knees, and elbows; clubfeet
Marked platyspondyly
Hypoplastic pelvis
Thoracic hypoplasia
Incomplete or absent, shortened, or distally tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae
Unossified or partially ossified metacarpals and middle and proximal phalanges
Occasionally, extraskeletal manifestations including encephalocele and omphalocele [
Note: Individuals with a diagnosis of
• Perinatal lethal short-limbed dwarfism
• Severe, dislocated hips, knees, and elbows; clubfeet
• Marked platyspondyly
• Hypoplastic pelvis
• Thoracic hypoplasia
• Incomplete or absent, shortened, or distally tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae
• Unossified or partially ossified metacarpals and middle and proximal phalanges
• Occasionally, extraskeletal manifestations including encephalocele and omphalocele [
## Piepkorn Osteochondrodysplasia
Piepkorn osteochondrodysplasia (POCD)
Perinatal-lethal micromelic dwarfism with flipper-like limbs
Polysyndactyly. Complete syndactyly of all fingers and toes with missing or hypoplastic thumbs and halluces. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly.
Pronounced cranofacial dysmorphism including macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos
Other manifestations: Cleft palate, omphalocele, cardiac and genitourinary defects
• Perinatal-lethal micromelic dwarfism with flipper-like limbs
• Polysyndactyly. Complete syndactyly of all fingers and toes with missing or hypoplastic thumbs and halluces. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly.
• Pronounced cranofacial dysmorphism including macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos
• Other manifestations: Cleft palate, omphalocele, cardiac and genitourinary defects
## Atelosteogenesis Type III
Milder than AOI; survival beyond the neonatal period is possible with intensive and invasive respiratory support [
Laryngotracheobronchomalacia
Dislocated hips, knees, and elbows; clubfeet
Mild vertebral hypoplasia
Distal tapering of the humeri and femora
Short and broad tubular bones of the hands and feet
• Milder than AOI; survival beyond the neonatal period is possible with intensive and invasive respiratory support [
• Laryngotracheobronchomalacia
• Dislocated hips, knees, and elbows; clubfeet
• Mild vertebral hypoplasia
• Distal tapering of the humeri and femora
• Short and broad tubular bones of the hands and feet
## Establishing the Diagnosis
The diagnosis of
The diagnosis of other
Note: Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of
Note: To date, such variants have not been identified as a cause of Larsen syndrome, AOI, POCD or AOIII. Multiexon
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other skeletal dysplasias,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
Note: To date such variants have not been identified as a cause of Larsen syndrome, AOI, POCD, or AOIII. Multiexon
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date deletions/duplications have not been identified as a cause of
• Note: To date, such variants have not been identified as a cause of Larsen syndrome, AOI, POCD or AOIII. Multiexon
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of
Note: To date, such variants have not been identified as a cause of Larsen syndrome, AOI, POCD or AOIII. Multiexon
For an introduction to multigene panels click
• Note: To date, such variants have not been identified as a cause of Larsen syndrome, AOI, POCD or AOIII. Multiexon
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other skeletal dysplasias,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
Note: To date such variants have not been identified as a cause of Larsen syndrome, AOI, POCD, or AOIII. Multiexon
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date deletions/duplications have not been identified as a cause of
## Clinical Characteristics
To date, more than 100 individuals with a pathogenic variant(s) in
Individuals with SCT syndrome have normal or near-normal birth length; however, progressive vertebral fusion results in poor growth of the trunk and short stature becomes evident postnatally. Stature is typically 3-6 SD below the mean.
Scoliosis is common, but variable in severity and time of onset because of the extent and pattern of vertebral fusion. Some authors have observed deformity at birth, although the phenotype may only become evident later in childhood. The irregular nature of the vertebral anomalies can also give rise to other complications such as cervical spine instability [
Clubfeet,
SCT syndrome has been associated with retinal anomalies [
Dental enamel hypoplasia has been reported in at least two unrelated instances [
Intelligence is normal.
Larsen syndrome is compatible with survival into adulthood [
Intrafamilial variation in Larsen syndrome can be remarkable. In a large family segregating one of the recurring pathogenic variants leading to Larsen syndrome, some individuals had cleft palate and multiple large joint dislocations, whereas others who had no major anomalies had short stature and very mild clinical and radiographic features, such as short distal phalanges and supernumerary carpal and tarsal bones [
In their study of 20 unrelated families with a total of 52 affected individuals,
Stature is mildly affected. In 14 of 20 probands height was below the tenth centile; height was rarely below the first centile and in one individual was above the 97th centile [
Spinal abnormalities were observed on x-rays in 16 (84%) of 19 probands. Cervical kyphosis was noted in 50%, usually from subluxation or fusion of the bodies of C2, C3, and C4, which was commonly associated with posterior vertebral arch dysraphism (i.e., dysplasia of the vertebral laminae and hypoplasia of the lateral processes of all cervical vertebrae). Individuals with Larsen syndrome and cervical spine dysplasia are at significant risk for cervical cord myelopathy and secondary tetraparesis [
Craniofacial anomalies are found in all individuals with
Deafness is common [
Although laryngotracheomalacia has been reported in association with Larsen syndrome, few individuals with Larsen syndrome and a documented
Short, broad, spatulate distal phalanges, particularly of the thumb, are a common (67%;
On prenatal ultrasound examination, the findings of boomerang dysplasia and AOI consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements. Joint dislocations may be evident. Definitive diagnosis by ultrasound examination alone is possible [
The most conspicuous finding of AOIII is joint dislocations. A specific diagnosis of AOIII is seldom possible by prenatal ultrasound examination alone.
Infants with AOIII can survive the neonatal period but may require intensive and invasive support to do so. The infant reported by
Infants with AOIII have been born to parents with milder phenotypes (similar to Larsen syndrome). In these instances, the parents probably have a mild phenotype associated with somatic mosaicism, whereas their offspring with a non-mosaic germline pathogenic variant have a severe phenotype.
Neurodevelopment is mildy affected in some long-term survivors with AOIII [
POCD is a form of perinatal-lethal micromelic dwarfism described in fewer than five individuals in the literature. The condition is characterized by flipper-like limbs, a characteristic form of polysyndactyly with complete syndactyly of all fingers and toes. The thumbs and halluces are either hypoplastic or absent. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly. Craniofacial features include macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, cardiac anomalies, and genitourinary defects including sex reversal. The radiographic features of POCD at mid-gestation are characteristic: absent ossification of all long bones, vertebrae, pelvis, metacarpals, and metatarsals. Some ossification of the pubic bones, pedicles, ribs, scapulae, skull, and clavicles can be observed.
Larsen syndrome-associated pathogenic variants are spread predominantly over exons 2-5 and 27-33 [
Atelosteogenesis type III-causing pathogenic variants occur in exons 2-5, 13, and 27-33 [
The large majority of pathogenic variants reported in boomerang dysplasia and AOI are in exons 2-5 [
In some instances the same pathogenic variant is associated with different phenotypes (e.g.,
Recurrent pathogenic variants:
Clinical evidence suggests that somatic mosaicism can complicate the presentation of these conditions [
Germline
In contrast, other recessive disorders with multiple joint dislocations called Larsen syndrome in the past but not sharing other clinical characteristics of Larsen syndrome are best not referred to as Larsen syndrome [
Note:
No prevalence figures are available for any of the
• Larsen syndrome-associated pathogenic variants are spread predominantly over exons 2-5 and 27-33 [
• Atelosteogenesis type III-causing pathogenic variants occur in exons 2-5, 13, and 27-33 [
• The large majority of pathogenic variants reported in boomerang dysplasia and AOI are in exons 2-5 [
## Clinical Description
To date, more than 100 individuals with a pathogenic variant(s) in
Individuals with SCT syndrome have normal or near-normal birth length; however, progressive vertebral fusion results in poor growth of the trunk and short stature becomes evident postnatally. Stature is typically 3-6 SD below the mean.
Scoliosis is common, but variable in severity and time of onset because of the extent and pattern of vertebral fusion. Some authors have observed deformity at birth, although the phenotype may only become evident later in childhood. The irregular nature of the vertebral anomalies can also give rise to other complications such as cervical spine instability [
Clubfeet,
SCT syndrome has been associated with retinal anomalies [
Dental enamel hypoplasia has been reported in at least two unrelated instances [
Intelligence is normal.
Larsen syndrome is compatible with survival into adulthood [
Intrafamilial variation in Larsen syndrome can be remarkable. In a large family segregating one of the recurring pathogenic variants leading to Larsen syndrome, some individuals had cleft palate and multiple large joint dislocations, whereas others who had no major anomalies had short stature and very mild clinical and radiographic features, such as short distal phalanges and supernumerary carpal and tarsal bones [
In their study of 20 unrelated families with a total of 52 affected individuals,
Stature is mildly affected. In 14 of 20 probands height was below the tenth centile; height was rarely below the first centile and in one individual was above the 97th centile [
Spinal abnormalities were observed on x-rays in 16 (84%) of 19 probands. Cervical kyphosis was noted in 50%, usually from subluxation or fusion of the bodies of C2, C3, and C4, which was commonly associated with posterior vertebral arch dysraphism (i.e., dysplasia of the vertebral laminae and hypoplasia of the lateral processes of all cervical vertebrae). Individuals with Larsen syndrome and cervical spine dysplasia are at significant risk for cervical cord myelopathy and secondary tetraparesis [
Craniofacial anomalies are found in all individuals with
Deafness is common [
Although laryngotracheomalacia has been reported in association with Larsen syndrome, few individuals with Larsen syndrome and a documented
Short, broad, spatulate distal phalanges, particularly of the thumb, are a common (67%;
On prenatal ultrasound examination, the findings of boomerang dysplasia and AOI consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements. Joint dislocations may be evident. Definitive diagnosis by ultrasound examination alone is possible [
The most conspicuous finding of AOIII is joint dislocations. A specific diagnosis of AOIII is seldom possible by prenatal ultrasound examination alone.
Infants with AOIII can survive the neonatal period but may require intensive and invasive support to do so. The infant reported by
Infants with AOIII have been born to parents with milder phenotypes (similar to Larsen syndrome). In these instances, the parents probably have a mild phenotype associated with somatic mosaicism, whereas their offspring with a non-mosaic germline pathogenic variant have a severe phenotype.
Neurodevelopment is mildy affected in some long-term survivors with AOIII [
POCD is a form of perinatal-lethal micromelic dwarfism described in fewer than five individuals in the literature. The condition is characterized by flipper-like limbs, a characteristic form of polysyndactyly with complete syndactyly of all fingers and toes. The thumbs and halluces are either hypoplastic or absent. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly. Craniofacial features include macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, cardiac anomalies, and genitourinary defects including sex reversal. The radiographic features of POCD at mid-gestation are characteristic: absent ossification of all long bones, vertebrae, pelvis, metacarpals, and metatarsals. Some ossification of the pubic bones, pedicles, ribs, scapulae, skull, and clavicles can be observed.
## Spondylocarpotarsal Synostosis (SCT) Syndrome
Individuals with SCT syndrome have normal or near-normal birth length; however, progressive vertebral fusion results in poor growth of the trunk and short stature becomes evident postnatally. Stature is typically 3-6 SD below the mean.
Scoliosis is common, but variable in severity and time of onset because of the extent and pattern of vertebral fusion. Some authors have observed deformity at birth, although the phenotype may only become evident later in childhood. The irregular nature of the vertebral anomalies can also give rise to other complications such as cervical spine instability [
Clubfeet,
SCT syndrome has been associated with retinal anomalies [
Dental enamel hypoplasia has been reported in at least two unrelated instances [
Intelligence is normal.
## Larsen Syndrome
Larsen syndrome is compatible with survival into adulthood [
Intrafamilial variation in Larsen syndrome can be remarkable. In a large family segregating one of the recurring pathogenic variants leading to Larsen syndrome, some individuals had cleft palate and multiple large joint dislocations, whereas others who had no major anomalies had short stature and very mild clinical and radiographic features, such as short distal phalanges and supernumerary carpal and tarsal bones [
In their study of 20 unrelated families with a total of 52 affected individuals,
Stature is mildly affected. In 14 of 20 probands height was below the tenth centile; height was rarely below the first centile and in one individual was above the 97th centile [
Spinal abnormalities were observed on x-rays in 16 (84%) of 19 probands. Cervical kyphosis was noted in 50%, usually from subluxation or fusion of the bodies of C2, C3, and C4, which was commonly associated with posterior vertebral arch dysraphism (i.e., dysplasia of the vertebral laminae and hypoplasia of the lateral processes of all cervical vertebrae). Individuals with Larsen syndrome and cervical spine dysplasia are at significant risk for cervical cord myelopathy and secondary tetraparesis [
Craniofacial anomalies are found in all individuals with
Deafness is common [
Although laryngotracheomalacia has been reported in association with Larsen syndrome, few individuals with Larsen syndrome and a documented
Short, broad, spatulate distal phalanges, particularly of the thumb, are a common (67%;
## Atelosteogenesis Type I (AOI) / Boomerang Dysplasia
On prenatal ultrasound examination, the findings of boomerang dysplasia and AOI consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements. Joint dislocations may be evident. Definitive diagnosis by ultrasound examination alone is possible [
## Atelosteogenesis Type III (AOIII)
The most conspicuous finding of AOIII is joint dislocations. A specific diagnosis of AOIII is seldom possible by prenatal ultrasound examination alone.
Infants with AOIII can survive the neonatal period but may require intensive and invasive support to do so. The infant reported by
Infants with AOIII have been born to parents with milder phenotypes (similar to Larsen syndrome). In these instances, the parents probably have a mild phenotype associated with somatic mosaicism, whereas their offspring with a non-mosaic germline pathogenic variant have a severe phenotype.
Neurodevelopment is mildy affected in some long-term survivors with AOIII [
## Piepkorn Osteochondrodysplasia (POCD)
POCD is a form of perinatal-lethal micromelic dwarfism described in fewer than five individuals in the literature. The condition is characterized by flipper-like limbs, a characteristic form of polysyndactyly with complete syndactyly of all fingers and toes. The thumbs and halluces are either hypoplastic or absent. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly. Craniofacial features include macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, cardiac anomalies, and genitourinary defects including sex reversal. The radiographic features of POCD at mid-gestation are characteristic: absent ossification of all long bones, vertebrae, pelvis, metacarpals, and metatarsals. Some ossification of the pubic bones, pedicles, ribs, scapulae, skull, and clavicles can be observed.
## Genotype-Phenotype Correlations
Larsen syndrome-associated pathogenic variants are spread predominantly over exons 2-5 and 27-33 [
Atelosteogenesis type III-causing pathogenic variants occur in exons 2-5, 13, and 27-33 [
The large majority of pathogenic variants reported in boomerang dysplasia and AOI are in exons 2-5 [
In some instances the same pathogenic variant is associated with different phenotypes (e.g.,
Recurrent pathogenic variants:
Clinical evidence suggests that somatic mosaicism can complicate the presentation of these conditions [
• Larsen syndrome-associated pathogenic variants are spread predominantly over exons 2-5 and 27-33 [
• Atelosteogenesis type III-causing pathogenic variants occur in exons 2-5, 13, and 27-33 [
• The large majority of pathogenic variants reported in boomerang dysplasia and AOI are in exons 2-5 [
## Mosaicism
Clinical evidence suggests that somatic mosaicism can complicate the presentation of these conditions [
## Penetrance
Germline
## Nomenclature
In contrast, other recessive disorders with multiple joint dislocations called Larsen syndrome in the past but not sharing other clinical characteristics of Larsen syndrome are best not referred to as Larsen syndrome [
Note:
## Prevalence
No prevalence figures are available for any of the
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Spondylocarpotarsal Synostosis (SCT) Syndrome
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Genes of Interest in the Differential Diagnosis of Larsen Syndrome
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Also known as spondyloepiphyseal dysplasia, Omani type.
## Spondylocarpotarsal Synostosis (SCT) Syndrome
Genes of Interest in the Differential Diagnosis of Spondylocarpotarsal Synostosis (SCT) Syndrome
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
## Larsen Syndrome
Genes of Interest in the Differential Diagnosis of Larsen Syndrome
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Also known as spondyloepiphyseal dysplasia, Omani type.
## Management
To establish the extent of disease and needs in an individual diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with
To evaluate for cervical dysplasia, which can → cervical cord myelopathy
Evaluate cervical spine for instability prior to general anesthesia.
Treatment of Manifestations in Individuals with
Asymptomatic infants: Early intervention to improve cervical spine stability using posterior arthrodesis is successful.
Infants w/myelopathic signs: Function can be stabilized &/or improved by combination of anterior decompression & circumferential arthrodesis.
Ideally, by ENT & audiologist w/expertise in early-childhood otologic disorders
The expertise of an educator of the Deaf may be required. An important part of eval is determining appropriate habilitation option.
Recommended Surveillance for Individuals with
See
Delivery of an affected infant has the potential to be complicated by extended breech presentation due to dislocation of the hips and knees.
Search
• To evaluate for cervical dysplasia, which can → cervical cord myelopathy
• Evaluate cervical spine for instability prior to general anesthesia.
• Asymptomatic infants: Early intervention to improve cervical spine stability using posterior arthrodesis is successful.
• Infants w/myelopathic signs: Function can be stabilized &/or improved by combination of anterior decompression & circumferential arthrodesis.
• Ideally, by ENT & audiologist w/expertise in early-childhood otologic disorders
• The expertise of an educator of the Deaf may be required. An important part of eval is determining appropriate habilitation option.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with an
Recommended Evaluations Following Initial Diagnosis in Individuals with
To evaluate for cervical dysplasia, which can → cervical cord myelopathy
Evaluate cervical spine for instability prior to general anesthesia.
• To evaluate for cervical dysplasia, which can → cervical cord myelopathy
• Evaluate cervical spine for instability prior to general anesthesia.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Asymptomatic infants: Early intervention to improve cervical spine stability using posterior arthrodesis is successful.
Infants w/myelopathic signs: Function can be stabilized &/or improved by combination of anterior decompression & circumferential arthrodesis.
Ideally, by ENT & audiologist w/expertise in early-childhood otologic disorders
The expertise of an educator of the Deaf may be required. An important part of eval is determining appropriate habilitation option.
• Asymptomatic infants: Early intervention to improve cervical spine stability using posterior arthrodesis is successful.
• Infants w/myelopathic signs: Function can be stabilized &/or improved by combination of anterior decompression & circumferential arthrodesis.
• Ideally, by ENT & audiologist w/expertise in early-childhood otologic disorders
• The expertise of an educator of the Deaf may be required. An important part of eval is determining appropriate habilitation option.
## Surveillance
Recommended Surveillance for Individuals with
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Delivery of an affected infant has the potential to be complicated by extended breech presentation due to dislocation of the hips and knees.
## Therapies Under Investigation
Search
## Genetic Counseling
The following
Atelosteogenesis type I (AOI)
Atelosteogenesis type III (AOIII)
Boomerang dysplasia
Larsen syndrome
Spondylocarpotarsal synostosis (SCT) syndrome is inherited in an autosomal recessive manner.
The parents of some individuals diagnosed with an autosomal dominant
Alternatively, a proband with an autosomal dominant
Although the vast majority of lethal
Recommendations for the evaluation of parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with an autosomal dominant
If a parent of the proband is affected and/or is known to have the
Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or the parents appear to be clinically unaffected, recurrence risk to sibs is slightly greater than that of the general population because of the risk of parental somatic and/or germline mosaicism [
Each child of a proband who is heterozygous for an autosomal dominant
Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia.
Note: SCT syndrome is inherited in an autosomal recessive manner; heterozygotes for
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Consideration of molecular genetic testing for mutation of
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Atelosteogenesis type I (AOI)
• Atelosteogenesis type III (AOIII)
• Boomerang dysplasia
• Larsen syndrome
• The parents of some individuals diagnosed with an autosomal dominant
• Alternatively, a proband with an autosomal dominant
• Although the vast majority of lethal
• Recommendations for the evaluation of parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with an autosomal dominant
• If a parent of the proband is affected and/or is known to have the
• Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or the parents appear to be clinically unaffected, recurrence risk to sibs is slightly greater than that of the general population because of the risk of parental somatic and/or germline mosaicism [
• Each child of a proband who is heterozygous for an autosomal dominant
• Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
The following
Atelosteogenesis type I (AOI)
Atelosteogenesis type III (AOIII)
Boomerang dysplasia
Larsen syndrome
Spondylocarpotarsal synostosis (SCT) syndrome is inherited in an autosomal recessive manner.
• Atelosteogenesis type I (AOI)
• Atelosteogenesis type III (AOIII)
• Boomerang dysplasia
• Larsen syndrome
## Autosomal Dominant Inheritance ‒ Risk to Family Members
The parents of some individuals diagnosed with an autosomal dominant
Alternatively, a proband with an autosomal dominant
Although the vast majority of lethal
Recommendations for the evaluation of parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with an autosomal dominant
If a parent of the proband is affected and/or is known to have the
Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or the parents appear to be clinically unaffected, recurrence risk to sibs is slightly greater than that of the general population because of the risk of parental somatic and/or germline mosaicism [
Each child of a proband who is heterozygous for an autosomal dominant
Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant
• The parents of some individuals diagnosed with an autosomal dominant
• Alternatively, a proband with an autosomal dominant
• Although the vast majority of lethal
• Recommendations for the evaluation of parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with an autosomal dominant
• If a parent of the proband is affected and/or is known to have the
• Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent and/or the parents appear to be clinically unaffected, recurrence risk to sibs is slightly greater than that of the general population because of the risk of parental somatic and/or germline mosaicism [
• Each child of a proband who is heterozygous for an autosomal dominant
• Clinical evidence suggests that both germline and somatic mosaicism can complicate the presentation and recurrence risks associated with autosomal dominant
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia.
Note: SCT syndrome is inherited in an autosomal recessive manner; heterozygotes for
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are generally asymptomatic. One report described a parent of a child with typical SCT syndrome who had a height 2.2 SD below the mean and mild unilateral hip dysplasia.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Consideration of molecular genetic testing for mutation of
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## A Priori High-Risk Pregnancies
## A Priori Low-Risk Pregnancies
Consideration of molecular genetic testing for mutation of
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
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## Molecular Genetics
FLNB Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FLNB Disorders (
An N-terminal actin-binding domain
24 filamin repeats
Two "hinge" regions between filamin repeats 15 and 16 and 23 and 24, which are thought to confer flexibility to the protein
Filamin-B is expressed by endothelial cells and chondrocytes during development, playing an important role in embryonal skeletal development.
The cause of SCT syndrome is loss of function, which exerts a pathogenic effect at least in part through de-repression of transforming growth factor beta signaling.
For Larsen syndrome, AOI, POCD, and AOIII, it is not known whether the pathogenic variants disrupt protein interactions or facilitate novel interactions with filamin B.
Notable
Variants listed in the table have been provided by the author.
See
• An N-terminal actin-binding domain
• 24 filamin repeats
• Two "hinge" regions between filamin repeats 15 and 16 and 23 and 24, which are thought to confer flexibility to the protein
• The cause of SCT syndrome is loss of function, which exerts a pathogenic effect at least in part through de-repression of transforming growth factor beta signaling.
• For Larsen syndrome, AOI, POCD, and AOIII, it is not known whether the pathogenic variants disrupt protein interactions or facilitate novel interactions with filamin B.
## Molecular Pathogenesis
An N-terminal actin-binding domain
24 filamin repeats
Two "hinge" regions between filamin repeats 15 and 16 and 23 and 24, which are thought to confer flexibility to the protein
Filamin-B is expressed by endothelial cells and chondrocytes during development, playing an important role in embryonal skeletal development.
The cause of SCT syndrome is loss of function, which exerts a pathogenic effect at least in part through de-repression of transforming growth factor beta signaling.
For Larsen syndrome, AOI, POCD, and AOIII, it is not known whether the pathogenic variants disrupt protein interactions or facilitate novel interactions with filamin B.
Notable
Variants listed in the table have been provided by the author.
See
• An N-terminal actin-binding domain
• 24 filamin repeats
• Two "hinge" regions between filamin repeats 15 and 16 and 23 and 24, which are thought to confer flexibility to the protein
• The cause of SCT syndrome is loss of function, which exerts a pathogenic effect at least in part through de-repression of transforming growth factor beta signaling.
• For Larsen syndrome, AOI, POCD, and AOIII, it is not known whether the pathogenic variants disrupt protein interactions or facilitate novel interactions with filamin B.
## Chapter Notes
University of Otago Clinical Genetics Group
13 February 2020 (sw) Comprehensive update posted live
17 October 2013 (me) Comprehensive update posted live
9 October 2008 (me) Review posted live
20 May 2008 (sr) Original submission
• 13 February 2020 (sw) Comprehensive update posted live
• 17 October 2013 (me) Comprehensive update posted live
• 9 October 2008 (me) Review posted live
• 20 May 2008 (sr) Original submission
## Author Notes
University of Otago Clinical Genetics Group
## Revision History
13 February 2020 (sw) Comprehensive update posted live
17 October 2013 (me) Comprehensive update posted live
9 October 2008 (me) Review posted live
20 May 2008 (sr) Original submission
• 13 February 2020 (sw) Comprehensive update posted live
• 17 October 2013 (me) Comprehensive update posted live
• 9 October 2008 (me) Review posted live
• 20 May 2008 (sr) Original submission
## References
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[
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"LS Bicknell, C Farrington-Rock, Y Shafeghati, P Rump, Y Alanay, Y Alembik, N Al-Madani, H Firth, MH Karimi-Nejad, CA Kim, K Leask, M Maisenbacher, E Moran, JG Pappas, P Prontera, T de Ravel, JP Fryns, E Sweeney, A Fryer, S Unger, LC Wilson, RS Lachman, DL Rimoin, DH Cohn, D Krakow, S Robertson. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB.. J Med Genet. 2007;44:89-98",
"LS Bicknell, T Morgan, L Bonafé, MW Wessels, MG Bialer, PJ Willems, DH Cohn, D Krakow, SP Robertson. Mutations in FLNB cause boomerang dysplasia.. J Med Genet. 2005;42",
"J Bonaventure, C Lasselin, J Mellier, L Cohen-Solal, P Maroteaux. Linkage studies of four fibrillar collagen genes in three pedigrees with Larsen-like syndrome.. J Med Genet. 1992;29:465-70",
"F Cartault, P Munier, ML Jacquemont, J Vellayoudom, B Doray, C Payet, H Randrianaivo, JM Laville, A Munnich, V Cormier-Daire. Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome.. Eur J Hum Genet. 2015;23:49-53",
"J Clayton-Smith, D. Donnai. A further patient with the lethal type of Larsen syndrome.. J Med Genet. 1988;25:499-500",
"KE Coêlho, ES Ramos, TM Felix, L Martelli, JM de Pina-Neto, N Niikawa. Three new cases of spondylocarpotarsal synostosis syndrome: clinical and radiographic studies.. Am J Med Genet. 1998;77:12-5",
"PB Daniel, T Morgan, Y Alanay, E Bijlsma, TJ Cho, T Cole, F Collins, A David, K Devriendt, L Faivre, S Ikegawa, S Jacquemont, M Jesic, D Krakow, D Liebrecht, S Maitz, S Marlin, G Morin, T Nishikubo, G Nishimura, T Prescott, G Scarano, Y Shafeghati, F Skovby, S Tsutsumi, M Whiteford, M Zenker, SP Robertson. Disease-associated mutations in the actin-binding domain of filamin B cause cytoplasmic focal accumulations correlating with disease severity.. Hum Mutat. 2012;33:665-73",
"C Farrington-Rock, MH Firestein, LS Bicknell, A Superti-Furga, CA Bacino, V Cormier-Daire, M Le Merrer, C Baumann, J Roume, P Rump, JB Verheij, E Sweeney, DL Rimoin, RS Lachman, SP Robertson, DH Cohn, D Krakow. Mutations in two regions of FLNB result in atelosteogenesis I and III.. Hum Mutat. 2006;27:705-10",
"HC Herrmann, JH Kelly, MP Fried, M Strome. The association of a hearing deficit with Larsen’s syndrome.. J Otolaryngol. 1981;10:45-8",
"C Honeywell, L Langer, J Allanson. Spondylocarpotarsal synostosis with epiphyseal dysplasia.. Am J Med Genet. 2002;109:318-22",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"CE Johnston, JG Birch, JL Daniels. Cervical kyphosis in patients who have Larsen syndrome.. J Bone Joint Surg Am. 1996;78:538-45",
"D Krakow, SP Robertson, LM King, T Morgan, ET Sebald, C Bertolotto, S Wachsmann-Hogiu, D Acuna, SS Shapiro, T Tarafuta, S Aftimos, CA Kim, H Firth, CE Steiner, V Cormier-Daire, A Superti-Furga, L Bonafé, JM Graham, A Grix, CA Bacino, J Allanson, MG Bialer, RS Lachman, DL Rimoin, DH Cohn. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis.. Nat Genet. 2004;36:405-10",
"LO Langer, RJ Gorlin, D Donnai, BC Hamel, C Clericuzio. Spondylocarpotarsal synostosis syndrome (with or without unilateral unsegmented bar).. Am J Med Genet. 1994;51:1-8",
"JM Laville, P Lakermance, F Limouzy. Larsen’s syndrome: review of the literature and analysis of thirty-eight cases.. J Pediatr Orthop. 1994;14:63-73",
"RW Maack, HR Muntz. Ossicular abnormality in Larsen’s syndrome: a case report.. Am J Otolaryngol. 1991;12:51-3",
"M Madera, A Crawford, FT Mangano. Management of severe cervical kyphosis in a patient with Larsen syndrome. Case report.. J Neurosurg Pediatr. 2008;1:320-4",
"P Maroteaux, J Spranger, V Stanescu, B Le Marec, RA Pfeiffer, P Beighton, JF Mattei. Atelosteogenesis.. Am J Med Genet. 1982;13:15-25",
"JGC Meira, MAC Sarno, ÁCO Faria, GL Yamamoto, DR Bertola, GG Scheibler, DF Tavares, AX Acosta. Diagnosis of atelosteogenesis type i suggested by fetal ultrasonography and atypical paternal phenotype with mosaicism.. Rev Bras Ginecol Obstet. 2018;40:570-6",
"D Mitter, D Krakow, C Farrington-Rock, P Meinecke. Expanded clinical spectrum of spondylocarpotarsal synostosis syndrome and possible manifestation in a heterozygous father.. Am J Med Genet A. 2008;146A:779-83",
"R Petrella, JG Rabinowitz, B Steinmann, K Hirschhorn. Long-term follow-up of two sibs with Larsen syndrome possibly due to parental germ-line mosaicism.. Am J Med Genet. 1993;47:187-97",
"H Rehder, F Laccone, SG Kircher, RL Schild, C Rapp, R Bald, B Schulze, J Behunova, J Neesen, K Schoner. Piepkorn type of osteochondrodysplasia: Defining the severe end of FLNB-related skeletal disorders in three fetuses and a 106-year-old exhibit.. Am J Med Genet A. 2018;176:1559-68",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"H Sakaura, T Matsuoka, M Iwasaki, K Yonenobu, H Yoshikawa. Surgical treatment of cervical kyphosis in Larsen syndrome: Report of 3 cases and review of the literature.. Spine. 2007;32:E39-44",
"S Salian, A Shukla, H Shah, SN Bhat, VR Bhat, S Nampoothiri, R Shenoy, SR Phadke, SV Hariharan, KM Girisha. Seven additional families with spondylocarpotarsal synostosis syndrome with novel biallelic deleterious variants in FLNB.. Clin Genet. 2018;94:159-64",
"C Schultz, LO Langer, R Laxova, RM Pauli. Atelosteogenesis Type III: long-term survival, prenatal diagnosis, and evidence for dominant transmission.. Am J Med Genet. 1999;83:28-42",
"LH Seaver, E Boyd. Spondylocarpotarsal synostosis syndrome and cervical instability.. Am J Med Genet. 2000;91:340-4",
"DO Sillence, RS Lachman, T Jenkins, VM Riccardi, DL Rimoin. Spondlohumerofermoral hypoplasis (giant cell chondrodysplasia): a neonatally lethal short-limb skeletal dysplasia.. Am J Med Genet. 1982;13:7-14",
"CS Stanley, JW Thelin, JH Miles. Mixed hearing loss in Larsen syndrome.. Clin Genet. 1988;33:395-8",
"CE Steiner, M Torriani, DY Norato, AP Marques-de-Faria. Spondylocarpotarsal synostosis with ocular findings.. Am J Med Genet. 2000;91:131-4",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"HJ Stern, JM Graham, RS Lachman, W Horton, PM Bernini, PK Spiegel, J Bodurtha, EJ Ives, M Bocian, DL Rimoin. Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II.. Am J Med Genet. 1990;36:183-95",
"JM Topley, E Varady, GG Lestringant. Larsen syndrome in siblings with consanguineous parents.. Clin Dysmorphol. 1994;3:263-5",
"S Tsutsumi, A Maekawa, M Obata, T Morgan, SP Robertson, H Kurachi. A case of boomerang dysplasia with a novel causative mutation in filamin B: identification of typical imaging findings on ultrasonography and 3D-CT imaging.. Fetal Diagn Ther. 2012;32:216-20",
"K Ueno, M Tanaka, K Miyakoshi, C Zhao, H Shinmoto, G Nishimura, Y Yoshimura. Prenatal diagnosis of atelosteogenesis type I at 21 weeks' gestation.. Prenat Diagn. 2002;22:1071-5",
"K Yamaguchi, Y Ogawa, T Handa. Brain dysplasia associated with Larsen-like syndrome.. Pediatr Neurol. 1996;14:75-9",
"H Yang, Z Zheng, H Cai, H Li, X Ye, X Zhang, Z Wang, Q. Fu. Three novel missense mutations in the filamin B gene are associated with isolated congenital talipes equinovarus.. Hum Genet. 2016;135:1181-9"
] |
9/10/2008
|
13/2/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
fmf
|
fmf
|
[
"Recurrent Polyserositis",
"Recurrent Polyserositis",
"Familial Mediterranean Fever Type 1",
"Familial Mediterranean Fever Type 2",
"Pyrin",
"MEFV",
"Familial Mediterranean Fever"
] |
Familial Mediterranean Fever
|
Mordechai Shohat
|
Summary Familial Mediterranean fever (FMF) is divided into two phenotypes: type 1 and type 2. FMF type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms and severity vary among affected individuals, sometimes even among members of the same family. Amyloidosis, which can lead to kidney failure, is the most severe complication, if untreated. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual. The diagnosis of FMF is established in a proband with Tel Hashomer clinical criteria of major and minor features. Major features include fever, abdominal pain, chest pain, joint pain, and skin eruption. Minor features include increased erythrocyte sedimentation rate (ESR), leukocytosis, and elevated serum fibrinogen. Identification of biallelic FMF is usually inherited in an autosomal recessive manner, although recent studies have suggested that some heterozygotes manifest a spectrum of findings from classic FMF to mild FMF. For autosomal recessive FMF: In general, both parents of an affected individual with biallelic
|
Familial Mediterranean fever type 1
Familial Mediterranean fever type 2
For synonyms and outdated names see
• Familial Mediterranean fever type 1
• Familial Mediterranean fever type 2
## Diagnosis
Familial Mediterranean fever (FMF)
Recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis
Recurrent erysipelas-like erythema
Repeated laparotomies for "acute abdomen" with no pathology found
Amyloidosis of the AA type that characteristically develops after age 15 years in untreated individuals, even in those who do not have a history of recurrent inflammatory attacks
Favorable response to continuous colchicine treatment
A first-degree relative with FMF
Membership in an at-risk ethnic group
The minimal (and most current) clinical criteria used
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Fever AND:
One additional major feature and one minor feature
OR
Two minor features
Fever
Abdominal pain
Chest pain
Joint pain (See Note.)
Skin eruption
Note: It is important to make the correct diagnosis in individuals with recurrent monoarthritis. The criteria that suggest a diagnosis of FMF in persons with monoarthritis include a high fever, favorable response to colchicine, history of FMF in sibs and other family members, and an appropriate genotype [
Increased erythrocyte sedimentation rate (ESR)
Normal values:
Men age <50 years: <15 mm/h
Men age 50-85 years: <20 mm/h
Women age <50 years: <20 mm/h
Women age 50-85 years: <30 mm/h
Leukocytosis (normal value: 4.5-11.0 x 10
Elevated serum fibrinogen concentration (normal value: 200-400 mg/dL [2.00-4.00 g/L])
Note: Early in life FMF often begins with an atypical presentation characterized by attacks of fever alone, significantly delaying diagnosis and initiation of treatment. Although other diagnostic criteria for children have been suggested by
Molecular genetic testing approaches can include
Note: Up to 25% of individuals with FMF have only one
Targeted analysis for pathogenic variants can be performed first in individuals of Armenian, Turkish, Arab, North African Jewish, Iraqi Jewish, or Ashkenazi Jewish ancestry. Targeted analysis may include:
c.1105C>T (p.Pro369Ser)
c.1223G>A (p.Arg408Gln)
Note: These two variants in exon 3 have been shown to be in linkage disequilibrium [
c.1958G>A (p.Arg653His)
c.2040G>C (p.Met680Ile)
c.2076_2078del (p.Ile692del)
c.2080A>G (p.Met694Val)
c.2082G>A (p.Met694Ile)
c.2084A>G (p.Lys695Arg)
c.2177T>C (p.Val726Ala)
c.2230G>T (p.Ala744Ser)
c.2282G>A (p.Arg761His)
Note: (1) Other variants with exons 2, 3, and 10 are also among the most common. (2) The exons included and pathogenic variants detected may vary by laboratory and over time.
In individuals with suspected autosomal dominant inheritance, in addition to the above pathogenic variants, targeted testing for a few additional pathogenic variants may be considered:
c.1730C>A (p.Thr577Asn)
c.2064C>G (p.Tyr688Ter)
c.2076_2078delAAT (p.Ile692del)
c.2081_2083delTGA (p.Met694del)
For an introduction to multigene panels click
Molecular Genetic Testing Used in Familial Mediterranean Fever
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Up to 25% of individuals with FMF have only one
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Given the proposed gain-of-function mechanism for FMF and the lack of observed large intragenic deletions or duplications, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
In all instances in which the clinical picture suggests FMF but
• Recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis
• Recurrent erysipelas-like erythema
• Repeated laparotomies for "acute abdomen" with no pathology found
• Amyloidosis of the AA type that characteristically develops after age 15 years in untreated individuals, even in those who do not have a history of recurrent inflammatory attacks
• Favorable response to continuous colchicine treatment
• A first-degree relative with FMF
• Membership in an at-risk ethnic group
• One additional major feature and one minor feature
• OR
• Two minor features
• Fever
• Abdominal pain
• Chest pain
• Joint pain (See Note.)
• Skin eruption
• Increased erythrocyte sedimentation rate (ESR)
• Normal values:
• Men age <50 years: <15 mm/h
• Men age 50-85 years: <20 mm/h
• Women age <50 years: <20 mm/h
• Women age 50-85 years: <30 mm/h
• Men age <50 years: <15 mm/h
• Men age 50-85 years: <20 mm/h
• Women age <50 years: <20 mm/h
• Women age 50-85 years: <30 mm/h
• Leukocytosis (normal value: 4.5-11.0 x 10
• Elevated serum fibrinogen concentration (normal value: 200-400 mg/dL [2.00-4.00 g/L])
• Men age <50 years: <15 mm/h
• Men age 50-85 years: <20 mm/h
• Women age <50 years: <20 mm/h
• Women age 50-85 years: <30 mm/h
•
• c.1105C>T (p.Pro369Ser)
• c.1223G>A (p.Arg408Gln)
• Note: These two variants in exon 3 have been shown to be in linkage disequilibrium [
• c.1105C>T (p.Pro369Ser)
• c.1223G>A (p.Arg408Gln)
•
• c.1958G>A (p.Arg653His)
• c.2040G>C (p.Met680Ile)
• c.2076_2078del (p.Ile692del)
• c.2080A>G (p.Met694Val)
• c.2082G>A (p.Met694Ile)
• c.2084A>G (p.Lys695Arg)
• c.2177T>C (p.Val726Ala)
• c.2230G>T (p.Ala744Ser)
• c.2282G>A (p.Arg761His)
• Note: (1) Other variants with exons 2, 3, and 10 are also among the most common. (2) The exons included and pathogenic variants detected may vary by laboratory and over time.
• c.1958G>A (p.Arg653His)
• c.2040G>C (p.Met680Ile)
• c.2076_2078del (p.Ile692del)
• c.2080A>G (p.Met694Val)
• c.2082G>A (p.Met694Ile)
• c.2084A>G (p.Lys695Arg)
• c.2177T>C (p.Val726Ala)
• c.2230G>T (p.Ala744Ser)
• c.2282G>A (p.Arg761His)
• c.1105C>T (p.Pro369Ser)
• c.1223G>A (p.Arg408Gln)
• c.1958G>A (p.Arg653His)
• c.2040G>C (p.Met680Ile)
• c.2076_2078del (p.Ile692del)
• c.2080A>G (p.Met694Val)
• c.2082G>A (p.Met694Ile)
• c.2084A>G (p.Lys695Arg)
• c.2177T>C (p.Val726Ala)
• c.2230G>T (p.Ala744Ser)
• c.2282G>A (p.Arg761His)
•
• c.1730C>A (p.Thr577Asn)
• c.2064C>G (p.Tyr688Ter)
• c.2076_2078delAAT (p.Ile692del)
• c.2081_2083delTGA (p.Met694del)
• c.1730C>A (p.Thr577Asn)
• c.2064C>G (p.Tyr688Ter)
• c.2076_2078delAAT (p.Ile692del)
• c.2081_2083delTGA (p.Met694del)
• c.1730C>A (p.Thr577Asn)
• c.2064C>G (p.Tyr688Ter)
• c.2076_2078delAAT (p.Ile692del)
• c.2081_2083delTGA (p.Met694del)
## Suggestive Findings
Familial Mediterranean fever (FMF)
Recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis
Recurrent erysipelas-like erythema
Repeated laparotomies for "acute abdomen" with no pathology found
Amyloidosis of the AA type that characteristically develops after age 15 years in untreated individuals, even in those who do not have a history of recurrent inflammatory attacks
Favorable response to continuous colchicine treatment
A first-degree relative with FMF
Membership in an at-risk ethnic group
• Recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis
• Recurrent erysipelas-like erythema
• Repeated laparotomies for "acute abdomen" with no pathology found
• Amyloidosis of the AA type that characteristically develops after age 15 years in untreated individuals, even in those who do not have a history of recurrent inflammatory attacks
• Favorable response to continuous colchicine treatment
• A first-degree relative with FMF
• Membership in an at-risk ethnic group
## Establishing the Diagnosis
The minimal (and most current) clinical criteria used
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Fever AND:
One additional major feature and one minor feature
OR
Two minor features
Fever
Abdominal pain
Chest pain
Joint pain (See Note.)
Skin eruption
Note: It is important to make the correct diagnosis in individuals with recurrent monoarthritis. The criteria that suggest a diagnosis of FMF in persons with monoarthritis include a high fever, favorable response to colchicine, history of FMF in sibs and other family members, and an appropriate genotype [
Increased erythrocyte sedimentation rate (ESR)
Normal values:
Men age <50 years: <15 mm/h
Men age 50-85 years: <20 mm/h
Women age <50 years: <20 mm/h
Women age 50-85 years: <30 mm/h
Leukocytosis (normal value: 4.5-11.0 x 10
Elevated serum fibrinogen concentration (normal value: 200-400 mg/dL [2.00-4.00 g/L])
Note: Early in life FMF often begins with an atypical presentation characterized by attacks of fever alone, significantly delaying diagnosis and initiation of treatment. Although other diagnostic criteria for children have been suggested by
Molecular genetic testing approaches can include
Note: Up to 25% of individuals with FMF have only one
Targeted analysis for pathogenic variants can be performed first in individuals of Armenian, Turkish, Arab, North African Jewish, Iraqi Jewish, or Ashkenazi Jewish ancestry. Targeted analysis may include:
c.1105C>T (p.Pro369Ser)
c.1223G>A (p.Arg408Gln)
Note: These two variants in exon 3 have been shown to be in linkage disequilibrium [
c.1958G>A (p.Arg653His)
c.2040G>C (p.Met680Ile)
c.2076_2078del (p.Ile692del)
c.2080A>G (p.Met694Val)
c.2082G>A (p.Met694Ile)
c.2084A>G (p.Lys695Arg)
c.2177T>C (p.Val726Ala)
c.2230G>T (p.Ala744Ser)
c.2282G>A (p.Arg761His)
Note: (1) Other variants with exons 2, 3, and 10 are also among the most common. (2) The exons included and pathogenic variants detected may vary by laboratory and over time.
In individuals with suspected autosomal dominant inheritance, in addition to the above pathogenic variants, targeted testing for a few additional pathogenic variants may be considered:
c.1730C>A (p.Thr577Asn)
c.2064C>G (p.Tyr688Ter)
c.2076_2078delAAT (p.Ile692del)
c.2081_2083delTGA (p.Met694del)
For an introduction to multigene panels click
Molecular Genetic Testing Used in Familial Mediterranean Fever
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Up to 25% of individuals with FMF have only one
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Given the proposed gain-of-function mechanism for FMF and the lack of observed large intragenic deletions or duplications, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
In all instances in which the clinical picture suggests FMF but
• One additional major feature and one minor feature
• OR
• Two minor features
• Fever
• Abdominal pain
• Chest pain
• Joint pain (See Note.)
• Skin eruption
• Increased erythrocyte sedimentation rate (ESR)
• Normal values:
• Men age <50 years: <15 mm/h
• Men age 50-85 years: <20 mm/h
• Women age <50 years: <20 mm/h
• Women age 50-85 years: <30 mm/h
• Men age <50 years: <15 mm/h
• Men age 50-85 years: <20 mm/h
• Women age <50 years: <20 mm/h
• Women age 50-85 years: <30 mm/h
• Leukocytosis (normal value: 4.5-11.0 x 10
• Elevated serum fibrinogen concentration (normal value: 200-400 mg/dL [2.00-4.00 g/L])
• Men age <50 years: <15 mm/h
• Men age 50-85 years: <20 mm/h
• Women age <50 years: <20 mm/h
• Women age 50-85 years: <30 mm/h
•
• c.1105C>T (p.Pro369Ser)
• c.1223G>A (p.Arg408Gln)
• Note: These two variants in exon 3 have been shown to be in linkage disequilibrium [
• c.1105C>T (p.Pro369Ser)
• c.1223G>A (p.Arg408Gln)
•
• c.1958G>A (p.Arg653His)
• c.2040G>C (p.Met680Ile)
• c.2076_2078del (p.Ile692del)
• c.2080A>G (p.Met694Val)
• c.2082G>A (p.Met694Ile)
• c.2084A>G (p.Lys695Arg)
• c.2177T>C (p.Val726Ala)
• c.2230G>T (p.Ala744Ser)
• c.2282G>A (p.Arg761His)
• Note: (1) Other variants with exons 2, 3, and 10 are also among the most common. (2) The exons included and pathogenic variants detected may vary by laboratory and over time.
• c.1958G>A (p.Arg653His)
• c.2040G>C (p.Met680Ile)
• c.2076_2078del (p.Ile692del)
• c.2080A>G (p.Met694Val)
• c.2082G>A (p.Met694Ile)
• c.2084A>G (p.Lys695Arg)
• c.2177T>C (p.Val726Ala)
• c.2230G>T (p.Ala744Ser)
• c.2282G>A (p.Arg761His)
• c.1105C>T (p.Pro369Ser)
• c.1223G>A (p.Arg408Gln)
• c.1958G>A (p.Arg653His)
• c.2040G>C (p.Met680Ile)
• c.2076_2078del (p.Ile692del)
• c.2080A>G (p.Met694Val)
• c.2082G>A (p.Met694Ile)
• c.2084A>G (p.Lys695Arg)
• c.2177T>C (p.Val726Ala)
• c.2230G>T (p.Ala744Ser)
• c.2282G>A (p.Arg761His)
•
• c.1730C>A (p.Thr577Asn)
• c.2064C>G (p.Tyr688Ter)
• c.2076_2078delAAT (p.Ile692del)
• c.2081_2083delTGA (p.Met694del)
• c.1730C>A (p.Thr577Asn)
• c.2064C>G (p.Tyr688Ter)
• c.2076_2078delAAT (p.Ile692del)
• c.2081_2083delTGA (p.Met694del)
• c.1730C>A (p.Thr577Asn)
• c.2064C>G (p.Tyr688Ter)
• c.2076_2078delAAT (p.Ile692del)
• c.2081_2083delTGA (p.Met694del)
## Tel Hashomer Clinical Criteria
Fever AND:
One additional major feature and one minor feature
OR
Two minor features
Fever
Abdominal pain
Chest pain
Joint pain (See Note.)
Skin eruption
Note: It is important to make the correct diagnosis in individuals with recurrent monoarthritis. The criteria that suggest a diagnosis of FMF in persons with monoarthritis include a high fever, favorable response to colchicine, history of FMF in sibs and other family members, and an appropriate genotype [
Increased erythrocyte sedimentation rate (ESR)
Normal values:
Men age <50 years: <15 mm/h
Men age 50-85 years: <20 mm/h
Women age <50 years: <20 mm/h
Women age 50-85 years: <30 mm/h
Leukocytosis (normal value: 4.5-11.0 x 10
Elevated serum fibrinogen concentration (normal value: 200-400 mg/dL [2.00-4.00 g/L])
Note: Early in life FMF often begins with an atypical presentation characterized by attacks of fever alone, significantly delaying diagnosis and initiation of treatment. Although other diagnostic criteria for children have been suggested by
• One additional major feature and one minor feature
• OR
• Two minor features
• Fever
• Abdominal pain
• Chest pain
• Joint pain (See Note.)
• Skin eruption
• Increased erythrocyte sedimentation rate (ESR)
• Normal values:
• Men age <50 years: <15 mm/h
• Men age 50-85 years: <20 mm/h
• Women age <50 years: <20 mm/h
• Women age 50-85 years: <30 mm/h
• Men age <50 years: <15 mm/h
• Men age 50-85 years: <20 mm/h
• Women age <50 years: <20 mm/h
• Women age 50-85 years: <30 mm/h
• Leukocytosis (normal value: 4.5-11.0 x 10
• Elevated serum fibrinogen concentration (normal value: 200-400 mg/dL [2.00-4.00 g/L])
• Men age <50 years: <15 mm/h
• Men age 50-85 years: <20 mm/h
• Women age <50 years: <20 mm/h
• Women age 50-85 years: <30 mm/h
## Molecular Genetic Testing
Molecular genetic testing approaches can include
Note: Up to 25% of individuals with FMF have only one
Targeted analysis for pathogenic variants can be performed first in individuals of Armenian, Turkish, Arab, North African Jewish, Iraqi Jewish, or Ashkenazi Jewish ancestry. Targeted analysis may include:
c.1105C>T (p.Pro369Ser)
c.1223G>A (p.Arg408Gln)
Note: These two variants in exon 3 have been shown to be in linkage disequilibrium [
c.1958G>A (p.Arg653His)
c.2040G>C (p.Met680Ile)
c.2076_2078del (p.Ile692del)
c.2080A>G (p.Met694Val)
c.2082G>A (p.Met694Ile)
c.2084A>G (p.Lys695Arg)
c.2177T>C (p.Val726Ala)
c.2230G>T (p.Ala744Ser)
c.2282G>A (p.Arg761His)
Note: (1) Other variants with exons 2, 3, and 10 are also among the most common. (2) The exons included and pathogenic variants detected may vary by laboratory and over time.
In individuals with suspected autosomal dominant inheritance, in addition to the above pathogenic variants, targeted testing for a few additional pathogenic variants may be considered:
c.1730C>A (p.Thr577Asn)
c.2064C>G (p.Tyr688Ter)
c.2076_2078delAAT (p.Ile692del)
c.2081_2083delTGA (p.Met694del)
For an introduction to multigene panels click
Molecular Genetic Testing Used in Familial Mediterranean Fever
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Up to 25% of individuals with FMF have only one
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Given the proposed gain-of-function mechanism for FMF and the lack of observed large intragenic deletions or duplications, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
•
• c.1105C>T (p.Pro369Ser)
• c.1223G>A (p.Arg408Gln)
• Note: These two variants in exon 3 have been shown to be in linkage disequilibrium [
• c.1105C>T (p.Pro369Ser)
• c.1223G>A (p.Arg408Gln)
•
• c.1958G>A (p.Arg653His)
• c.2040G>C (p.Met680Ile)
• c.2076_2078del (p.Ile692del)
• c.2080A>G (p.Met694Val)
• c.2082G>A (p.Met694Ile)
• c.2084A>G (p.Lys695Arg)
• c.2177T>C (p.Val726Ala)
• c.2230G>T (p.Ala744Ser)
• c.2282G>A (p.Arg761His)
• Note: (1) Other variants with exons 2, 3, and 10 are also among the most common. (2) The exons included and pathogenic variants detected may vary by laboratory and over time.
• c.1958G>A (p.Arg653His)
• c.2040G>C (p.Met680Ile)
• c.2076_2078del (p.Ile692del)
• c.2080A>G (p.Met694Val)
• c.2082G>A (p.Met694Ile)
• c.2084A>G (p.Lys695Arg)
• c.2177T>C (p.Val726Ala)
• c.2230G>T (p.Ala744Ser)
• c.2282G>A (p.Arg761His)
• c.1105C>T (p.Pro369Ser)
• c.1223G>A (p.Arg408Gln)
• c.1958G>A (p.Arg653His)
• c.2040G>C (p.Met680Ile)
• c.2076_2078del (p.Ile692del)
• c.2080A>G (p.Met694Val)
• c.2082G>A (p.Met694Ile)
• c.2084A>G (p.Lys695Arg)
• c.2177T>C (p.Val726Ala)
• c.2230G>T (p.Ala744Ser)
• c.2282G>A (p.Arg761His)
•
• c.1730C>A (p.Thr577Asn)
• c.2064C>G (p.Tyr688Ter)
• c.2076_2078delAAT (p.Ile692del)
• c.2081_2083delTGA (p.Met694del)
• c.1730C>A (p.Thr577Asn)
• c.2064C>G (p.Tyr688Ter)
• c.2076_2078delAAT (p.Ile692del)
• c.2081_2083delTGA (p.Met694del)
• c.1730C>A (p.Thr577Asn)
• c.2064C>G (p.Tyr688Ter)
• c.2076_2078delAAT (p.Ile692del)
• c.2081_2083delTGA (p.Met694del)
## Colchicine Trial
In all instances in which the clinical picture suggests FMF but
## Clinical Characteristics
Familial Mediterranean fever (FMF) is divided into two phenotypes (types 1 and 2):
The attacks are commonly in the hip or knee, but may occur in the ankle, shoulder, temporomandibular joint, or sternoclavicular joint. The joint remains swollen and painful, as in chronic monoarthritis. Recurrent monoarthritis can be the sole manifestation of FMF; in individuals with monoarthritis the true diagnosis may not be established for some time and only after extensive investigations.
Attacks subside spontaneously only after several weeks or months; severe damage to the joint can result, and permanent deformity may require joint replacement. Approximately 5% of affected individuals have protracted arthritic attacks. There is evidence that arthritis, arthralgia, myalgia, and erysipelas-like erythema occur significantly more often among individuals with disease onset before age 18 years than in those with onset after age 18 years.
The age of onset of FMF attacks appears to be earlier in persons with amyloidosis than in those without amyloidosis. FMF-related manifestations of chest pain, arthritis, and erysipelas-like erythema are more common in those with amyloidosis. Long periods between disease onset and diagnosis are associated with a high risk of developing amyloidosis.
Clinically detectable pulmonary amyloidosis secondary to FMF is rare; only a few cases have been reported to date [
However, heterozygotes with a severe pathogenic variant can be symptomatic, and autosomal dominant transmission can occur. Three severe variants in exon 10 (2 in-frame deletions and 1 nonsense variant) have been identified: p.Met694del (common in northern European, Iranian, and Azari Turkish populations [
Heterozygotes typically have a later age of onset (mean age 18 years) and milder disease (manifest mainly by fever and abdominal symptoms) than persons with biallelic pathogenic variants. Most of the heterozygotes described by
Peritoneal malignant mesothelioma was reported in two persons with FMF who had recurrent peritoneal involvement during childhood. Both were homozygous for the pathogenic variant
Possible association with stroke, multiple sclerosis, and other demyelinating disorders was reported by
Lower bone mineral density was reported by
Increased serum homocysteine and lipoprotein(a) concentrations have been reported during attack-free periods [
Moderate to severe periodontitis was more common in individuals with amyloidosis. Serum levels of acute-phase reactants in people with FMF were reduced significantly following nonsurgical periodontal therapy [
Sex, serum amyloid A concentration, and genes involved in predisposition to arthritis [
Major histocompatibility complex class I chain-related gene A (
The A5 allele had a protective effect against amyloidosis in some
The A9 allele exacerbated the age of onset in
The A4 allele dramatically reduced the frequency of attacks [
Previously used names no longer in common use for the disease that is now generally known as familial Mediterranean fever are "familial paroxysmal polyserositis" and "periodic disease."
FMF predominantly affects populations living in the Mediterranean region, especially North African Jews, Armenians, Turks, and Arabs. The pathogenic variant
FMF occurs less frequently in many other countries, where it shows considerable clinical variability [
• The attacks are commonly in the hip or knee, but may occur in the ankle, shoulder, temporomandibular joint, or sternoclavicular joint. The joint remains swollen and painful, as in chronic monoarthritis. Recurrent monoarthritis can be the sole manifestation of FMF; in individuals with monoarthritis the true diagnosis may not be established for some time and only after extensive investigations.
• Attacks subside spontaneously only after several weeks or months; severe damage to the joint can result, and permanent deformity may require joint replacement. Approximately 5% of affected individuals have protracted arthritic attacks. There is evidence that arthritis, arthralgia, myalgia, and erysipelas-like erythema occur significantly more often among individuals with disease onset before age 18 years than in those with onset after age 18 years.
• The age of onset of FMF attacks appears to be earlier in persons with amyloidosis than in those without amyloidosis. FMF-related manifestations of chest pain, arthritis, and erysipelas-like erythema are more common in those with amyloidosis. Long periods between disease onset and diagnosis are associated with a high risk of developing amyloidosis.
• Clinically detectable pulmonary amyloidosis secondary to FMF is rare; only a few cases have been reported to date [
• Peritoneal malignant mesothelioma was reported in two persons with FMF who had recurrent peritoneal involvement during childhood. Both were homozygous for the pathogenic variant
• Possible association with stroke, multiple sclerosis, and other demyelinating disorders was reported by
• Lower bone mineral density was reported by
• Increased serum homocysteine and lipoprotein(a) concentrations have been reported during attack-free periods [
• Moderate to severe periodontitis was more common in individuals with amyloidosis. Serum levels of acute-phase reactants in people with FMF were reduced significantly following nonsurgical periodontal therapy [
• Sex, serum amyloid A concentration, and genes involved in predisposition to arthritis [
• Major histocompatibility complex class I chain-related gene A (
• The A5 allele had a protective effect against amyloidosis in some
• The A9 allele exacerbated the age of onset in
• The A4 allele dramatically reduced the frequency of attacks [
• The A5 allele had a protective effect against amyloidosis in some
• The A9 allele exacerbated the age of onset in
• The A4 allele dramatically reduced the frequency of attacks [
• The A5 allele had a protective effect against amyloidosis in some
• The A9 allele exacerbated the age of onset in
• The A4 allele dramatically reduced the frequency of attacks [
## Clinical Description
Familial Mediterranean fever (FMF) is divided into two phenotypes (types 1 and 2):
The attacks are commonly in the hip or knee, but may occur in the ankle, shoulder, temporomandibular joint, or sternoclavicular joint. The joint remains swollen and painful, as in chronic monoarthritis. Recurrent monoarthritis can be the sole manifestation of FMF; in individuals with monoarthritis the true diagnosis may not be established for some time and only after extensive investigations.
Attacks subside spontaneously only after several weeks or months; severe damage to the joint can result, and permanent deformity may require joint replacement. Approximately 5% of affected individuals have protracted arthritic attacks. There is evidence that arthritis, arthralgia, myalgia, and erysipelas-like erythema occur significantly more often among individuals with disease onset before age 18 years than in those with onset after age 18 years.
The age of onset of FMF attacks appears to be earlier in persons with amyloidosis than in those without amyloidosis. FMF-related manifestations of chest pain, arthritis, and erysipelas-like erythema are more common in those with amyloidosis. Long periods between disease onset and diagnosis are associated with a high risk of developing amyloidosis.
Clinically detectable pulmonary amyloidosis secondary to FMF is rare; only a few cases have been reported to date [
However, heterozygotes with a severe pathogenic variant can be symptomatic, and autosomal dominant transmission can occur. Three severe variants in exon 10 (2 in-frame deletions and 1 nonsense variant) have been identified: p.Met694del (common in northern European, Iranian, and Azari Turkish populations [
Heterozygotes typically have a later age of onset (mean age 18 years) and milder disease (manifest mainly by fever and abdominal symptoms) than persons with biallelic pathogenic variants. Most of the heterozygotes described by
Peritoneal malignant mesothelioma was reported in two persons with FMF who had recurrent peritoneal involvement during childhood. Both were homozygous for the pathogenic variant
Possible association with stroke, multiple sclerosis, and other demyelinating disorders was reported by
Lower bone mineral density was reported by
Increased serum homocysteine and lipoprotein(a) concentrations have been reported during attack-free periods [
Moderate to severe periodontitis was more common in individuals with amyloidosis. Serum levels of acute-phase reactants in people with FMF were reduced significantly following nonsurgical periodontal therapy [
• The attacks are commonly in the hip or knee, but may occur in the ankle, shoulder, temporomandibular joint, or sternoclavicular joint. The joint remains swollen and painful, as in chronic monoarthritis. Recurrent monoarthritis can be the sole manifestation of FMF; in individuals with monoarthritis the true diagnosis may not be established for some time and only after extensive investigations.
• Attacks subside spontaneously only after several weeks or months; severe damage to the joint can result, and permanent deformity may require joint replacement. Approximately 5% of affected individuals have protracted arthritic attacks. There is evidence that arthritis, arthralgia, myalgia, and erysipelas-like erythema occur significantly more often among individuals with disease onset before age 18 years than in those with onset after age 18 years.
• The age of onset of FMF attacks appears to be earlier in persons with amyloidosis than in those without amyloidosis. FMF-related manifestations of chest pain, arthritis, and erysipelas-like erythema are more common in those with amyloidosis. Long periods between disease onset and diagnosis are associated with a high risk of developing amyloidosis.
• Clinically detectable pulmonary amyloidosis secondary to FMF is rare; only a few cases have been reported to date [
• Peritoneal malignant mesothelioma was reported in two persons with FMF who had recurrent peritoneal involvement during childhood. Both were homozygous for the pathogenic variant
• Possible association with stroke, multiple sclerosis, and other demyelinating disorders was reported by
• Lower bone mineral density was reported by
• Increased serum homocysteine and lipoprotein(a) concentrations have been reported during attack-free periods [
• Moderate to severe periodontitis was more common in individuals with amyloidosis. Serum levels of acute-phase reactants in people with FMF were reduced significantly following nonsurgical periodontal therapy [
## Genotype-Phenotype Correlations
Sex, serum amyloid A concentration, and genes involved in predisposition to arthritis [
Major histocompatibility complex class I chain-related gene A (
The A5 allele had a protective effect against amyloidosis in some
The A9 allele exacerbated the age of onset in
The A4 allele dramatically reduced the frequency of attacks [
• Sex, serum amyloid A concentration, and genes involved in predisposition to arthritis [
• Major histocompatibility complex class I chain-related gene A (
• The A5 allele had a protective effect against amyloidosis in some
• The A9 allele exacerbated the age of onset in
• The A4 allele dramatically reduced the frequency of attacks [
• The A5 allele had a protective effect against amyloidosis in some
• The A9 allele exacerbated the age of onset in
• The A4 allele dramatically reduced the frequency of attacks [
• The A5 allele had a protective effect against amyloidosis in some
• The A9 allele exacerbated the age of onset in
• The A4 allele dramatically reduced the frequency of attacks [
## Nomenclature
Previously used names no longer in common use for the disease that is now generally known as familial Mediterranean fever are "familial paroxysmal polyserositis" and "periodic disease."
## Prevalence
FMF predominantly affects populations living in the Mediterranean region, especially North African Jews, Armenians, Turks, and Arabs. The pathogenic variant
FMF occurs less frequently in many other countries, where it shows considerable clinical variability [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
The following diseases have been reported to occur more commonly in individuals with familial Mediterranean fever:
## Differential Diagnosis
Individuals of western European descent with clinical features of FMF rarely have
Acute rheumatoid arthritis
Rheumatic fever
Septic arthritis
Collagen vascular diseases
Pleurisy
Pulmonary embolism
• Acute rheumatoid arthritis
• Rheumatic fever
• Septic arthritis
• Collagen vascular diseases
• Pleurisy
• Pulmonary embolism
## Management
To establish the extent of disease and needs in an individual diagnosed with familial Mediterranean fever (FMF), the following evaluations are recommended:
Physical examination to assess joint problems
Urinalysis for the presence of protein. If proteinuria is found, further evaluation is required including measurement of 24-hour urinary protein, kidney function tests, and consider a rectal biopsy for the presence of amyloid.
Consultation with a clinical geneticist and/or genetic counselor
For information on treatment with colchicine see
During an acute episode, the therapeutic approach should be mainly supportive, including administration of intravenous saline for hydration and use of nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol or dipyrone for pain relief [
Febrile and inflammatory episodes are usually treated with NSAIDs.
End-stage kidney disease caused by renal amyloidosis should be treated as for other causes of kidney failure. The long-term outcome of live related-donor kidney transplantation in individuals with FMF-related amyloidosis is similar to that in the general transplant population [
Individuals who do not have the p.Met694Val pathogenic variant and who are only mildly affected (those with infrequent inflammatory attacks) should either be treated with colchicine or be monitored every six months for the presence of proteinuria.
Continuous treatment with colchicine appears to be less indicated for individuals who are homozygous or compound heterozygous for the pathogenic variant p.Glu148Gln. Colchicine should only be given to these individuals if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis.
Complications of colchicine use occasionally include myopathy and toxic epidermal necrolysis-like reaction.
Treatment with colchicine 1.0 mg/day prevents renal amyloidosis even if the FMF attacks do not respond to the medication.
All individuals with FMF including those not currently being treated, those being treated with colchicine, and those receiving medication other than colchicine should undergo an annual physical examination, a urine spot test for protein, and an evaluation for hematuria [
Molecular genetic testing should be offered to all first-degree relatives and other at-risk family members as early as possible whether or not they have symptoms. This is especially important when the p.Met694Val allele is present because other affected family members may not have inflammatory attacks, but nevertheless remain at risk for amyloidosis (FMF type 2) and thus need to be treated with colchicine (1.0 mg/day) to prevent the development of renal amyloidosis. Note: About 15% of individuals with autosomal dominant FMF develop amyloidosis and end-stage kidney failure if untreated.
See
The decrease of blood nitric oxide (NO) levels in individuals with FMF may trigger fever by initiating the production of IL-6. Plasma NO levels in those with FMF were significantly increased during attack-free periods following treatment with ImmunoGuard
The role of biologics such as other anti-tumor necrosis factor (TNF) agents (adalimumab and golimumab) in the treatment of FMF has recently been investigated [
One study showed that the selective serotonin reuptake inhibitor (SSRI) paroxetine significantly decreased the number of acute attacks in individuals with colchicine-resistant FMF, several of whom also suffered from depression. The authors suggested that the depression may have triggered the attacks, and that treatment of the depression had the effect of suppressing the attacks [
Search
• Physical examination to assess joint problems
• Urinalysis for the presence of protein. If proteinuria is found, further evaluation is required including measurement of 24-hour urinary protein, kidney function tests, and consider a rectal biopsy for the presence of amyloid.
• Consultation with a clinical geneticist and/or genetic counselor
• Individuals who do not have the p.Met694Val pathogenic variant and who are only mildly affected (those with infrequent inflammatory attacks) should either be treated with colchicine or be monitored every six months for the presence of proteinuria.
• Continuous treatment with colchicine appears to be less indicated for individuals who are homozygous or compound heterozygous for the pathogenic variant p.Glu148Gln. Colchicine should only be given to these individuals if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with familial Mediterranean fever (FMF), the following evaluations are recommended:
Physical examination to assess joint problems
Urinalysis for the presence of protein. If proteinuria is found, further evaluation is required including measurement of 24-hour urinary protein, kidney function tests, and consider a rectal biopsy for the presence of amyloid.
Consultation with a clinical geneticist and/or genetic counselor
• Physical examination to assess joint problems
• Urinalysis for the presence of protein. If proteinuria is found, further evaluation is required including measurement of 24-hour urinary protein, kidney function tests, and consider a rectal biopsy for the presence of amyloid.
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
For information on treatment with colchicine see
During an acute episode, the therapeutic approach should be mainly supportive, including administration of intravenous saline for hydration and use of nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol or dipyrone for pain relief [
Febrile and inflammatory episodes are usually treated with NSAIDs.
End-stage kidney disease caused by renal amyloidosis should be treated as for other causes of kidney failure. The long-term outcome of live related-donor kidney transplantation in individuals with FMF-related amyloidosis is similar to that in the general transplant population [
## Prevention of Primary Manifestations
Individuals who do not have the p.Met694Val pathogenic variant and who are only mildly affected (those with infrequent inflammatory attacks) should either be treated with colchicine or be monitored every six months for the presence of proteinuria.
Continuous treatment with colchicine appears to be less indicated for individuals who are homozygous or compound heterozygous for the pathogenic variant p.Glu148Gln. Colchicine should only be given to these individuals if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis.
Complications of colchicine use occasionally include myopathy and toxic epidermal necrolysis-like reaction.
• Individuals who do not have the p.Met694Val pathogenic variant and who are only mildly affected (those with infrequent inflammatory attacks) should either be treated with colchicine or be monitored every six months for the presence of proteinuria.
• Continuous treatment with colchicine appears to be less indicated for individuals who are homozygous or compound heterozygous for the pathogenic variant p.Glu148Gln. Colchicine should only be given to these individuals if they develop severe inflammatory episodes and/or proteinuria as a result of amyloidosis.
## Prevention of Secondary Complications
Treatment with colchicine 1.0 mg/day prevents renal amyloidosis even if the FMF attacks do not respond to the medication.
## Surveillance
All individuals with FMF including those not currently being treated, those being treated with colchicine, and those receiving medication other than colchicine should undergo an annual physical examination, a urine spot test for protein, and an evaluation for hematuria [
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
Molecular genetic testing should be offered to all first-degree relatives and other at-risk family members as early as possible whether or not they have symptoms. This is especially important when the p.Met694Val allele is present because other affected family members may not have inflammatory attacks, but nevertheless remain at risk for amyloidosis (FMF type 2) and thus need to be treated with colchicine (1.0 mg/day) to prevent the development of renal amyloidosis. Note: About 15% of individuals with autosomal dominant FMF develop amyloidosis and end-stage kidney failure if untreated.
See
## Pregnancy Management
## Therapies Under Investigation
The decrease of blood nitric oxide (NO) levels in individuals with FMF may trigger fever by initiating the production of IL-6. Plasma NO levels in those with FMF were significantly increased during attack-free periods following treatment with ImmunoGuard
The role of biologics such as other anti-tumor necrosis factor (TNF) agents (adalimumab and golimumab) in the treatment of FMF has recently been investigated [
One study showed that the selective serotonin reuptake inhibitor (SSRI) paroxetine significantly decreased the number of acute attacks in individuals with colchicine-resistant FMF, several of whom also suffered from depression. The authors suggested that the depression may have triggered the attacks, and that treatment of the depression had the effect of suppressing the attacks [
Search
## Genetic Counseling
Familial Mediterranean fever (FMF) is generally inherited in an autosomal recessive manner.
For some affected individuals, the family history of FMF is consistent with an autosomal dominant manner of inheritance. In these families, presumed heterozygotes manifest FMF within a phenotypic spectrum from mild to classic findings.
True autosomal dominant inheritance of FMF has been reported in individuals with severe pathogenic variants, including the in-frame deletion p.Met694del and two missense variants (p.Met694Val and p.Thr577Asn). Although the clinical severity of autosomal dominant FMF is typically reduced compared to autosomal recessive FMF, it is important to identify individuals with autosomal dominant FMF as about 15% of them develop amyloidosis and end-stage kidney failure if untreated.
The appearance of autosomal dominant inheritance may alternatively be the result of failure to detect a second, existing pathogenic variant. Identification of the second variant may require non-routine testing such as sequencing of the entire gene or sequencing of non-coding regions of the gene.
Other possible explanations for the appearance of autosomal dominant inheritance include: digenic inheritance with a pathogenic variant in another recurrent fever-related gene, the presence of modifying alleles in related genes, the presence of certain environmental factors, or coexistence of another autoinflammatory disease [
The parents of an individual with biallelic
Heterozygotes are usually asymptomatic; however, a parent who is heterozygous for a severe
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children may be born to an affected individual and a carrier, or even to two affected individuals resulting in pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations). Thus, it is appropriate to consider molecular genetic testing of the parents of the proband.
If both parents are heterozygous for an
At conception, each sib of an affected individual has a 25% chance of inheriting two
Heterozygotes are usually asymptomatic (see
If one parent has two
At conception, each sib of an individual with two pathogenic variants has a 50% chance of inheriting two pathogenic variants and being affected and a 50% chance of being heterozygous.
Heterozygotes are usually asymptomatic (see
Offspring inherit one
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may have two
Autosomal dominant inheritance of FMF has been reported in individuals with severe pathogenic variants, including frameshift variant p.Met694del, and two missense variants, p.Met694Val and p.Thr577Asn. The penetrance of autosomal dominant FMF is incomplete and the clinical severity is less than in autosomal recessive FMF. It is important to identify individuals with autosomal dominant FMF as about 15% of them develop amyloidosis and end-stage kidney failure if untreated.
To date, all individuals diagnosed with autosomal dominant FMF inherited an
Recommendations for the evaluation of parents of a proband with autosomal dominant FMF include molecular genetic testing.
The risk to the sibs of the proband depends on the genetic status of the proband's parents: if one parent of the proband is heterozygous for an
The actual risk to sibs of being affected may be lower than 50% because the penetrance of autosomal dominant FMF is incomplete.
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• True autosomal dominant inheritance of FMF has been reported in individuals with severe pathogenic variants, including the in-frame deletion p.Met694del and two missense variants (p.Met694Val and p.Thr577Asn). Although the clinical severity of autosomal dominant FMF is typically reduced compared to autosomal recessive FMF, it is important to identify individuals with autosomal dominant FMF as about 15% of them develop amyloidosis and end-stage kidney failure if untreated.
• The appearance of autosomal dominant inheritance may alternatively be the result of failure to detect a second, existing pathogenic variant. Identification of the second variant may require non-routine testing such as sequencing of the entire gene or sequencing of non-coding regions of the gene.
• Other possible explanations for the appearance of autosomal dominant inheritance include: digenic inheritance with a pathogenic variant in another recurrent fever-related gene, the presence of modifying alleles in related genes, the presence of certain environmental factors, or coexistence of another autoinflammatory disease [
• The parents of an individual with biallelic
• Heterozygotes are usually asymptomatic; however, a parent who is heterozygous for a severe
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children may be born to an affected individual and a carrier, or even to two affected individuals resulting in pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations). Thus, it is appropriate to consider molecular genetic testing of the parents of the proband.
• If both parents are heterozygous for an
• At conception, each sib of an affected individual has a 25% chance of inheriting two
• Heterozygotes are usually asymptomatic (see
• At conception, each sib of an affected individual has a 25% chance of inheriting two
• Heterozygotes are usually asymptomatic (see
• If one parent has two
• At conception, each sib of an individual with two pathogenic variants has a 50% chance of inheriting two pathogenic variants and being affected and a 50% chance of being heterozygous.
• Heterozygotes are usually asymptomatic (see
• At conception, each sib of an individual with two pathogenic variants has a 50% chance of inheriting two pathogenic variants and being affected and a 50% chance of being heterozygous.
• Heterozygotes are usually asymptomatic (see
• At conception, each sib of an affected individual has a 25% chance of inheriting two
• Heterozygotes are usually asymptomatic (see
• At conception, each sib of an individual with two pathogenic variants has a 50% chance of inheriting two pathogenic variants and being affected and a 50% chance of being heterozygous.
• Heterozygotes are usually asymptomatic (see
• Offspring inherit one
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may have two
• To date, all individuals diagnosed with autosomal dominant FMF inherited an
• Recommendations for the evaluation of parents of a proband with autosomal dominant FMF include molecular genetic testing.
• The risk to the sibs of the proband depends on the genetic status of the proband's parents: if one parent of the proband is heterozygous for an
• The actual risk to sibs of being affected may be lower than 50% because the penetrance of autosomal dominant FMF is incomplete.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Familial Mediterranean fever (FMF) is generally inherited in an autosomal recessive manner.
For some affected individuals, the family history of FMF is consistent with an autosomal dominant manner of inheritance. In these families, presumed heterozygotes manifest FMF within a phenotypic spectrum from mild to classic findings.
True autosomal dominant inheritance of FMF has been reported in individuals with severe pathogenic variants, including the in-frame deletion p.Met694del and two missense variants (p.Met694Val and p.Thr577Asn). Although the clinical severity of autosomal dominant FMF is typically reduced compared to autosomal recessive FMF, it is important to identify individuals with autosomal dominant FMF as about 15% of them develop amyloidosis and end-stage kidney failure if untreated.
The appearance of autosomal dominant inheritance may alternatively be the result of failure to detect a second, existing pathogenic variant. Identification of the second variant may require non-routine testing such as sequencing of the entire gene or sequencing of non-coding regions of the gene.
Other possible explanations for the appearance of autosomal dominant inheritance include: digenic inheritance with a pathogenic variant in another recurrent fever-related gene, the presence of modifying alleles in related genes, the presence of certain environmental factors, or coexistence of another autoinflammatory disease [
• True autosomal dominant inheritance of FMF has been reported in individuals with severe pathogenic variants, including the in-frame deletion p.Met694del and two missense variants (p.Met694Val and p.Thr577Asn). Although the clinical severity of autosomal dominant FMF is typically reduced compared to autosomal recessive FMF, it is important to identify individuals with autosomal dominant FMF as about 15% of them develop amyloidosis and end-stage kidney failure if untreated.
• The appearance of autosomal dominant inheritance may alternatively be the result of failure to detect a second, existing pathogenic variant. Identification of the second variant may require non-routine testing such as sequencing of the entire gene or sequencing of non-coding regions of the gene.
• Other possible explanations for the appearance of autosomal dominant inheritance include: digenic inheritance with a pathogenic variant in another recurrent fever-related gene, the presence of modifying alleles in related genes, the presence of certain environmental factors, or coexistence of another autoinflammatory disease [
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an individual with biallelic
Heterozygotes are usually asymptomatic; however, a parent who is heterozygous for a severe
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children may be born to an affected individual and a carrier, or even to two affected individuals resulting in pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations). Thus, it is appropriate to consider molecular genetic testing of the parents of the proband.
If both parents are heterozygous for an
At conception, each sib of an affected individual has a 25% chance of inheriting two
Heterozygotes are usually asymptomatic (see
If one parent has two
At conception, each sib of an individual with two pathogenic variants has a 50% chance of inheriting two pathogenic variants and being affected and a 50% chance of being heterozygous.
Heterozygotes are usually asymptomatic (see
Offspring inherit one
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may have two
• The parents of an individual with biallelic
• Heterozygotes are usually asymptomatic; however, a parent who is heterozygous for a severe
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children may be born to an affected individual and a carrier, or even to two affected individuals resulting in pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations). Thus, it is appropriate to consider molecular genetic testing of the parents of the proband.
• If both parents are heterozygous for an
• At conception, each sib of an affected individual has a 25% chance of inheriting two
• Heterozygotes are usually asymptomatic (see
• At conception, each sib of an affected individual has a 25% chance of inheriting two
• Heterozygotes are usually asymptomatic (see
• If one parent has two
• At conception, each sib of an individual with two pathogenic variants has a 50% chance of inheriting two pathogenic variants and being affected and a 50% chance of being heterozygous.
• Heterozygotes are usually asymptomatic (see
• At conception, each sib of an individual with two pathogenic variants has a 50% chance of inheriting two pathogenic variants and being affected and a 50% chance of being heterozygous.
• Heterozygotes are usually asymptomatic (see
• At conception, each sib of an affected individual has a 25% chance of inheriting two
• Heterozygotes are usually asymptomatic (see
• At conception, each sib of an individual with two pathogenic variants has a 50% chance of inheriting two pathogenic variants and being affected and a 50% chance of being heterozygous.
• Heterozygotes are usually asymptomatic (see
• Offspring inherit one
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may have two
## Autosomal Dominant Inheritance – Risk to Family Members
Autosomal dominant inheritance of FMF has been reported in individuals with severe pathogenic variants, including frameshift variant p.Met694del, and two missense variants, p.Met694Val and p.Thr577Asn. The penetrance of autosomal dominant FMF is incomplete and the clinical severity is less than in autosomal recessive FMF. It is important to identify individuals with autosomal dominant FMF as about 15% of them develop amyloidosis and end-stage kidney failure if untreated.
To date, all individuals diagnosed with autosomal dominant FMF inherited an
Recommendations for the evaluation of parents of a proband with autosomal dominant FMF include molecular genetic testing.
The risk to the sibs of the proband depends on the genetic status of the proband's parents: if one parent of the proband is heterozygous for an
The actual risk to sibs of being affected may be lower than 50% because the penetrance of autosomal dominant FMF is incomplete.
• To date, all individuals diagnosed with autosomal dominant FMF inherited an
• Recommendations for the evaluation of parents of a proband with autosomal dominant FMF include molecular genetic testing.
• The risk to the sibs of the proband depends on the genetic status of the proband's parents: if one parent of the proband is heterozygous for an
• The actual risk to sibs of being affected may be lower than 50% because the penetrance of autosomal dominant FMF is incomplete.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Italy
•
•
•
•
•
•
• Italy
•
## Molecular Genetics
Familial Mediterranean Fever: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Familial Mediterranean Fever (
The p.Glu148Gln variant is predominant in Ashkenazi and Iraqi Jews, Armenians, and Turks, and has been associated with a generally mild form of FMF. Indeed, many individuals who are either homozygous for p.Glu148Gln or compound heterozygous for this variant and a pathogenic variant other than p.Met694Val are asymptomatic. Such individuals are also at low risk (if any) of developing amyloidosis. The possible exception is those who are compound heterozygous for the alleles p.[Glu148Gln];[p.Met694Val]; such individuals may be clinically affected and also at risk of developing amyloidosis [
Reduced penetrance of this pathogenic variant has been suggested and could explain the considerable proportion of genetically affected individuals in this population who remained asymptomatic [
The
30.1% were homozygous;
39.8% were compound heterozygous;
19.3% were heterozygous;
10.8% had none of the listed variants, although p.Ala744Ser and p.Arg761His were detected in a few individuals after sequencing exon 10 only.
Possible explanations:
The second undetected variant may be in an intron, or situated some distance from the gene itself, or possibly even in a neighboring gene, and thus missed by routine testing. This may explain the failure to detect in a substantial number of affected individuals either a second pathogenic variant when the gene and promoter region were fully sequenced or a common haplotype in their families [
Selected
Variants listed in the table have been provided by the author.
The pyrin protein exists in several isoforms of unknown function. The recombinant full-length isoform (pyrin.fl) is cytoplasmic, whereas an alternatively spliced isoform lacking exon 2 (pyrin.DeltaEx2) concentrates in the nucleus. Native pyrin, mainly consisting of pyrin.fl, is also cytoplasmic in monocytes but is predominantly nuclear in other cell types [
• The p.Glu148Gln variant is predominant in Ashkenazi and Iraqi Jews, Armenians, and Turks, and has been associated with a generally mild form of FMF. Indeed, many individuals who are either homozygous for p.Glu148Gln or compound heterozygous for this variant and a pathogenic variant other than p.Met694Val are asymptomatic. Such individuals are also at low risk (if any) of developing amyloidosis. The possible exception is those who are compound heterozygous for the alleles p.[Glu148Gln];[p.Met694Val]; such individuals may be clinically affected and also at risk of developing amyloidosis [
• Reduced penetrance of this pathogenic variant has been suggested and could explain the considerable proportion of genetically affected individuals in this population who remained asymptomatic [
• The
• 30.1% were homozygous;
• 39.8% were compound heterozygous;
• 19.3% were heterozygous;
• 10.8% had none of the listed variants, although p.Ala744Ser and p.Arg761His were detected in a few individuals after sequencing exon 10 only.
• Possible explanations:
• The second undetected variant may be in an intron, or situated some distance from the gene itself, or possibly even in a neighboring gene, and thus missed by routine testing. This may explain the failure to detect in a substantial number of affected individuals either a second pathogenic variant when the gene and promoter region were fully sequenced or a common haplotype in their families [
• 30.1% were homozygous;
• 39.8% were compound heterozygous;
• 19.3% were heterozygous;
• 10.8% had none of the listed variants, although p.Ala744Ser and p.Arg761His were detected in a few individuals after sequencing exon 10 only.
• The second undetected variant may be in an intron, or situated some distance from the gene itself, or possibly even in a neighboring gene, and thus missed by routine testing. This may explain the failure to detect in a substantial number of affected individuals either a second pathogenic variant when the gene and promoter region were fully sequenced or a common haplotype in their families [
• 30.1% were homozygous;
• 39.8% were compound heterozygous;
• 19.3% were heterozygous;
• 10.8% had none of the listed variants, although p.Ala744Ser and p.Arg761His were detected in a few individuals after sequencing exon 10 only.
• The second undetected variant may be in an intron, or situated some distance from the gene itself, or possibly even in a neighboring gene, and thus missed by routine testing. This may explain the failure to detect in a substantial number of affected individuals either a second pathogenic variant when the gene and promoter region were fully sequenced or a common haplotype in their families [
## Chapter Notes
Professor Mordechai Shohat, MD has been involved with research into familial Mediterranean fever, including the molecular analysis of
For further information about familial Mediterranean fever, contact Professor Shohat:
Phone: +972-3-937-7659
Fax: +972-3-937-7660
Email:
Gabrielle J Halpern, MB, ChB; Rabin Medical Center (2000-2016)
Mordechai Shohat, MD (2000-present)
15 December 2016 (sw) Comprehensive update posted live
19 June 2014 (me) Comprehensive update posted live
26 April 2012 (me) Comprehensive update posted live
30 April 2009 (me) Comprehensive update posted live
25 February 2008 (ms) Revision: clarification of PFAPA in Differential Diagnosis
2 January 2008 (ms) Revision: Molecular Genetics, Pathologic allelic variants
28 February 2007 (me) Comprehensive update posted live
5 November 2004 (me) Comprehensive update posted live
13 November 2002 (me) Comprehensive update posted live
8 August 2000 (me) Review posted live
4 April 2000 (ms) Original submission
• 15 December 2016 (sw) Comprehensive update posted live
• 19 June 2014 (me) Comprehensive update posted live
• 26 April 2012 (me) Comprehensive update posted live
• 30 April 2009 (me) Comprehensive update posted live
• 25 February 2008 (ms) Revision: clarification of PFAPA in Differential Diagnosis
• 2 January 2008 (ms) Revision: Molecular Genetics, Pathologic allelic variants
• 28 February 2007 (me) Comprehensive update posted live
• 5 November 2004 (me) Comprehensive update posted live
• 13 November 2002 (me) Comprehensive update posted live
• 8 August 2000 (me) Review posted live
• 4 April 2000 (ms) Original submission
## Author Notes
Professor Mordechai Shohat, MD has been involved with research into familial Mediterranean fever, including the molecular analysis of
For further information about familial Mediterranean fever, contact Professor Shohat:
Phone: +972-3-937-7659
Fax: +972-3-937-7660
Email:
## Author History
Gabrielle J Halpern, MB, ChB; Rabin Medical Center (2000-2016)
Mordechai Shohat, MD (2000-present)
## Revision History
15 December 2016 (sw) Comprehensive update posted live
19 June 2014 (me) Comprehensive update posted live
26 April 2012 (me) Comprehensive update posted live
30 April 2009 (me) Comprehensive update posted live
25 February 2008 (ms) Revision: clarification of PFAPA in Differential Diagnosis
2 January 2008 (ms) Revision: Molecular Genetics, Pathologic allelic variants
28 February 2007 (me) Comprehensive update posted live
5 November 2004 (me) Comprehensive update posted live
13 November 2002 (me) Comprehensive update posted live
8 August 2000 (me) Review posted live
4 April 2000 (ms) Original submission
• 15 December 2016 (sw) Comprehensive update posted live
• 19 June 2014 (me) Comprehensive update posted live
• 26 April 2012 (me) Comprehensive update posted live
• 30 April 2009 (me) Comprehensive update posted live
• 25 February 2008 (ms) Revision: clarification of PFAPA in Differential Diagnosis
• 2 January 2008 (ms) Revision: Molecular Genetics, Pathologic allelic variants
• 28 February 2007 (me) Comprehensive update posted live
• 5 November 2004 (me) Comprehensive update posted live
• 13 November 2002 (me) Comprehensive update posted live
• 8 August 2000 (me) Review posted live
• 4 April 2000 (ms) Original submission
## References
## Literature Cited
|
[] |
8/8/2000
|
15/12/2016
|
25/2/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
focal-dh
|
focal-dh
|
[
"Focal Dermal Hypoplasia",
"Goltz Syndrome",
"Goltz-Gorlin Syndrome",
"Goltz Syndrome",
"Goltz-Gorlin Syndrome",
"Focal Dermal Hypoplasia (FDH)",
"Protein-serine O-palmitoleoyltransferase porcupine",
"PORCN",
"PORCN-Related Developmental Disorders"
] |
V Reid Sutton
|
Summary
|
## Diagnosis
A
Note: The lines of Blaschko correspond to cell migration pathways evident during embryonic and fetal skin development. Like dermatomes, the lines of Blaschko are linear on the limbs and circumferential on the trunk. Unlike dermatomes, the lines of Blaschko do not correspond to innervation patterns.
Note: (1) Per ACMG/AMG variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Tiered molecular testing approaches can include a combination of
Note: (1) Several females and most males have somatic mosaicism for either a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Estimates based on 170 individual positive test results curated in the
Most 46,XY males and some females are mosaic for pathogenic variants in
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Reported deletions have ranged from an intragenic deletion (exons 1-4) [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Note: The lines of Blaschko correspond to cell migration pathways evident during embryonic and fetal skin development. Like dermatomes, the lines of Blaschko are linear on the limbs and circumferential on the trunk. Unlike dermatomes, the lines of Blaschko do not correspond to innervation patterns.
•
• Note: (1) Several females and most males have somatic mosaicism for either a
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
A
Note: The lines of Blaschko correspond to cell migration pathways evident during embryonic and fetal skin development. Like dermatomes, the lines of Blaschko are linear on the limbs and circumferential on the trunk. Unlike dermatomes, the lines of Blaschko do not correspond to innervation patterns.
• Note: The lines of Blaschko correspond to cell migration pathways evident during embryonic and fetal skin development. Like dermatomes, the lines of Blaschko are linear on the limbs and circumferential on the trunk. Unlike dermatomes, the lines of Blaschko do not correspond to innervation patterns.
•
## Establishing the Diagnosis
Note: (1) Per ACMG/AMG variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Tiered molecular testing approaches can include a combination of
Note: (1) Several females and most males have somatic mosaicism for either a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Estimates based on 170 individual positive test results curated in the
Most 46,XY males and some females are mosaic for pathogenic variants in
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Reported deletions have ranged from an intragenic deletion (exons 1-4) [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Note: (1) Several females and most males have somatic mosaicism for either a
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Females account for 90% of individuals with
The phenotypes in both males and females are highly variable due to tissue mosaicism: females have random X-chromosome inactivation (functional mosaicism), while most males have postzygotic somatic mosaicism.
EM = electron microscopy
Other integumentary system abnormalities include wiry hair, sparse hair, patchy alopecia of the scalp, and abnormal nails. The nails can be absent (anonychia), small (micronychia), hypoplastic, or dysplastic, often with longitudinal ridging, splitting, or V-shaped nicking [
Verrucous papillomas are found in the oral mucosa of the mouth, nose, pharynx, larynx, trachea, and esophagus. Large papillomas of the larynx can obstruct breathing during anesthesia or can cause obstructive sleep apnea. Papillomas in the esophagus or larynx can also cause or contribute to severe gastroesophageal reflux disease (GERD).
The vaginal or rectal mucosa are also common sites for papillomas, where they can be confused with genital warts.
Dental abnormalities and eye findings, both of which result from abnormalities in ectodermal appendage development, are described separately below.
Additionally, reduction defects of the long bones ranging from leg length discrepancies to transverse defects of the distal radius/ulna or tibia/fibula are commonly seen.
Less common limb malformations that may be present at birth and impair function include camptodactyly (contraction deformities of the digits) and brachydactyly (shortening of the digits).
Costovertebral segmentation abnormalities including fused ribs, bifid ribs, hemivertebrae, and butterfly vertebrae are present at birth but are often not evident on physical examination and may only be seen in radiographs of the chest and/or spine. Although these malformations do not typically cause problems in infancy or early childhood, they may cause scoliosis as the child grows. Kyphosis or kyphoscoliosis is seen in approximately 10% of affected individuals [
Diastasis pubis, an abnormal separation of the symphysis pubis, may be an incidental finding or may present in adolescence or adulthood with pain. The gap between the pubic bones in the average non-pregnant adult is 4-5 mm. An abnormal gap is considered to be 1 cm or more, sometimes with the two bones being slightly out of alignment. In some individuals, diastasis pubis may cause pain with walking or in the symphysis pubis, legs, groin, and lower abdomen.
Fibrous dysplasia of bone (i.e., replacement of medullary bone with trabeculae of woven bone containing fluid-filled cysts embedded in a fibrous matrix) may affect any bone at any time. On radiographs the bone appears radiolucent, with what is classically described as a "ground-glass" appearance. Fibrous dysplasia may be asymptomatic or become evident when it is the site of a pathologic fracture.
Giant cell-like tumors of long bones, reported on occasion, may develop in childhood, adolescence, or adulthood. They typically become evident when a pathologic bone fracture occurs at the site of the lesion [
Osteopathia striata, a striated appearance of the bones evident on plain radiographs, is common and may be seen in childhood, adolescence, and adulthood. It is currently unclear if individuals with this finding are at increased risk for general osteoporosis. Of note, a spontaneous patella fracture related to osteoporosis in an individual with a
Strabismus and/or nystagmus can be observed when visual impairment in infancy is significant.
Cleft lip and palate can be present and may lead to difficulty with feeding. More severe facial clefting can cause feeding, breathing, and vision problems, as well as significant cosmetic concerns [
Enamel hypoplasia that predisposes to dental caries is the most common problem. Other findings include: hypodontia, oligodontia, supernumerary teeth, and dental crowding leading to malocclusion of both primary and secondary dentition; vertical grooving of the teeth; microdontia (small teeth); taurodontia (prism-shaped molars); fused teeth; and abnormal root morphology [
Soft tissue abnormalities include generalized gingivitis and intraoral lipomas and papillomas [
Other developmental abnormalities of the digestive system are rare but may have severe consequences; they include abdominal wall defects and diaphragmatic hernia.
Severe GERD has been reported in infancy and childhood, leading to feeding difficulties with frequent vomiting and/or discomfort/distress. GERD likely results from esophageal papillomas [
Structural brain abnormalities and spina bifida [
Epilepsy has been reported [
An adult female with multiple cutaneous basal cell carcinomas has been reported. Whether basal cell carcinoma is more prevalent in individuals with a
When the first affected female in the family has milder manifestations than affected females in subsequent generations [
Because relatively few affected males have been reported, no comprehensive data for a "typical" male phenotype exist.
Affected males may have any of the features seen in affected females, including typical skin findings; sparse, brittle hair; nail dystrophy; microphthalmia; syndactyly; split-hand/foot malformation; costovertebral segmentation abnormalities; osteopathia striata; and diastasis pubis [
Affected males most often have somatic mosaicism for a
Histopathologic and ultrastructural studies of the skin have shown the following:
A thinned dermis with disordered connective tissue and decreased number of collagen bundles and elastin fibers [
Rests of mature adipose tissue scattered throughout the reticular and papillary dermis [
Verrucous papillomas that resemble squamous papillomas with hyperplastic, stratified squamous epithelium overlying a fibrovascular core. Verrucous papillomas lack the typical morphologic evidence of human papilloma virus infection and stain negative for Epstein-Barr virus RNA [
From biopsies from Blaschkoid streaks, findings of increased papillary dermal blood vessels, decreased thickness of the dermis, and adipocytes high in the dermis strongly point to the diagnosis of a
Information on genotype-phenotype correlations in
Available data suggest that the level of X-chromosome inactivation correlates with severity of the phenotype in some (familial) cases [
Note: All females with deletions in
Most affected males to date have somatic mosaicism for a
Non-mosaic
Most males are mosaic for a hemizygous somatic
The title of this
"Gorlin-Goltz syndrome" is another name for
• Verrucous papillomas are found in the oral mucosa of the mouth, nose, pharynx, larynx, trachea, and esophagus. Large papillomas of the larynx can obstruct breathing during anesthesia or can cause obstructive sleep apnea. Papillomas in the esophagus or larynx can also cause or contribute to severe gastroesophageal reflux disease (GERD).
• The vaginal or rectal mucosa are also common sites for papillomas, where they can be confused with genital warts.
• A thinned dermis with disordered connective tissue and decreased number of collagen bundles and elastin fibers [
• Rests of mature adipose tissue scattered throughout the reticular and papillary dermis [
• Verrucous papillomas that resemble squamous papillomas with hyperplastic, stratified squamous epithelium overlying a fibrovascular core. Verrucous papillomas lack the typical morphologic evidence of human papilloma virus infection and stain negative for Epstein-Barr virus RNA [
• From biopsies from Blaschkoid streaks, findings of increased papillary dermal blood vessels, decreased thickness of the dermis, and adipocytes high in the dermis strongly point to the diagnosis of a
• Available data suggest that the level of X-chromosome inactivation correlates with severity of the phenotype in some (familial) cases [
• Note: All females with deletions in
• Most affected males to date have somatic mosaicism for a
• Non-mosaic
## Clinical Description
Females account for 90% of individuals with
The phenotypes in both males and females are highly variable due to tissue mosaicism: females have random X-chromosome inactivation (functional mosaicism), while most males have postzygotic somatic mosaicism.
EM = electron microscopy
Other integumentary system abnormalities include wiry hair, sparse hair, patchy alopecia of the scalp, and abnormal nails. The nails can be absent (anonychia), small (micronychia), hypoplastic, or dysplastic, often with longitudinal ridging, splitting, or V-shaped nicking [
Verrucous papillomas are found in the oral mucosa of the mouth, nose, pharynx, larynx, trachea, and esophagus. Large papillomas of the larynx can obstruct breathing during anesthesia or can cause obstructive sleep apnea. Papillomas in the esophagus or larynx can also cause or contribute to severe gastroesophageal reflux disease (GERD).
The vaginal or rectal mucosa are also common sites for papillomas, where they can be confused with genital warts.
Dental abnormalities and eye findings, both of which result from abnormalities in ectodermal appendage development, are described separately below.
Additionally, reduction defects of the long bones ranging from leg length discrepancies to transverse defects of the distal radius/ulna or tibia/fibula are commonly seen.
Less common limb malformations that may be present at birth and impair function include camptodactyly (contraction deformities of the digits) and brachydactyly (shortening of the digits).
Costovertebral segmentation abnormalities including fused ribs, bifid ribs, hemivertebrae, and butterfly vertebrae are present at birth but are often not evident on physical examination and may only be seen in radiographs of the chest and/or spine. Although these malformations do not typically cause problems in infancy or early childhood, they may cause scoliosis as the child grows. Kyphosis or kyphoscoliosis is seen in approximately 10% of affected individuals [
Diastasis pubis, an abnormal separation of the symphysis pubis, may be an incidental finding or may present in adolescence or adulthood with pain. The gap between the pubic bones in the average non-pregnant adult is 4-5 mm. An abnormal gap is considered to be 1 cm or more, sometimes with the two bones being slightly out of alignment. In some individuals, diastasis pubis may cause pain with walking or in the symphysis pubis, legs, groin, and lower abdomen.
Fibrous dysplasia of bone (i.e., replacement of medullary bone with trabeculae of woven bone containing fluid-filled cysts embedded in a fibrous matrix) may affect any bone at any time. On radiographs the bone appears radiolucent, with what is classically described as a "ground-glass" appearance. Fibrous dysplasia may be asymptomatic or become evident when it is the site of a pathologic fracture.
Giant cell-like tumors of long bones, reported on occasion, may develop in childhood, adolescence, or adulthood. They typically become evident when a pathologic bone fracture occurs at the site of the lesion [
Osteopathia striata, a striated appearance of the bones evident on plain radiographs, is common and may be seen in childhood, adolescence, and adulthood. It is currently unclear if individuals with this finding are at increased risk for general osteoporosis. Of note, a spontaneous patella fracture related to osteoporosis in an individual with a
Strabismus and/or nystagmus can be observed when visual impairment in infancy is significant.
Cleft lip and palate can be present and may lead to difficulty with feeding. More severe facial clefting can cause feeding, breathing, and vision problems, as well as significant cosmetic concerns [
Enamel hypoplasia that predisposes to dental caries is the most common problem. Other findings include: hypodontia, oligodontia, supernumerary teeth, and dental crowding leading to malocclusion of both primary and secondary dentition; vertical grooving of the teeth; microdontia (small teeth); taurodontia (prism-shaped molars); fused teeth; and abnormal root morphology [
Soft tissue abnormalities include generalized gingivitis and intraoral lipomas and papillomas [
Other developmental abnormalities of the digestive system are rare but may have severe consequences; they include abdominal wall defects and diaphragmatic hernia.
Severe GERD has been reported in infancy and childhood, leading to feeding difficulties with frequent vomiting and/or discomfort/distress. GERD likely results from esophageal papillomas [
Structural brain abnormalities and spina bifida [
Epilepsy has been reported [
An adult female with multiple cutaneous basal cell carcinomas has been reported. Whether basal cell carcinoma is more prevalent in individuals with a
When the first affected female in the family has milder manifestations than affected females in subsequent generations [
Because relatively few affected males have been reported, no comprehensive data for a "typical" male phenotype exist.
Affected males may have any of the features seen in affected females, including typical skin findings; sparse, brittle hair; nail dystrophy; microphthalmia; syndactyly; split-hand/foot malformation; costovertebral segmentation abnormalities; osteopathia striata; and diastasis pubis [
Affected males most often have somatic mosaicism for a
Histopathologic and ultrastructural studies of the skin have shown the following:
A thinned dermis with disordered connective tissue and decreased number of collagen bundles and elastin fibers [
Rests of mature adipose tissue scattered throughout the reticular and papillary dermis [
Verrucous papillomas that resemble squamous papillomas with hyperplastic, stratified squamous epithelium overlying a fibrovascular core. Verrucous papillomas lack the typical morphologic evidence of human papilloma virus infection and stain negative for Epstein-Barr virus RNA [
From biopsies from Blaschkoid streaks, findings of increased papillary dermal blood vessels, decreased thickness of the dermis, and adipocytes high in the dermis strongly point to the diagnosis of a
• Verrucous papillomas are found in the oral mucosa of the mouth, nose, pharynx, larynx, trachea, and esophagus. Large papillomas of the larynx can obstruct breathing during anesthesia or can cause obstructive sleep apnea. Papillomas in the esophagus or larynx can also cause or contribute to severe gastroesophageal reflux disease (GERD).
• The vaginal or rectal mucosa are also common sites for papillomas, where they can be confused with genital warts.
• A thinned dermis with disordered connective tissue and decreased number of collagen bundles and elastin fibers [
• Rests of mature adipose tissue scattered throughout the reticular and papillary dermis [
• Verrucous papillomas that resemble squamous papillomas with hyperplastic, stratified squamous epithelium overlying a fibrovascular core. Verrucous papillomas lack the typical morphologic evidence of human papilloma virus infection and stain negative for Epstein-Barr virus RNA [
• From biopsies from Blaschkoid streaks, findings of increased papillary dermal blood vessels, decreased thickness of the dermis, and adipocytes high in the dermis strongly point to the diagnosis of a
## Affected Females
Other integumentary system abnormalities include wiry hair, sparse hair, patchy alopecia of the scalp, and abnormal nails. The nails can be absent (anonychia), small (micronychia), hypoplastic, or dysplastic, often with longitudinal ridging, splitting, or V-shaped nicking [
Verrucous papillomas are found in the oral mucosa of the mouth, nose, pharynx, larynx, trachea, and esophagus. Large papillomas of the larynx can obstruct breathing during anesthesia or can cause obstructive sleep apnea. Papillomas in the esophagus or larynx can also cause or contribute to severe gastroesophageal reflux disease (GERD).
The vaginal or rectal mucosa are also common sites for papillomas, where they can be confused with genital warts.
Dental abnormalities and eye findings, both of which result from abnormalities in ectodermal appendage development, are described separately below.
Additionally, reduction defects of the long bones ranging from leg length discrepancies to transverse defects of the distal radius/ulna or tibia/fibula are commonly seen.
Less common limb malformations that may be present at birth and impair function include camptodactyly (contraction deformities of the digits) and brachydactyly (shortening of the digits).
Costovertebral segmentation abnormalities including fused ribs, bifid ribs, hemivertebrae, and butterfly vertebrae are present at birth but are often not evident on physical examination and may only be seen in radiographs of the chest and/or spine. Although these malformations do not typically cause problems in infancy or early childhood, they may cause scoliosis as the child grows. Kyphosis or kyphoscoliosis is seen in approximately 10% of affected individuals [
Diastasis pubis, an abnormal separation of the symphysis pubis, may be an incidental finding or may present in adolescence or adulthood with pain. The gap between the pubic bones in the average non-pregnant adult is 4-5 mm. An abnormal gap is considered to be 1 cm or more, sometimes with the two bones being slightly out of alignment. In some individuals, diastasis pubis may cause pain with walking or in the symphysis pubis, legs, groin, and lower abdomen.
Fibrous dysplasia of bone (i.e., replacement of medullary bone with trabeculae of woven bone containing fluid-filled cysts embedded in a fibrous matrix) may affect any bone at any time. On radiographs the bone appears radiolucent, with what is classically described as a "ground-glass" appearance. Fibrous dysplasia may be asymptomatic or become evident when it is the site of a pathologic fracture.
Giant cell-like tumors of long bones, reported on occasion, may develop in childhood, adolescence, or adulthood. They typically become evident when a pathologic bone fracture occurs at the site of the lesion [
Osteopathia striata, a striated appearance of the bones evident on plain radiographs, is common and may be seen in childhood, adolescence, and adulthood. It is currently unclear if individuals with this finding are at increased risk for general osteoporosis. Of note, a spontaneous patella fracture related to osteoporosis in an individual with a
Strabismus and/or nystagmus can be observed when visual impairment in infancy is significant.
Cleft lip and palate can be present and may lead to difficulty with feeding. More severe facial clefting can cause feeding, breathing, and vision problems, as well as significant cosmetic concerns [
Enamel hypoplasia that predisposes to dental caries is the most common problem. Other findings include: hypodontia, oligodontia, supernumerary teeth, and dental crowding leading to malocclusion of both primary and secondary dentition; vertical grooving of the teeth; microdontia (small teeth); taurodontia (prism-shaped molars); fused teeth; and abnormal root morphology [
Soft tissue abnormalities include generalized gingivitis and intraoral lipomas and papillomas [
Other developmental abnormalities of the digestive system are rare but may have severe consequences; they include abdominal wall defects and diaphragmatic hernia.
Severe GERD has been reported in infancy and childhood, leading to feeding difficulties with frequent vomiting and/or discomfort/distress. GERD likely results from esophageal papillomas [
Structural brain abnormalities and spina bifida [
Epilepsy has been reported [
An adult female with multiple cutaneous basal cell carcinomas has been reported. Whether basal cell carcinoma is more prevalent in individuals with a
When the first affected female in the family has milder manifestations than affected females in subsequent generations [
• Verrucous papillomas are found in the oral mucosa of the mouth, nose, pharynx, larynx, trachea, and esophagus. Large papillomas of the larynx can obstruct breathing during anesthesia or can cause obstructive sleep apnea. Papillomas in the esophagus or larynx can also cause or contribute to severe gastroesophageal reflux disease (GERD).
• The vaginal or rectal mucosa are also common sites for papillomas, where they can be confused with genital warts.
## Affected Males
Because relatively few affected males have been reported, no comprehensive data for a "typical" male phenotype exist.
Affected males may have any of the features seen in affected females, including typical skin findings; sparse, brittle hair; nail dystrophy; microphthalmia; syndactyly; split-hand/foot malformation; costovertebral segmentation abnormalities; osteopathia striata; and diastasis pubis [
Affected males most often have somatic mosaicism for a
## Pathology
Histopathologic and ultrastructural studies of the skin have shown the following:
A thinned dermis with disordered connective tissue and decreased number of collagen bundles and elastin fibers [
Rests of mature adipose tissue scattered throughout the reticular and papillary dermis [
Verrucous papillomas that resemble squamous papillomas with hyperplastic, stratified squamous epithelium overlying a fibrovascular core. Verrucous papillomas lack the typical morphologic evidence of human papilloma virus infection and stain negative for Epstein-Barr virus RNA [
From biopsies from Blaschkoid streaks, findings of increased papillary dermal blood vessels, decreased thickness of the dermis, and adipocytes high in the dermis strongly point to the diagnosis of a
• A thinned dermis with disordered connective tissue and decreased number of collagen bundles and elastin fibers [
• Rests of mature adipose tissue scattered throughout the reticular and papillary dermis [
• Verrucous papillomas that resemble squamous papillomas with hyperplastic, stratified squamous epithelium overlying a fibrovascular core. Verrucous papillomas lack the typical morphologic evidence of human papilloma virus infection and stain negative for Epstein-Barr virus RNA [
• From biopsies from Blaschkoid streaks, findings of increased papillary dermal blood vessels, decreased thickness of the dermis, and adipocytes high in the dermis strongly point to the diagnosis of a
## Genotype-Phenotype Correlations
Information on genotype-phenotype correlations in
Available data suggest that the level of X-chromosome inactivation correlates with severity of the phenotype in some (familial) cases [
Note: All females with deletions in
Most affected males to date have somatic mosaicism for a
Non-mosaic
• Available data suggest that the level of X-chromosome inactivation correlates with severity of the phenotype in some (familial) cases [
• Note: All females with deletions in
• Most affected males to date have somatic mosaicism for a
• Non-mosaic
## Penetrance
Most males are mosaic for a hemizygous somatic
## Nomenclature
The title of this
"Gorlin-Goltz syndrome" is another name for
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
Poikiloderma; sparse hair, eyelashes, &/or eyebrows/lashes; small stature; skeletal & dental abnormalities; cataracts; & ↑ risk for cancer, esp osteosarcoma
Skin phenotype is similar to
Hyperkeratotic lesions occur in ~1/3 of persons.
Skeletal abnormalities incl dysplasias, absent or malformed bones (e.g., absent radii), osteopenia, & delayed bone formation.
MLS syndrome can have skin & ophthalmologic manifestations similar to
Skin vesicles & scarring in a Blaschko linear pattern are seen in MLS syndrome
MLS syndrome mainly affects females, as it is usually lethal in males.
Alopecia, hypodontia, abnormal tooth shape, & dystrophic nails
Characteristic skin lesions evolve through 4 stages: (I) blistering (birth to age ~4 mos); (II) a wart-like rash (for several months); (III) swirling macular hyperpigmentation (age ~6 mos into adulthood); and (IV) linear hypopigmentation.
Neovascularization of the retina, present in some persons, predisposes to retinal detachment.
Varying combinations of limb malformations (split-hand/foot malformation, syndactyly) & ectodermal findings (skin erosions, hypoplastic breast tissue, hypopigmentation of skin, nail dysplasia, alopecia, dental abnormalities)
Skin manifestations are typically not in a Blaschko distribution & ocular colobomas & microphthalmia are rare.
Affects both males & females
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance;
• Poikiloderma; sparse hair, eyelashes, &/or eyebrows/lashes; small stature; skeletal & dental abnormalities; cataracts; & ↑ risk for cancer, esp osteosarcoma
• Skin phenotype is similar to
• Hyperkeratotic lesions occur in ~1/3 of persons.
• Skeletal abnormalities incl dysplasias, absent or malformed bones (e.g., absent radii), osteopenia, & delayed bone formation.
• MLS syndrome can have skin & ophthalmologic manifestations similar to
• Skin vesicles & scarring in a Blaschko linear pattern are seen in MLS syndrome
• MLS syndrome mainly affects females, as it is usually lethal in males.
• Alopecia, hypodontia, abnormal tooth shape, & dystrophic nails
• Characteristic skin lesions evolve through 4 stages: (I) blistering (birth to age ~4 mos); (II) a wart-like rash (for several months); (III) swirling macular hyperpigmentation (age ~6 mos into adulthood); and (IV) linear hypopigmentation.
• Neovascularization of the retina, present in some persons, predisposes to retinal detachment.
• Varying combinations of limb malformations (split-hand/foot malformation, syndactyly) & ectodermal findings (skin erosions, hypoplastic breast tissue, hypopigmentation of skin, nail dysplasia, alopecia, dental abnormalities)
• Skin manifestations are typically not in a Blaschko distribution & ocular colobomas & microphthalmia are rare.
• Affects both males & females
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with a
Eval by otolaryngologist for evidence of laryngeal or peritonsillar verrucous papillomas, which can cause obstructive sleep apnea
Sleep study to evaluate for obstructive sleep apnea (often due to airway papillomas)
Eval by cleft palate team if relevant
Exam by dentist beginning w/dental eruption
Consider abdominal ultrasound to evaluate for diaphragmatic hernia.
Eval by gastroenterologist if GERD is an issue
Assess feeding & nutrition.
Kidney ultrasound to evaluate for structural anomalies of kidneys & urinary collecting system
Eval by pediatric gynecologist prior to puberty. Imaging studies of reproductive tract should be considered, as anomalies can affect fertility.
Community or
Social work involvement for parental support;
Home nursing referral.
GERD = gastroesophageal reflux disease; MOI = mode of inheritance;
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Airway (hypopharyngeal, tonsillar, & tracheal) papillomas can be managed w/surgery or laser therapy.
Symptomatic papillomas of esophagus can be removed endoscopically
Aesthetic treatment w/colored contact lens to give appearance of round pupil
Tinted glasses for those w/photophobia
Regular dental care & good oral hygiene, diet counseling
Consider fissure sealants to minimize risk of dental caries.
Orthodontic care may be indicated when dental malocclusion is present.
Composite veneers & other aesthetic procedures may be used to improve appearance of abnormal teeth.
Standard treatment per urologist or nephrologist
In persons w/structural kidney malformations, standard treatments to reduce risk for urinary tract infections.
Developmental services (early intervention w/OT, PT, & speech therapy)
Educational support
Eval & mgmt of emotional lability or withdrawn behaviors w/developmental pediatrician
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Monitor for symptoms of GERD & swallowing difficulties.
Monitor for symptoms of obstructive sleep apnea (snoring, gasping, breathing pauses).
GERD = gastroesophageal reflux disease
Because some individuals with severe skin manifestations may have hypohidrosis (and thus be at increased risk for heat intolerance), care should be taken to prevent exposure to extreme heat.
See
For affected women, management of pregnancy should be guided by standard obstetric principles, taking into account potential complications of
Search
• Eval by otolaryngologist for evidence of laryngeal or peritonsillar verrucous papillomas, which can cause obstructive sleep apnea
• Sleep study to evaluate for obstructive sleep apnea (often due to airway papillomas)
• Eval by cleft palate team if relevant
• Exam by dentist beginning w/dental eruption
• Consider abdominal ultrasound to evaluate for diaphragmatic hernia.
• Eval by gastroenterologist if GERD is an issue
• Assess feeding & nutrition.
• Kidney ultrasound to evaluate for structural anomalies of kidneys & urinary collecting system
• Eval by pediatric gynecologist prior to puberty. Imaging studies of reproductive tract should be considered, as anomalies can affect fertility.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Airway (hypopharyngeal, tonsillar, & tracheal) papillomas can be managed w/surgery or laser therapy.
• Symptomatic papillomas of esophagus can be removed endoscopically
• Aesthetic treatment w/colored contact lens to give appearance of round pupil
• Tinted glasses for those w/photophobia
• Regular dental care & good oral hygiene, diet counseling
• Consider fissure sealants to minimize risk of dental caries.
• Orthodontic care may be indicated when dental malocclusion is present.
• Composite veneers & other aesthetic procedures may be used to improve appearance of abnormal teeth.
• Standard treatment per urologist or nephrologist
• In persons w/structural kidney malformations, standard treatments to reduce risk for urinary tract infections.
• Developmental services (early intervention w/OT, PT, & speech therapy)
• Educational support
• Eval & mgmt of emotional lability or withdrawn behaviors w/developmental pediatrician
• Monitor for symptoms of GERD & swallowing difficulties.
• Monitor for symptoms of obstructive sleep apnea (snoring, gasping, breathing pauses).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Eval by otolaryngologist for evidence of laryngeal or peritonsillar verrucous papillomas, which can cause obstructive sleep apnea
Sleep study to evaluate for obstructive sleep apnea (often due to airway papillomas)
Eval by cleft palate team if relevant
Exam by dentist beginning w/dental eruption
Consider abdominal ultrasound to evaluate for diaphragmatic hernia.
Eval by gastroenterologist if GERD is an issue
Assess feeding & nutrition.
Kidney ultrasound to evaluate for structural anomalies of kidneys & urinary collecting system
Eval by pediatric gynecologist prior to puberty. Imaging studies of reproductive tract should be considered, as anomalies can affect fertility.
Community or
Social work involvement for parental support;
Home nursing referral.
GERD = gastroesophageal reflux disease; MOI = mode of inheritance;
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Eval by otolaryngologist for evidence of laryngeal or peritonsillar verrucous papillomas, which can cause obstructive sleep apnea
• Sleep study to evaluate for obstructive sleep apnea (often due to airway papillomas)
• Eval by cleft palate team if relevant
• Exam by dentist beginning w/dental eruption
• Consider abdominal ultrasound to evaluate for diaphragmatic hernia.
• Eval by gastroenterologist if GERD is an issue
• Assess feeding & nutrition.
• Kidney ultrasound to evaluate for structural anomalies of kidneys & urinary collecting system
• Eval by pediatric gynecologist prior to puberty. Imaging studies of reproductive tract should be considered, as anomalies can affect fertility.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Airway (hypopharyngeal, tonsillar, & tracheal) papillomas can be managed w/surgery or laser therapy.
Symptomatic papillomas of esophagus can be removed endoscopically
Aesthetic treatment w/colored contact lens to give appearance of round pupil
Tinted glasses for those w/photophobia
Regular dental care & good oral hygiene, diet counseling
Consider fissure sealants to minimize risk of dental caries.
Orthodontic care may be indicated when dental malocclusion is present.
Composite veneers & other aesthetic procedures may be used to improve appearance of abnormal teeth.
Standard treatment per urologist or nephrologist
In persons w/structural kidney malformations, standard treatments to reduce risk for urinary tract infections.
Developmental services (early intervention w/OT, PT, & speech therapy)
Educational support
Eval & mgmt of emotional lability or withdrawn behaviors w/developmental pediatrician
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
• Airway (hypopharyngeal, tonsillar, & tracheal) papillomas can be managed w/surgery or laser therapy.
• Symptomatic papillomas of esophagus can be removed endoscopically
• Aesthetic treatment w/colored contact lens to give appearance of round pupil
• Tinted glasses for those w/photophobia
• Regular dental care & good oral hygiene, diet counseling
• Consider fissure sealants to minimize risk of dental caries.
• Orthodontic care may be indicated when dental malocclusion is present.
• Composite veneers & other aesthetic procedures may be used to improve appearance of abnormal teeth.
• Standard treatment per urologist or nephrologist
• In persons w/structural kidney malformations, standard treatments to reduce risk for urinary tract infections.
• Developmental services (early intervention w/OT, PT, & speech therapy)
• Educational support
• Eval & mgmt of emotional lability or withdrawn behaviors w/developmental pediatrician
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Monitor for symptoms of GERD & swallowing difficulties.
Monitor for symptoms of obstructive sleep apnea (snoring, gasping, breathing pauses).
GERD = gastroesophageal reflux disease
• Monitor for symptoms of GERD & swallowing difficulties.
• Monitor for symptoms of obstructive sleep apnea (snoring, gasping, breathing pauses).
## Agents/Circumstances to Avoid
Because some individuals with severe skin manifestations may have hypohidrosis (and thus be at increased risk for heat intolerance), care should be taken to prevent exposure to extreme heat.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
For affected women, management of pregnancy should be guided by standard obstetric principles, taking into account potential complications of
## Therapies Under Investigation
Search
## Genetic Counseling
Females account for 90% of individuals with
Approximately 95% of females with a
Approximately 5% of females with a
Female probands with a maternally inherited
Less frequently, an affected female inherited the pathogenic variant from a father mosaic for a
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
* If a proband with a
If the proband has a germline
The proband has a
The proband inherited a pathogenic variant from a mosaic parent (a parent with somatic and germline mosaicism may be apparently asymptomatic or mildly/minimally affected).
Note: Testing parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level somatic mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, should therefore be considered. Testing of parental leukocyte DNA will not detect a pathogenic variant that is present in the germ cells only.
An apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
Live-born affected males are rare, and most affected males have somatic mosaicism for a
If a germline
The father of an affected male will not have the disorder nor will he be hemizygous for the
If the mother of the proband:
Is affected and/or known to be heterozygous for a
Is mosaic for a
Is clinically unaffected and a
Is clinically unaffected but her genetic status is unknown, the risk to sibs is greater than that of the general population because of the possibility of low-level parental mosaicism and the possibility that the mother is heterozygous with favorable skewing of X-chromosome inactivation or heterozygous for a hypomorphic
If the father has the
If a male proband is mosaic for a postzygotic pathogenic variant (most live-born males are mosaic based on evidence from both molecular studies and clinical reports), the mother does not have the
If the mother of the proband has a
At conception, the risk that the
If the proband is mosaic for a
The risk to an affected male of having an affected daughter is as high as 100% depending on the level of mosaicism in his germline. The daughter of a male proband will typically be more severely affected than the male proband [
Males do not transmit their X chromosome to their sons and thus their sons are not at risk of inheriting the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to affected individuals and apparently asymptomatic female family members at risk of having a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Approximately 95% of females with a
• Approximately 5% of females with a
• Female probands with a maternally inherited
• Less frequently, an affected female inherited the pathogenic variant from a father mosaic for a
• Female probands with a maternally inherited
• Less frequently, an affected female inherited the pathogenic variant from a father mosaic for a
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• * If a proband with a
• If the proband has a germline
• The proband has a
• The proband inherited a pathogenic variant from a mosaic parent (a parent with somatic and germline mosaicism may be apparently asymptomatic or mildly/minimally affected).
• Note: Testing parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level somatic mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, should therefore be considered. Testing of parental leukocyte DNA will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a mosaic parent (a parent with somatic and germline mosaicism may be apparently asymptomatic or mildly/minimally affected).
• Note: Testing parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level somatic mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, should therefore be considered. Testing of parental leukocyte DNA will not detect a pathogenic variant that is present in the germ cells only.
• An apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• Female probands with a maternally inherited
• Less frequently, an affected female inherited the pathogenic variant from a father mosaic for a
• The proband has a
• The proband inherited a pathogenic variant from a mosaic parent (a parent with somatic and germline mosaicism may be apparently asymptomatic or mildly/minimally affected).
• Note: Testing parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level somatic mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, should therefore be considered. Testing of parental leukocyte DNA will not detect a pathogenic variant that is present in the germ cells only.
• Live-born affected males are rare, and most affected males have somatic mosaicism for a
• If a germline
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• If the mother of the proband:
• Is affected and/or known to be heterozygous for a
• Is mosaic for a
• Is clinically unaffected and a
• Is clinically unaffected but her genetic status is unknown, the risk to sibs is greater than that of the general population because of the possibility of low-level parental mosaicism and the possibility that the mother is heterozygous with favorable skewing of X-chromosome inactivation or heterozygous for a hypomorphic
• Is affected and/or known to be heterozygous for a
• Is mosaic for a
• Is clinically unaffected and a
• Is clinically unaffected but her genetic status is unknown, the risk to sibs is greater than that of the general population because of the possibility of low-level parental mosaicism and the possibility that the mother is heterozygous with favorable skewing of X-chromosome inactivation or heterozygous for a hypomorphic
• If the father has the
• Is affected and/or known to be heterozygous for a
• Is mosaic for a
• Is clinically unaffected and a
• Is clinically unaffected but her genetic status is unknown, the risk to sibs is greater than that of the general population because of the possibility of low-level parental mosaicism and the possibility that the mother is heterozygous with favorable skewing of X-chromosome inactivation or heterozygous for a hypomorphic
• If a male proband is mosaic for a postzygotic pathogenic variant (most live-born males are mosaic based on evidence from both molecular studies and clinical reports), the mother does not have the
• If the mother of the proband has a
• At conception, the risk that the
• If the proband is mosaic for a
• The risk to an affected male of having an affected daughter is as high as 100% depending on the level of mosaicism in his germline. The daughter of a male proband will typically be more severely affected than the male proband [
• Males do not transmit their X chromosome to their sons and thus their sons are not at risk of inheriting the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to affected individuals and apparently asymptomatic female family members at risk of having a
## Mode of Inheritance
Females account for 90% of individuals with
## Risk to Family Members
Approximately 95% of females with a
Approximately 5% of females with a
Female probands with a maternally inherited
Less frequently, an affected female inherited the pathogenic variant from a father mosaic for a
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
* If a proband with a
If the proband has a germline
The proband has a
The proband inherited a pathogenic variant from a mosaic parent (a parent with somatic and germline mosaicism may be apparently asymptomatic or mildly/minimally affected).
Note: Testing parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level somatic mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, should therefore be considered. Testing of parental leukocyte DNA will not detect a pathogenic variant that is present in the germ cells only.
An apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
Live-born affected males are rare, and most affected males have somatic mosaicism for a
If a germline
The father of an affected male will not have the disorder nor will he be hemizygous for the
If the mother of the proband:
Is affected and/or known to be heterozygous for a
Is mosaic for a
Is clinically unaffected and a
Is clinically unaffected but her genetic status is unknown, the risk to sibs is greater than that of the general population because of the possibility of low-level parental mosaicism and the possibility that the mother is heterozygous with favorable skewing of X-chromosome inactivation or heterozygous for a hypomorphic
If the father has the
If a male proband is mosaic for a postzygotic pathogenic variant (most live-born males are mosaic based on evidence from both molecular studies and clinical reports), the mother does not have the
If the mother of the proband has a
At conception, the risk that the
If the proband is mosaic for a
The risk to an affected male of having an affected daughter is as high as 100% depending on the level of mosaicism in his germline. The daughter of a male proband will typically be more severely affected than the male proband [
Males do not transmit their X chromosome to their sons and thus their sons are not at risk of inheriting the
• Approximately 95% of females with a
• Approximately 5% of females with a
• Female probands with a maternally inherited
• Less frequently, an affected female inherited the pathogenic variant from a father mosaic for a
• Female probands with a maternally inherited
• Less frequently, an affected female inherited the pathogenic variant from a father mosaic for a
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• * If a proband with a
• If the proband has a germline
• The proband has a
• The proband inherited a pathogenic variant from a mosaic parent (a parent with somatic and germline mosaicism may be apparently asymptomatic or mildly/minimally affected).
• Note: Testing parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level somatic mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, should therefore be considered. Testing of parental leukocyte DNA will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a mosaic parent (a parent with somatic and germline mosaicism may be apparently asymptomatic or mildly/minimally affected).
• Note: Testing parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level somatic mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, should therefore be considered. Testing of parental leukocyte DNA will not detect a pathogenic variant that is present in the germ cells only.
• An apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• Female probands with a maternally inherited
• Less frequently, an affected female inherited the pathogenic variant from a father mosaic for a
• The proband has a
• The proband inherited a pathogenic variant from a mosaic parent (a parent with somatic and germline mosaicism may be apparently asymptomatic or mildly/minimally affected).
• Note: Testing parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level somatic mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, should therefore be considered. Testing of parental leukocyte DNA will not detect a pathogenic variant that is present in the germ cells only.
• Live-born affected males are rare, and most affected males have somatic mosaicism for a
• If a germline
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• If the mother of the proband:
• Is affected and/or known to be heterozygous for a
• Is mosaic for a
• Is clinically unaffected and a
• Is clinically unaffected but her genetic status is unknown, the risk to sibs is greater than that of the general population because of the possibility of low-level parental mosaicism and the possibility that the mother is heterozygous with favorable skewing of X-chromosome inactivation or heterozygous for a hypomorphic
• Is affected and/or known to be heterozygous for a
• Is mosaic for a
• Is clinically unaffected and a
• Is clinically unaffected but her genetic status is unknown, the risk to sibs is greater than that of the general population because of the possibility of low-level parental mosaicism and the possibility that the mother is heterozygous with favorable skewing of X-chromosome inactivation or heterozygous for a hypomorphic
• If the father has the
• Is affected and/or known to be heterozygous for a
• Is mosaic for a
• Is clinically unaffected and a
• Is clinically unaffected but her genetic status is unknown, the risk to sibs is greater than that of the general population because of the possibility of low-level parental mosaicism and the possibility that the mother is heterozygous with favorable skewing of X-chromosome inactivation or heterozygous for a hypomorphic
• If a male proband is mosaic for a postzygotic pathogenic variant (most live-born males are mosaic based on evidence from both molecular studies and clinical reports), the mother does not have the
• If the mother of the proband has a
• At conception, the risk that the
• If the proband is mosaic for a
• The risk to an affected male of having an affected daughter is as high as 100% depending on the level of mosaicism in his germline. The daughter of a male proband will typically be more severely affected than the male proband [
• Males do not transmit their X chromosome to their sons and thus their sons are not at risk of inheriting the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to affected individuals and apparently asymptomatic female family members at risk of having a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to affected individuals and apparently asymptomatic female family members at risk of having a
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
PORCN-Related Developmental Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PORCN-Related Developmental Disorders (
Loss of function of orthologs in mouse cells and
## Molecular Pathogenesis
Loss of function of orthologs in mouse cells and
## Chapter Notes
Bret Bostwick, MD; Baylor College of Medicine Houston (2016-2023)Ignatia B Van den Veyver, MD; Baylor College of Medicine Houston (2008-2023)V Reid Sutton, MD (2008-present)
15 June 2023 (sw) Comprehensive update posted live
21 July 2016 (bp) Comprehensive update posted live
11 April 2013 (me) Comprehensive update posted live
15 May 2008 (me) Review posted live
6 February 2008 (vrs) Original submission
• 15 June 2023 (sw) Comprehensive update posted live
• 21 July 2016 (bp) Comprehensive update posted live
• 11 April 2013 (me) Comprehensive update posted live
• 15 May 2008 (me) Review posted live
• 6 February 2008 (vrs) Original submission
## Author Notes
## Author History
Bret Bostwick, MD; Baylor College of Medicine Houston (2016-2023)Ignatia B Van den Veyver, MD; Baylor College of Medicine Houston (2008-2023)V Reid Sutton, MD (2008-present)
## Revision History
15 June 2023 (sw) Comprehensive update posted live
21 July 2016 (bp) Comprehensive update posted live
11 April 2013 (me) Comprehensive update posted live
15 May 2008 (me) Review posted live
6 February 2008 (vrs) Original submission
• 15 June 2023 (sw) Comprehensive update posted live
• 21 July 2016 (bp) Comprehensive update posted live
• 11 April 2013 (me) Comprehensive update posted live
• 15 May 2008 (me) Review posted live
• 6 February 2008 (vrs) Original submission
## References
## Literature Cited
Ectodermal manifestations include yellowish-pink areas representing fat herniation (white arrowheads), patchy aplasia (black arrowheads), hyper- & hypopigmentation following lines of Blaschko (black arrows indicating the border), and hypopigmented areas of poikiloderma (circled regions). The nail phenotype ranges from longitudinal ridging (1) to hypoplastic (2).
Hands showing syndactyly (black arrow) and split-hand malformation (black arrowhead) with only four digits (oligodactyly) on the left hand. The appearance of the left hand has been somewhat modified by partial surgical repair.
Highly variable limb malformations
Feet showing syndactyly (black arrows), split-foot malformation or ectrodactyly (black arrowheads), oligodactyly (3, 6, 7, 8, 10, 11, 12), and distal transverse limb defect (13)
Adapted from
Note facial features of pointed chin and small right ear.
|
[] |
15/5/2008
|
15/6/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
folate-mal
|
folate-mal
|
[
"Congenital Folate Malabsorption",
"Congenital Folate Malabsorption",
"Proton-coupled folate transporter",
"SLC46A1",
"Hereditary Folate Malabsorption"
] |
Hereditary Folate Malabsorption
|
I David Goldman
|
Summary Hereditary folate malabsorption (HFM) is characterized by folate deficiency due to impaired intestinal folate absorption and impaired folate transport into the central nervous system. Findings include poor feeding, failure to thrive, and anemia. There can be leukopenia and thrombocytopenia, diarrhea and/or oral mucositis, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections, most often The diagnosis of HFM is established in a proband with: anemia, impaired absorption of an oral folate load, and very low cerebrospinal fluid (CSF) folate concentration (even after correction of the serum folate concentration); and/or biallelic pathogenic variants in HFM is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
Hereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system.
HFM
Anorexia with poor weight gain and failure to thrive
Diarrhea and/or oral mucositis
Infections with unusual organisms (typically pneumonia caused by
Neurologic manifestations including developmental delays, cognitive and behavioral disorders, motor disorders, and, frequently, seizures
Anemia, typically with macrocytic red cell indices, macrocytosis, and neutrophil hypersegmentation on peripheral smear, associated with low serum folate. Note: Normocytic anemia is possible when there is accompanying poor nutrition and/or iron deficiency.
In ~30% of individuals, thrombocytopenia and/or pancytopenia
Low erythrocyte folate concentration (normal: >200 ng/mL)
Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, the normal level is 10-45 nmol/L to age 12 years or as specified by the laboratory.
After an oral load of 5 mg of folic acid, measurement of serum folate concentration over a minimum of four hours demonstrates little or no increase in affected individuals; in unaffected individuals the serum folate concentration increases to at least 200-3,000 nmol/L [
Low CSF folate concentration even after correction of the serum folate level:
Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
Normal CSF folate levels are higher in infancy and through adolescence (see
Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
Following intramuscular administration of 5 mg of 5-formyltetrahydrofolate (5-formylTHF or leucovorin), the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, the CSF folate concentration remains far below the serum folate concentration in individuals with HFM, a finding consistent with impaired folate transport across the blood-choroid plexus-CSF barrier [
The diagnosis of HFM
With anemia, impaired absorption of an oral folate load, and low serum and CSF folate concentrations (the latter even after correction of the serum folate level);
By the identification of biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
The recommended approach to molecular genetic testing is
Note: Targeted analysis for founder variants can be performed first in individuals of Puerto Rican or Japanese ancestry (see
Molecular Genetic Testing Used in Hereditary Folate Malabsorption
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
One variant found in several individuals of Japanese ancestry was a single-nucleotide deep intron 3 variant that generated a cryptic splice donor site resulting in a 168-bp insertion [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, large intragenic
• Anorexia with poor weight gain and failure to thrive
• Diarrhea and/or oral mucositis
• Infections with unusual organisms (typically pneumonia caused by
• Neurologic manifestations including developmental delays, cognitive and behavioral disorders, motor disorders, and, frequently, seizures
•
• Anemia, typically with macrocytic red cell indices, macrocytosis, and neutrophil hypersegmentation on peripheral smear, associated with low serum folate. Note: Normocytic anemia is possible when there is accompanying poor nutrition and/or iron deficiency.
• In ~30% of individuals, thrombocytopenia and/or pancytopenia
• Anemia, typically with macrocytic red cell indices, macrocytosis, and neutrophil hypersegmentation on peripheral smear, associated with low serum folate. Note: Normocytic anemia is possible when there is accompanying poor nutrition and/or iron deficiency.
• In ~30% of individuals, thrombocytopenia and/or pancytopenia
•
• Low erythrocyte folate concentration (normal: >200 ng/mL)
• Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, the normal level is 10-45 nmol/L to age 12 years or as specified by the laboratory.
• After an oral load of 5 mg of folic acid, measurement of serum folate concentration over a minimum of four hours demonstrates little or no increase in affected individuals; in unaffected individuals the serum folate concentration increases to at least 200-3,000 nmol/L [
• Low erythrocyte folate concentration (normal: >200 ng/mL)
• Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, the normal level is 10-45 nmol/L to age 12 years or as specified by the laboratory.
• After an oral load of 5 mg of folic acid, measurement of serum folate concentration over a minimum of four hours demonstrates little or no increase in affected individuals; in unaffected individuals the serum folate concentration increases to at least 200-3,000 nmol/L [
•
• Low CSF folate concentration even after correction of the serum folate level:
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Following intramuscular administration of 5 mg of 5-formyltetrahydrofolate (5-formylTHF or leucovorin), the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, the CSF folate concentration remains far below the serum folate concentration in individuals with HFM, a finding consistent with impaired folate transport across the blood-choroid plexus-CSF barrier [
• Low CSF folate concentration even after correction of the serum folate level:
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Following intramuscular administration of 5 mg of 5-formyltetrahydrofolate (5-formylTHF or leucovorin), the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, the CSF folate concentration remains far below the serum folate concentration in individuals with HFM, a finding consistent with impaired folate transport across the blood-choroid plexus-CSF barrier [
• Anemia, typically with macrocytic red cell indices, macrocytosis, and neutrophil hypersegmentation on peripheral smear, associated with low serum folate. Note: Normocytic anemia is possible when there is accompanying poor nutrition and/or iron deficiency.
• In ~30% of individuals, thrombocytopenia and/or pancytopenia
• Low erythrocyte folate concentration (normal: >200 ng/mL)
• Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, the normal level is 10-45 nmol/L to age 12 years or as specified by the laboratory.
• After an oral load of 5 mg of folic acid, measurement of serum folate concentration over a minimum of four hours demonstrates little or no increase in affected individuals; in unaffected individuals the serum folate concentration increases to at least 200-3,000 nmol/L [
• Low CSF folate concentration even after correction of the serum folate level:
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Following intramuscular administration of 5 mg of 5-formyltetrahydrofolate (5-formylTHF or leucovorin), the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, the CSF folate concentration remains far below the serum folate concentration in individuals with HFM, a finding consistent with impaired folate transport across the blood-choroid plexus-CSF barrier [
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• With anemia, impaired absorption of an oral folate load, and low serum and CSF folate concentrations (the latter even after correction of the serum folate level);
• By the identification of biallelic pathogenic (or likely pathogenic) variants in
## Suggestive Findings
HFM
Anorexia with poor weight gain and failure to thrive
Diarrhea and/or oral mucositis
Infections with unusual organisms (typically pneumonia caused by
Neurologic manifestations including developmental delays, cognitive and behavioral disorders, motor disorders, and, frequently, seizures
Anemia, typically with macrocytic red cell indices, macrocytosis, and neutrophil hypersegmentation on peripheral smear, associated with low serum folate. Note: Normocytic anemia is possible when there is accompanying poor nutrition and/or iron deficiency.
In ~30% of individuals, thrombocytopenia and/or pancytopenia
Low erythrocyte folate concentration (normal: >200 ng/mL)
Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, the normal level is 10-45 nmol/L to age 12 years or as specified by the laboratory.
After an oral load of 5 mg of folic acid, measurement of serum folate concentration over a minimum of four hours demonstrates little or no increase in affected individuals; in unaffected individuals the serum folate concentration increases to at least 200-3,000 nmol/L [
Low CSF folate concentration even after correction of the serum folate level:
Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
Normal CSF folate levels are higher in infancy and through adolescence (see
Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
Following intramuscular administration of 5 mg of 5-formyltetrahydrofolate (5-formylTHF or leucovorin), the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, the CSF folate concentration remains far below the serum folate concentration in individuals with HFM, a finding consistent with impaired folate transport across the blood-choroid plexus-CSF barrier [
• Anorexia with poor weight gain and failure to thrive
• Diarrhea and/or oral mucositis
• Infections with unusual organisms (typically pneumonia caused by
• Neurologic manifestations including developmental delays, cognitive and behavioral disorders, motor disorders, and, frequently, seizures
•
• Anemia, typically with macrocytic red cell indices, macrocytosis, and neutrophil hypersegmentation on peripheral smear, associated with low serum folate. Note: Normocytic anemia is possible when there is accompanying poor nutrition and/or iron deficiency.
• In ~30% of individuals, thrombocytopenia and/or pancytopenia
• Anemia, typically with macrocytic red cell indices, macrocytosis, and neutrophil hypersegmentation on peripheral smear, associated with low serum folate. Note: Normocytic anemia is possible when there is accompanying poor nutrition and/or iron deficiency.
• In ~30% of individuals, thrombocytopenia and/or pancytopenia
•
• Low erythrocyte folate concentration (normal: >200 ng/mL)
• Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, the normal level is 10-45 nmol/L to age 12 years or as specified by the laboratory.
• After an oral load of 5 mg of folic acid, measurement of serum folate concentration over a minimum of four hours demonstrates little or no increase in affected individuals; in unaffected individuals the serum folate concentration increases to at least 200-3,000 nmol/L [
• Low erythrocyte folate concentration (normal: >200 ng/mL)
• Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, the normal level is 10-45 nmol/L to age 12 years or as specified by the laboratory.
• After an oral load of 5 mg of folic acid, measurement of serum folate concentration over a minimum of four hours demonstrates little or no increase in affected individuals; in unaffected individuals the serum folate concentration increases to at least 200-3,000 nmol/L [
•
• Low CSF folate concentration even after correction of the serum folate level:
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Following intramuscular administration of 5 mg of 5-formyltetrahydrofolate (5-formylTHF or leucovorin), the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, the CSF folate concentration remains far below the serum folate concentration in individuals with HFM, a finding consistent with impaired folate transport across the blood-choroid plexus-CSF barrier [
• Low CSF folate concentration even after correction of the serum folate level:
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Following intramuscular administration of 5 mg of 5-formyltetrahydrofolate (5-formylTHF or leucovorin), the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, the CSF folate concentration remains far below the serum folate concentration in individuals with HFM, a finding consistent with impaired folate transport across the blood-choroid plexus-CSF barrier [
• Anemia, typically with macrocytic red cell indices, macrocytosis, and neutrophil hypersegmentation on peripheral smear, associated with low serum folate. Note: Normocytic anemia is possible when there is accompanying poor nutrition and/or iron deficiency.
• In ~30% of individuals, thrombocytopenia and/or pancytopenia
• Low erythrocyte folate concentration (normal: >200 ng/mL)
• Very low baseline serum folate concentrations in untreated individuals (typically <1.5 nmol/L). In countries in which grains are folate supplemented, the normal level is 10-45 nmol/L to age 12 years or as specified by the laboratory.
• After an oral load of 5 mg of folic acid, measurement of serum folate concentration over a minimum of four hours demonstrates little or no increase in affected individuals; in unaffected individuals the serum folate concentration increases to at least 200-3,000 nmol/L [
• Low CSF folate concentration even after correction of the serum folate level:
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
• Following intramuscular administration of 5 mg of 5-formyltetrahydrofolate (5-formylTHF or leucovorin), the CSF folate concentration peaks transiently at one to two hours and returns to the baseline value within approximately 24 hours. However, the CSF folate concentration remains far below the serum folate concentration in individuals with HFM, a finding consistent with impaired folate transport across the blood-choroid plexus-CSF barrier [
• Baseline CSF folate concentration in untreated affected individuals is typically <1.5 nmol/L.
• Normal CSF folate levels are higher in infancy and through adolescence (see
• Note: In unaffected adults, normal CSF folate levels are 2-3 times the normal serum folate concentration.
## Establishing the Diagnosis
The diagnosis of HFM
With anemia, impaired absorption of an oral folate load, and low serum and CSF folate concentrations (the latter even after correction of the serum folate level);
By the identification of biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
The recommended approach to molecular genetic testing is
Note: Targeted analysis for founder variants can be performed first in individuals of Puerto Rican or Japanese ancestry (see
Molecular Genetic Testing Used in Hereditary Folate Malabsorption
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
One variant found in several individuals of Japanese ancestry was a single-nucleotide deep intron 3 variant that generated a cryptic splice donor site resulting in a 168-bp insertion [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, large intragenic
• With anemia, impaired absorption of an oral folate load, and low serum and CSF folate concentrations (the latter even after correction of the serum folate level);
• By the identification of biallelic pathogenic (or likely pathogenic) variants in
## Clinical Characteristics
Hereditary folate malabsorption (HFM) is characterized by (1) impaired intestinal absorption of folates causing systemic folate deficiency and (2) impaired transport of folates across the blood-choroid plexus-cerebrospinal fluid (CSF) barrier, resulting in central nervous system folate deficiency. Infants with HFM may be born with adequate stores of folate but subsequently are unable to absorb folate from breast milk or formula and thus rapidly become folate deficient. Low serum and CSF folate concentrations are documented prior to the onset of clinical signs within one month after birth. One infant presented with pancytopenia (macrocytic) and pneumonia at age one month [
Because of the rarity of HFM, genotype-phenotype correlations have not as yet been established. Anecdotally, a benign clinical phenotype was seen in an individual (now age 41 years) with homozygous
Fifty-three individuals with HFM (44 with genotypic confirmation) have been reported from 45 families. Another six affected individuals are known to the author [
Three carriers of the common Puerto Rican
## Clinical Description
Hereditary folate malabsorption (HFM) is characterized by (1) impaired intestinal absorption of folates causing systemic folate deficiency and (2) impaired transport of folates across the blood-choroid plexus-cerebrospinal fluid (CSF) barrier, resulting in central nervous system folate deficiency. Infants with HFM may be born with adequate stores of folate but subsequently are unable to absorb folate from breast milk or formula and thus rapidly become folate deficient. Low serum and CSF folate concentrations are documented prior to the onset of clinical signs within one month after birth. One infant presented with pancytopenia (macrocytic) and pneumonia at age one month [
## Genotype-Phenotype Correlations
Because of the rarity of HFM, genotype-phenotype correlations have not as yet been established. Anecdotally, a benign clinical phenotype was seen in an individual (now age 41 years) with homozygous
## Prevalence
Fifty-three individuals with HFM (44 with genotypic confirmation) have been reported from 45 families. Another six affected individuals are known to the author [
Three carriers of the common Puerto Rican
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The differential diagnosis of hereditary folate malabsorption (HFM) includes hereditary disorders (see
Vitamin B
Nutritional folate deficiency as a result of inadequate dietary folate
Intestinal disease associated with folate malabsorption
The use of phenytoin for the treatment of seizure disorders
Hereditary Disorders in the Differential Diagnosis of Hereditary Folate Malabsorption
AR = autosomal recessive; CMV = cytomegalovirus; CSF = cerebrospinal fluid; DD = developmental delay; HFM = hereditary folate malabsorption; MOI = mode of inheritance; SCID = severe combined immunodeficiency; XL = X-linked
Note: A variety of
• Vitamin B
• Nutritional folate deficiency as a result of inadequate dietary folate
• Intestinal disease associated with folate malabsorption
• The use of phenytoin for the treatment of seizure disorders
## Management
No clinical practice guidelines for hereditary folate malabsorption (HFM) have been published.
To establish the extent of disease and needs in a child diagnosed with HFM, the evaluations summarized in
Hereditary Folate Malabsorption: Recommended Evaluations Following Initial Diagnosis
Serum & CSF folate concentrations
CSF homocysteine concentration
Eval by metabolic genetic specialist
Assessment by pediatric neurologist to determine baseline neurologic status
Assess for mvmt disorders or seizures.
Formal developmental assessment
Formal cognitive testing
Community or
Social work involvement for parental support;
Home nursing referral.
CBC = complete blood count; CSF = cerebral spinal fluid; HFM = hereditary folate malabsorption; MOI = mode of inheritance
A high CSF homocysteine concentration is the most sensitive indicator of folate deficiency and inadequate CSF folate levels.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
The goal of treatment is to prevent, reverse, or mitigate hematologic, immunologic, and neurologic deficits and to optimize the cognitive development of children with this disorder. Complete reversal of the systemic consequences of folate deficiency is easily achieved. While correction of the neurologic consequences is more difficult, favorable neurologic outcomes are possible when adequate treatment is initiated promptly after birth [
"Folates" refers to a family of B
Based on the current understanding of folate transport and metabolism, the following reduced folates can be used to treat HFM:
5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid or leucovorin, is a racemic, stable form of this folate. Leucovorin is available in oral and intramuscular formulations. There is considerable experience in dosing with this folate form (see
The active, physiologic, isomer of 5-formylTHF is (6S)5-formylTHF (also known as Isovorin
The physiologic folate predominant in blood and tissues, (6S)5-methyltetrahydrofolate or (6S)5-methylTHF, is available commercially as Metafolin
Note: If at all possible, folic acid should be avoided as a treatment of HFM (see
Because HFM is rare, controlled studies to establish optimal treatment have not been possible. The oral dose of 5-formylTHF required to overcome the loss of the proton-coupled folate transporter (PCFT)-mediated intestinal folate absorption appears to vary among individuals. The dose required to obviate the neurologic consequences is much higher than that needed to correct the systemic folate deficiency. The dose should be guided by its effect on trough CSF folate concentrations. The endpoint is CSF folate concentrations as close as possible to the normal range for the affected individual's age.
The reported oral dose of 5-formylTHF associated with a "good" outcome is approximately 150-200 mg daily [
Note: Normal CSF folate is ~100 nmol/L for infants to age two years, decreasing to ~75 nmol/L by age five years and to ~65 nmol/L by age 19 years [
The intramuscular dose required to achieve adequate serum and CSF folate levels is much lower than the oral dose. With intramuscular injections of approximately 1 mg/day of 5-formylTHF, the anemia, immunologic, and gastrointestinal manifestations will fully resolve. However, the endpoint for treatment is based on achieving an adequate CSF folate level to mitigate the neurologic consequences of HFM, which will require much higher folate doses. It would appear that the maximum achievable CSF folate levels are in the range of 40-50 nmol/L [
Hereditary Folate Malabsorption: Supportive Care
On very rare occasions when transfusion is required, administer blood products appropriate to the person's immunologic status (e.g., washed packed red blood cells in those w/IgA deficiency).
Bleeding complications from thrombocytopenia have not been reported.
Folate replacement therapy will rapidly correct immune deficiencies.
The most common infection,
ASM = anti-seizure medication
The following should be monitored periodically to assess the adequacy of treatment, and more frequently following initial diagnosis when treatment is being optimized.
Recommended Surveillance for Individuals with Hereditary Folate Malabsorption
Serum folate concentrations
Trough CSF folate concentration
CSF homocysteine concentrations
Close follow up w/neurologist most frequently during infancy, then childhood, & into adolescence
Changes in neurologic status may warrant re-evaluating CSF folate level.
CBC = complete blood count; CSF = cerebrospinal fluid
Monitoring of the trough CSF folate concentration is critical to assure that the dose of folate is sufficient to achieve CSF folate concentrations as close to normal as possible for the affected individual's age.
A high CSF homocysteine concentration is the most sensitive indicator of folate deficiency and low CSF folate levels.
If possible, folic acid should be avoided as a treatment for HFM. Although folic acid is very stable and inexpensive, and is the most common pharmacologic source of folate, it is not a physiologic folate. Folic acid binds very tightly to folate receptors, which transport the physiologic folate, 5-methylTHF, into cells by an endocytic mechanism [
It is appropriate to evaluate newborn sibs and apparently asymptomatic younger sibs of a proband to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Early treatment will prevent or fully reverse the hematologic, immunologic, and gastrointestinal complications of HFM. Achievement of adequate CSF folate levels can prevent or mitigate the neurologic consequences of HFM and optimize the cognitive development of children with this disorder.
If the pathogenic variants in the family are known, molecular genetic testing of younger at-risk sibs who have not undergone prenatal testing should be performed immediately after birth. Those with biallelic
If the pathogenic variants in the family are not known and genetic testing is not possible, assessment of serum and CSF folate levels and, if warranted, intestinal absorption of folate in at-risk sibs should commence immediately after birth, or as soon as the diagnosis is confirmed in the proband.
See
There is no systematic information on the outcome of pregnancy in women with HFM.
Although PCFT is highly expressed in the placenta [
Women with HFM who wish to become pregnant should increase their dose of 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive. Prenatal vitamins are available containing 5-methylTHF rather than folic acid.
Of note, infants with HFM do not appear to be at an increased risk for malformations (e.g., neural tube defects) typically associated with maternal folate deficiency during pregnancy, assuming that maternal folate intake has been increased well before attempting conception.
Search
• Serum & CSF folate concentrations
• CSF homocysteine concentration
• Eval by metabolic genetic specialist
• Assessment by pediatric neurologist to determine baseline neurologic status
• Assess for mvmt disorders or seizures.
• Formal developmental assessment
• Formal cognitive testing
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• 5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid or leucovorin, is a racemic, stable form of this folate. Leucovorin is available in oral and intramuscular formulations. There is considerable experience in dosing with this folate form (see
• The active, physiologic, isomer of 5-formylTHF is (6S)5-formylTHF (also known as Isovorin
• The physiologic folate predominant in blood and tissues, (6S)5-methyltetrahydrofolate or (6S)5-methylTHF, is available commercially as Metafolin
• The reported oral dose of 5-formylTHF associated with a "good" outcome is approximately 150-200 mg daily [
• Note: Normal CSF folate is ~100 nmol/L for infants to age two years, decreasing to ~75 nmol/L by age five years and to ~65 nmol/L by age 19 years [
• The intramuscular dose required to achieve adequate serum and CSF folate levels is much lower than the oral dose. With intramuscular injections of approximately 1 mg/day of 5-formylTHF, the anemia, immunologic, and gastrointestinal manifestations will fully resolve. However, the endpoint for treatment is based on achieving an adequate CSF folate level to mitigate the neurologic consequences of HFM, which will require much higher folate doses. It would appear that the maximum achievable CSF folate levels are in the range of 40-50 nmol/L [
• On very rare occasions when transfusion is required, administer blood products appropriate to the person's immunologic status (e.g., washed packed red blood cells in those w/IgA deficiency).
• Bleeding complications from thrombocytopenia have not been reported.
• Folate replacement therapy will rapidly correct immune deficiencies.
• The most common infection,
• Serum folate concentrations
• Trough CSF folate concentration
• CSF homocysteine concentrations
• Close follow up w/neurologist most frequently during infancy, then childhood, & into adolescence
• Changes in neurologic status may warrant re-evaluating CSF folate level.
• If the pathogenic variants in the family are known, molecular genetic testing of younger at-risk sibs who have not undergone prenatal testing should be performed immediately after birth. Those with biallelic
• If the pathogenic variants in the family are not known and genetic testing is not possible, assessment of serum and CSF folate levels and, if warranted, intestinal absorption of folate in at-risk sibs should commence immediately after birth, or as soon as the diagnosis is confirmed in the proband.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in a child diagnosed with HFM, the evaluations summarized in
Hereditary Folate Malabsorption: Recommended Evaluations Following Initial Diagnosis
Serum & CSF folate concentrations
CSF homocysteine concentration
Eval by metabolic genetic specialist
Assessment by pediatric neurologist to determine baseline neurologic status
Assess for mvmt disorders or seizures.
Formal developmental assessment
Formal cognitive testing
Community or
Social work involvement for parental support;
Home nursing referral.
CBC = complete blood count; CSF = cerebral spinal fluid; HFM = hereditary folate malabsorption; MOI = mode of inheritance
A high CSF homocysteine concentration is the most sensitive indicator of folate deficiency and inadequate CSF folate levels.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Serum & CSF folate concentrations
• CSF homocysteine concentration
• Eval by metabolic genetic specialist
• Assessment by pediatric neurologist to determine baseline neurologic status
• Assess for mvmt disorders or seizures.
• Formal developmental assessment
• Formal cognitive testing
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
The goal of treatment is to prevent, reverse, or mitigate hematologic, immunologic, and neurologic deficits and to optimize the cognitive development of children with this disorder. Complete reversal of the systemic consequences of folate deficiency is easily achieved. While correction of the neurologic consequences is more difficult, favorable neurologic outcomes are possible when adequate treatment is initiated promptly after birth [
"Folates" refers to a family of B
Based on the current understanding of folate transport and metabolism, the following reduced folates can be used to treat HFM:
5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid or leucovorin, is a racemic, stable form of this folate. Leucovorin is available in oral and intramuscular formulations. There is considerable experience in dosing with this folate form (see
The active, physiologic, isomer of 5-formylTHF is (6S)5-formylTHF (also known as Isovorin
The physiologic folate predominant in blood and tissues, (6S)5-methyltetrahydrofolate or (6S)5-methylTHF, is available commercially as Metafolin
Note: If at all possible, folic acid should be avoided as a treatment of HFM (see
Because HFM is rare, controlled studies to establish optimal treatment have not been possible. The oral dose of 5-formylTHF required to overcome the loss of the proton-coupled folate transporter (PCFT)-mediated intestinal folate absorption appears to vary among individuals. The dose required to obviate the neurologic consequences is much higher than that needed to correct the systemic folate deficiency. The dose should be guided by its effect on trough CSF folate concentrations. The endpoint is CSF folate concentrations as close as possible to the normal range for the affected individual's age.
The reported oral dose of 5-formylTHF associated with a "good" outcome is approximately 150-200 mg daily [
Note: Normal CSF folate is ~100 nmol/L for infants to age two years, decreasing to ~75 nmol/L by age five years and to ~65 nmol/L by age 19 years [
The intramuscular dose required to achieve adequate serum and CSF folate levels is much lower than the oral dose. With intramuscular injections of approximately 1 mg/day of 5-formylTHF, the anemia, immunologic, and gastrointestinal manifestations will fully resolve. However, the endpoint for treatment is based on achieving an adequate CSF folate level to mitigate the neurologic consequences of HFM, which will require much higher folate doses. It would appear that the maximum achievable CSF folate levels are in the range of 40-50 nmol/L [
Hereditary Folate Malabsorption: Supportive Care
On very rare occasions when transfusion is required, administer blood products appropriate to the person's immunologic status (e.g., washed packed red blood cells in those w/IgA deficiency).
Bleeding complications from thrombocytopenia have not been reported.
Folate replacement therapy will rapidly correct immune deficiencies.
The most common infection,
ASM = anti-seizure medication
• 5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid or leucovorin, is a racemic, stable form of this folate. Leucovorin is available in oral and intramuscular formulations. There is considerable experience in dosing with this folate form (see
• The active, physiologic, isomer of 5-formylTHF is (6S)5-formylTHF (also known as Isovorin
• The physiologic folate predominant in blood and tissues, (6S)5-methyltetrahydrofolate or (6S)5-methylTHF, is available commercially as Metafolin
• The reported oral dose of 5-formylTHF associated with a "good" outcome is approximately 150-200 mg daily [
• Note: Normal CSF folate is ~100 nmol/L for infants to age two years, decreasing to ~75 nmol/L by age five years and to ~65 nmol/L by age 19 years [
• The intramuscular dose required to achieve adequate serum and CSF folate levels is much lower than the oral dose. With intramuscular injections of approximately 1 mg/day of 5-formylTHF, the anemia, immunologic, and gastrointestinal manifestations will fully resolve. However, the endpoint for treatment is based on achieving an adequate CSF folate level to mitigate the neurologic consequences of HFM, which will require much higher folate doses. It would appear that the maximum achievable CSF folate levels are in the range of 40-50 nmol/L [
• On very rare occasions when transfusion is required, administer blood products appropriate to the person's immunologic status (e.g., washed packed red blood cells in those w/IgA deficiency).
• Bleeding complications from thrombocytopenia have not been reported.
• Folate replacement therapy will rapidly correct immune deficiencies.
• The most common infection,
## Targeted Therapy
The goal of treatment is to prevent, reverse, or mitigate hematologic, immunologic, and neurologic deficits and to optimize the cognitive development of children with this disorder. Complete reversal of the systemic consequences of folate deficiency is easily achieved. While correction of the neurologic consequences is more difficult, favorable neurologic outcomes are possible when adequate treatment is initiated promptly after birth [
"Folates" refers to a family of B
Based on the current understanding of folate transport and metabolism, the following reduced folates can be used to treat HFM:
5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid or leucovorin, is a racemic, stable form of this folate. Leucovorin is available in oral and intramuscular formulations. There is considerable experience in dosing with this folate form (see
The active, physiologic, isomer of 5-formylTHF is (6S)5-formylTHF (also known as Isovorin
The physiologic folate predominant in blood and tissues, (6S)5-methyltetrahydrofolate or (6S)5-methylTHF, is available commercially as Metafolin
Note: If at all possible, folic acid should be avoided as a treatment of HFM (see
Because HFM is rare, controlled studies to establish optimal treatment have not been possible. The oral dose of 5-formylTHF required to overcome the loss of the proton-coupled folate transporter (PCFT)-mediated intestinal folate absorption appears to vary among individuals. The dose required to obviate the neurologic consequences is much higher than that needed to correct the systemic folate deficiency. The dose should be guided by its effect on trough CSF folate concentrations. The endpoint is CSF folate concentrations as close as possible to the normal range for the affected individual's age.
The reported oral dose of 5-formylTHF associated with a "good" outcome is approximately 150-200 mg daily [
Note: Normal CSF folate is ~100 nmol/L for infants to age two years, decreasing to ~75 nmol/L by age five years and to ~65 nmol/L by age 19 years [
The intramuscular dose required to achieve adequate serum and CSF folate levels is much lower than the oral dose. With intramuscular injections of approximately 1 mg/day of 5-formylTHF, the anemia, immunologic, and gastrointestinal manifestations will fully resolve. However, the endpoint for treatment is based on achieving an adequate CSF folate level to mitigate the neurologic consequences of HFM, which will require much higher folate doses. It would appear that the maximum achievable CSF folate levels are in the range of 40-50 nmol/L [
• 5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid or leucovorin, is a racemic, stable form of this folate. Leucovorin is available in oral and intramuscular formulations. There is considerable experience in dosing with this folate form (see
• The active, physiologic, isomer of 5-formylTHF is (6S)5-formylTHF (also known as Isovorin
• The physiologic folate predominant in blood and tissues, (6S)5-methyltetrahydrofolate or (6S)5-methylTHF, is available commercially as Metafolin
• The reported oral dose of 5-formylTHF associated with a "good" outcome is approximately 150-200 mg daily [
• Note: Normal CSF folate is ~100 nmol/L for infants to age two years, decreasing to ~75 nmol/L by age five years and to ~65 nmol/L by age 19 years [
• The intramuscular dose required to achieve adequate serum and CSF folate levels is much lower than the oral dose. With intramuscular injections of approximately 1 mg/day of 5-formylTHF, the anemia, immunologic, and gastrointestinal manifestations will fully resolve. However, the endpoint for treatment is based on achieving an adequate CSF folate level to mitigate the neurologic consequences of HFM, which will require much higher folate doses. It would appear that the maximum achievable CSF folate levels are in the range of 40-50 nmol/L [
##
Based on the current understanding of folate transport and metabolism, the following reduced folates can be used to treat HFM:
5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid or leucovorin, is a racemic, stable form of this folate. Leucovorin is available in oral and intramuscular formulations. There is considerable experience in dosing with this folate form (see
The active, physiologic, isomer of 5-formylTHF is (6S)5-formylTHF (also known as Isovorin
The physiologic folate predominant in blood and tissues, (6S)5-methyltetrahydrofolate or (6S)5-methylTHF, is available commercially as Metafolin
Note: If at all possible, folic acid should be avoided as a treatment of HFM (see
• 5-formyltetrahydrofolate (5-formylTHF), also known as folinic acid or leucovorin, is a racemic, stable form of this folate. Leucovorin is available in oral and intramuscular formulations. There is considerable experience in dosing with this folate form (see
• The active, physiologic, isomer of 5-formylTHF is (6S)5-formylTHF (also known as Isovorin
• The physiologic folate predominant in blood and tissues, (6S)5-methyltetrahydrofolate or (6S)5-methylTHF, is available commercially as Metafolin
##
Because HFM is rare, controlled studies to establish optimal treatment have not been possible. The oral dose of 5-formylTHF required to overcome the loss of the proton-coupled folate transporter (PCFT)-mediated intestinal folate absorption appears to vary among individuals. The dose required to obviate the neurologic consequences is much higher than that needed to correct the systemic folate deficiency. The dose should be guided by its effect on trough CSF folate concentrations. The endpoint is CSF folate concentrations as close as possible to the normal range for the affected individual's age.
The reported oral dose of 5-formylTHF associated with a "good" outcome is approximately 150-200 mg daily [
Note: Normal CSF folate is ~100 nmol/L for infants to age two years, decreasing to ~75 nmol/L by age five years and to ~65 nmol/L by age 19 years [
The intramuscular dose required to achieve adequate serum and CSF folate levels is much lower than the oral dose. With intramuscular injections of approximately 1 mg/day of 5-formylTHF, the anemia, immunologic, and gastrointestinal manifestations will fully resolve. However, the endpoint for treatment is based on achieving an adequate CSF folate level to mitigate the neurologic consequences of HFM, which will require much higher folate doses. It would appear that the maximum achievable CSF folate levels are in the range of 40-50 nmol/L [
• The reported oral dose of 5-formylTHF associated with a "good" outcome is approximately 150-200 mg daily [
• Note: Normal CSF folate is ~100 nmol/L for infants to age two years, decreasing to ~75 nmol/L by age five years and to ~65 nmol/L by age 19 years [
• The intramuscular dose required to achieve adequate serum and CSF folate levels is much lower than the oral dose. With intramuscular injections of approximately 1 mg/day of 5-formylTHF, the anemia, immunologic, and gastrointestinal manifestations will fully resolve. However, the endpoint for treatment is based on achieving an adequate CSF folate level to mitigate the neurologic consequences of HFM, which will require much higher folate doses. It would appear that the maximum achievable CSF folate levels are in the range of 40-50 nmol/L [
## Supportive Care
Hereditary Folate Malabsorption: Supportive Care
On very rare occasions when transfusion is required, administer blood products appropriate to the person's immunologic status (e.g., washed packed red blood cells in those w/IgA deficiency).
Bleeding complications from thrombocytopenia have not been reported.
Folate replacement therapy will rapidly correct immune deficiencies.
The most common infection,
ASM = anti-seizure medication
• On very rare occasions when transfusion is required, administer blood products appropriate to the person's immunologic status (e.g., washed packed red blood cells in those w/IgA deficiency).
• Bleeding complications from thrombocytopenia have not been reported.
• Folate replacement therapy will rapidly correct immune deficiencies.
• The most common infection,
## Surveillance
The following should be monitored periodically to assess the adequacy of treatment, and more frequently following initial diagnosis when treatment is being optimized.
Recommended Surveillance for Individuals with Hereditary Folate Malabsorption
Serum folate concentrations
Trough CSF folate concentration
CSF homocysteine concentrations
Close follow up w/neurologist most frequently during infancy, then childhood, & into adolescence
Changes in neurologic status may warrant re-evaluating CSF folate level.
CBC = complete blood count; CSF = cerebrospinal fluid
Monitoring of the trough CSF folate concentration is critical to assure that the dose of folate is sufficient to achieve CSF folate concentrations as close to normal as possible for the affected individual's age.
A high CSF homocysteine concentration is the most sensitive indicator of folate deficiency and low CSF folate levels.
• Serum folate concentrations
• Trough CSF folate concentration
• CSF homocysteine concentrations
• Close follow up w/neurologist most frequently during infancy, then childhood, & into adolescence
• Changes in neurologic status may warrant re-evaluating CSF folate level.
## Agents/Circumstances to Avoid
If possible, folic acid should be avoided as a treatment for HFM. Although folic acid is very stable and inexpensive, and is the most common pharmacologic source of folate, it is not a physiologic folate. Folic acid binds very tightly to folate receptors, which transport the physiologic folate, 5-methylTHF, into cells by an endocytic mechanism [
## Evaluation of Relatives at Risk
It is appropriate to evaluate newborn sibs and apparently asymptomatic younger sibs of a proband to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Early treatment will prevent or fully reverse the hematologic, immunologic, and gastrointestinal complications of HFM. Achievement of adequate CSF folate levels can prevent or mitigate the neurologic consequences of HFM and optimize the cognitive development of children with this disorder.
If the pathogenic variants in the family are known, molecular genetic testing of younger at-risk sibs who have not undergone prenatal testing should be performed immediately after birth. Those with biallelic
If the pathogenic variants in the family are not known and genetic testing is not possible, assessment of serum and CSF folate levels and, if warranted, intestinal absorption of folate in at-risk sibs should commence immediately after birth, or as soon as the diagnosis is confirmed in the proband.
See
• If the pathogenic variants in the family are known, molecular genetic testing of younger at-risk sibs who have not undergone prenatal testing should be performed immediately after birth. Those with biallelic
• If the pathogenic variants in the family are not known and genetic testing is not possible, assessment of serum and CSF folate levels and, if warranted, intestinal absorption of folate in at-risk sibs should commence immediately after birth, or as soon as the diagnosis is confirmed in the proband.
## Pregnancy Management
There is no systematic information on the outcome of pregnancy in women with HFM.
Although PCFT is highly expressed in the placenta [
Women with HFM who wish to become pregnant should increase their dose of 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive. Prenatal vitamins are available containing 5-methylTHF rather than folic acid.
Of note, infants with HFM do not appear to be at an increased risk for malformations (e.g., neural tube defects) typically associated with maternal folate deficiency during pregnancy, assuming that maternal folate intake has been increased well before attempting conception.
## Therapies Under Investigation
Search
## Genetic Counseling
Hereditary folate malabsorption (HFM) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin.
Carrier testing of at-risk relatives requires prior identification of the
See Management,
Women with HFM who wish to become pregnant should increase their dose of 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive (see
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin.
• Women with HFM who wish to become pregnant should increase their dose of 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Hereditary folate malabsorption (HFM) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and do not have clinically apparent evidence of folate deficiency. It is unclear at this time whether heterozygotes may have a mild decrease in serum folate and hemoglobin.
## Carrier Detection
Carrier testing of at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
Women with HFM who wish to become pregnant should increase their dose of 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive (see
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Women with HFM who wish to become pregnant should increase their dose of 5-formylTHF intake above the maintenance dose well in advance of attempting to conceive (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
Hereditary Folate Malabsorption: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hereditary Folate Malabsorption (
Hydropathy analysis by the substituted cysteine accessibility model predicted a protein with twelve transmembrane domains [
Single-nucleotide variants within transmembrane domains, causing amino acid substitutions, result in unstable proteins, proteins with markedly impaired function, or complete loss of protein. Some of the mutated proteins trafficked to the cell membrane and some did not. Three mutated isoforms had residual transport activity upon transfection into HeLa cells null for constitutive folate-specific transporters [
Notable
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
Hydropathy analysis by the substituted cysteine accessibility model predicted a protein with twelve transmembrane domains [
Single-nucleotide variants within transmembrane domains, causing amino acid substitutions, result in unstable proteins, proteins with markedly impaired function, or complete loss of protein. Some of the mutated proteins trafficked to the cell membrane and some did not. Three mutated isoforms had residual transport activity upon transfection into HeLa cells null for constitutive folate-specific transporters [
Notable
Variants listed in the table have been provided by the author.
## Chapter Notes
Ndeye Diop-Bove, PhD; Albert Einstein College of Medicine (2010-2017)I David Goldman, MD (2008-present)David Kronn, MD; New York Medical College (2008-2022)Kris M Mahadeo, MD, MPH; Albert Einstein College of Medicine (2010-2011)Sang Hee Min, MD; Albert Einstein College of Medicine (2008-2011)Claudio Sandoval, MD; New York Medical College (2008-2010)
15 February 2024 (cm) Revision: Treatment of Manifestations section revised to include
5 May 2022 (sw) Comprehensive update posted live
27 April 2017 (ma) Comprehensive update posted live
5 June 2014 (me) Comprehensive update posted live
8 December 2011 (me) Comprehensive update posted live
6 May 2010 (me) Comprehensive update posted live
17 June 2008 (me) Review posted live
4 March 2008 (idg) Initial submission
• 15 February 2024 (cm) Revision: Treatment of Manifestations section revised to include
• 5 May 2022 (sw) Comprehensive update posted live
• 27 April 2017 (ma) Comprehensive update posted live
• 5 June 2014 (me) Comprehensive update posted live
• 8 December 2011 (me) Comprehensive update posted live
• 6 May 2010 (me) Comprehensive update posted live
• 17 June 2008 (me) Review posted live
• 4 March 2008 (idg) Initial submission
## Author History
Ndeye Diop-Bove, PhD; Albert Einstein College of Medicine (2010-2017)I David Goldman, MD (2008-present)David Kronn, MD; New York Medical College (2008-2022)Kris M Mahadeo, MD, MPH; Albert Einstein College of Medicine (2010-2011)Sang Hee Min, MD; Albert Einstein College of Medicine (2008-2011)Claudio Sandoval, MD; New York Medical College (2008-2010)
## Revision History
15 February 2024 (cm) Revision: Treatment of Manifestations section revised to include
5 May 2022 (sw) Comprehensive update posted live
27 April 2017 (ma) Comprehensive update posted live
5 June 2014 (me) Comprehensive update posted live
8 December 2011 (me) Comprehensive update posted live
6 May 2010 (me) Comprehensive update posted live
17 June 2008 (me) Review posted live
4 March 2008 (idg) Initial submission
• 15 February 2024 (cm) Revision: Treatment of Manifestations section revised to include
• 5 May 2022 (sw) Comprehensive update posted live
• 27 April 2017 (ma) Comprehensive update posted live
• 5 June 2014 (me) Comprehensive update posted live
• 8 December 2011 (me) Comprehensive update posted live
• 6 May 2010 (me) Comprehensive update posted live
• 17 June 2008 (me) Review posted live
• 4 March 2008 (idg) Initial submission
## Key Sections in this
## References
## Literature Cited
|
[] |
17/6/2008
|
5/5/2022
|
15/2/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
folr1-cft-def
|
folr1-cft-def
|
[
"Folate Receptor-Alpha Deficiency",
"FOLR1 Deficiency",
"FOLRα Deficiency",
"FRα Deficiency",
"Folate Receptor-Alpha Deficiency",
"FOLR1 Deficiency",
"FOLRa Deficiency",
"FRa Deficiency",
"Folate receptor alpha",
"FOLR1",
"FOLR1-Related Cerebral Folate Transport Deficiency"
] |
I David Goldman
|
Summary Treatment with 5-formyltetrahydrofolate (5-formylTHF; also known as folinic acid or leucovorin) can result in substantial improvement in neurologic findings when started at a young age. Treatment of asymptomatic or mildly symptomatic younger sibs at the time of diagnosis of their older sibs can either prevent the neurologic signs of this disorder or result in marked or complete regression of the neurologic findings. The diagnosis of
|
## Diagnosis
Developmental delays, particularly in cognition, speech, and gait
Developmental delays in motor, cognitive, speech, and language
Movement disorders, including ocular (nystagmus, strabismus), hypotonia, abnormalities of gait, ataxia, tremors, and myoclonic jerks
Seizures, typically myoclonic or tonic. Can be severe with status epilepticus. Initial seizures may be associated with fever.
Behavior issues that can include autistic spectrum disorder
Very low concentration of cerebral spinal fluid (CSF) 5-methyltetrahydrofolate (5-methylTHF) (typically ≤10 nmol/L [
Normal plasma and red blood cell folate levels, indicating the absence of folate deficiency due to inadequate dietary intake or impaired intestinal absorption
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. While exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth, sensitivity can be lower using these methods than using gene-targeted deletion/duplication analysis.
One intronic variant outside of the exon and the consensus splice junction typically identified by standard sequencing has been reported [
•
• Developmental delays, particularly in cognition, speech, and gait
• Developmental delays, particularly in cognition, speech, and gait
•
• Developmental delays in motor, cognitive, speech, and language
• Movement disorders, including ocular (nystagmus, strabismus), hypotonia, abnormalities of gait, ataxia, tremors, and myoclonic jerks
• Seizures, typically myoclonic or tonic. Can be severe with status epilepticus. Initial seizures may be associated with fever.
• Behavior issues that can include autistic spectrum disorder
• Developmental delays in motor, cognitive, speech, and language
• Movement disorders, including ocular (nystagmus, strabismus), hypotonia, abnormalities of gait, ataxia, tremors, and myoclonic jerks
• Seizures, typically myoclonic or tonic. Can be severe with status epilepticus. Initial seizures may be associated with fever.
• Behavior issues that can include autistic spectrum disorder
• Developmental delays, particularly in cognition, speech, and gait
• Developmental delays in motor, cognitive, speech, and language
• Movement disorders, including ocular (nystagmus, strabismus), hypotonia, abnormalities of gait, ataxia, tremors, and myoclonic jerks
• Seizures, typically myoclonic or tonic. Can be severe with status epilepticus. Initial seizures may be associated with fever.
• Behavior issues that can include autistic spectrum disorder
• Very low concentration of cerebral spinal fluid (CSF) 5-methyltetrahydrofolate (5-methylTHF) (typically ≤10 nmol/L [
• Normal plasma and red blood cell folate levels, indicating the absence of folate deficiency due to inadequate dietary intake or impaired intestinal absorption
## Suggestive Findings
Developmental delays, particularly in cognition, speech, and gait
Developmental delays in motor, cognitive, speech, and language
Movement disorders, including ocular (nystagmus, strabismus), hypotonia, abnormalities of gait, ataxia, tremors, and myoclonic jerks
Seizures, typically myoclonic or tonic. Can be severe with status epilepticus. Initial seizures may be associated with fever.
Behavior issues that can include autistic spectrum disorder
Very low concentration of cerebral spinal fluid (CSF) 5-methyltetrahydrofolate (5-methylTHF) (typically ≤10 nmol/L [
Normal plasma and red blood cell folate levels, indicating the absence of folate deficiency due to inadequate dietary intake or impaired intestinal absorption
•
• Developmental delays, particularly in cognition, speech, and gait
• Developmental delays, particularly in cognition, speech, and gait
•
• Developmental delays in motor, cognitive, speech, and language
• Movement disorders, including ocular (nystagmus, strabismus), hypotonia, abnormalities of gait, ataxia, tremors, and myoclonic jerks
• Seizures, typically myoclonic or tonic. Can be severe with status epilepticus. Initial seizures may be associated with fever.
• Behavior issues that can include autistic spectrum disorder
• Developmental delays in motor, cognitive, speech, and language
• Movement disorders, including ocular (nystagmus, strabismus), hypotonia, abnormalities of gait, ataxia, tremors, and myoclonic jerks
• Seizures, typically myoclonic or tonic. Can be severe with status epilepticus. Initial seizures may be associated with fever.
• Behavior issues that can include autistic spectrum disorder
• Developmental delays, particularly in cognition, speech, and gait
• Developmental delays in motor, cognitive, speech, and language
• Movement disorders, including ocular (nystagmus, strabismus), hypotonia, abnormalities of gait, ataxia, tremors, and myoclonic jerks
• Seizures, typically myoclonic or tonic. Can be severe with status epilepticus. Initial seizures may be associated with fever.
• Behavior issues that can include autistic spectrum disorder
• Very low concentration of cerebral spinal fluid (CSF) 5-methyltetrahydrofolate (5-methylTHF) (typically ≤10 nmol/L [
• Normal plasma and red blood cell folate levels, indicating the absence of folate deficiency due to inadequate dietary intake or impaired intestinal absorption
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. While exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth, sensitivity can be lower using these methods than using gene-targeted deletion/duplication analysis.
One intronic variant outside of the exon and the consensus splice junction typically identified by standard sequencing has been reported [
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. While exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth, sensitivity can be lower using these methods than using gene-targeted deletion/duplication analysis.
One intronic variant outside of the exon and the consensus splice junction typically identified by standard sequencing has been reported [
## Clinical Characteristics
Individuals with untreated
Reports describe the consequences of untreated
The early clinical signs in untreated children with
In a child who has not been treated with 5-formylTHF, neurologic findings worsen over time, resulting in developmental regression and onset of ataxia, tremors, and hypotonia. Subsequently, untreated children have severe cognitive decline, become increasingly immobile, and develop seizures that are difficult to treat with conventional anti-seizure medications. In addition to these findings, "drop" attacks provoked by specific movements (e.g., washing face or hands) have been reported [
Despite these incapacitating severe neurologic findings, untreated individuals can live well into adulthood.
Following initiation of treatment with 5-formylTHF (see Management,
Although limited, data are available regarding younger sibs who were diagnosed with
No clinically relevant genotype-phenotype correlations are known.
Although there is a spectrum of clinical presentations and severity associated with
Cerebral folate deficiency is a generic term describing a condition in which there is a reduction in the concentration of folate in the CSF with otherwise normal folate homeostasis. The term "
It is likely that the prevalence is greater than currently appreciated given the nonspecific signs and symptoms of untreated
To date only five families have been reported in which affected individuals were compound heterozygous for
Five Finnish individuals were reported with the same
Two individuals from different cities in Germany were reported with the same compound heterozygous pathogenic variants,
Individuals from Turkey [
• Five Finnish individuals were reported with the same
• Two individuals from different cities in Germany were reported with the same compound heterozygous pathogenic variants,
• Individuals from Turkey [
## Clinical Description
Individuals with untreated
Reports describe the consequences of untreated
The early clinical signs in untreated children with
In a child who has not been treated with 5-formylTHF, neurologic findings worsen over time, resulting in developmental regression and onset of ataxia, tremors, and hypotonia. Subsequently, untreated children have severe cognitive decline, become increasingly immobile, and develop seizures that are difficult to treat with conventional anti-seizure medications. In addition to these findings, "drop" attacks provoked by specific movements (e.g., washing face or hands) have been reported [
Despite these incapacitating severe neurologic findings, untreated individuals can live well into adulthood.
Following initiation of treatment with 5-formylTHF (see Management,
Although limited, data are available regarding younger sibs who were diagnosed with
## Untreated Individuals
Reports describe the consequences of untreated
The early clinical signs in untreated children with
In a child who has not been treated with 5-formylTHF, neurologic findings worsen over time, resulting in developmental regression and onset of ataxia, tremors, and hypotonia. Subsequently, untreated children have severe cognitive decline, become increasingly immobile, and develop seizures that are difficult to treat with conventional anti-seizure medications. In addition to these findings, "drop" attacks provoked by specific movements (e.g., washing face or hands) have been reported [
Despite these incapacitating severe neurologic findings, untreated individuals can live well into adulthood.
Following initiation of treatment with 5-formylTHF (see Management,
## Treated Individuals
Although limited, data are available regarding younger sibs who were diagnosed with
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations are known.
Although there is a spectrum of clinical presentations and severity associated with
## Nomenclature
Cerebral folate deficiency is a generic term describing a condition in which there is a reduction in the concentration of folate in the CSF with otherwise normal folate homeostasis. The term "
## Prevalence
It is likely that the prevalence is greater than currently appreciated given the nonspecific signs and symptoms of untreated
To date only five families have been reported in which affected individuals were compound heterozygous for
Five Finnish individuals were reported with the same
Two individuals from different cities in Germany were reported with the same compound heterozygous pathogenic variants,
Individuals from Turkey [
• Five Finnish individuals were reported with the same
• Two individuals from different cities in Germany were reported with the same compound heterozygous pathogenic variants,
• Individuals from Turkey [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Recent reviews that include a comprehensive description of the differential diagnosis of cerebral folate deficiency are
Loss of function of the proton-coupled folate transporter (PCFT) protein (encoded by
Loss of function of FOLR1 (encoded by
Hereditary Disorders in the Differential Diagnosis of
No response to folic acid
Corrects w/5-formylTHF
Can occur w/isolated macrocytosis w/o anemia
Defect in remethylation of homocysteine to methionine
Plasma folate is low but not accompanied by anemia.
Treated w/betaine
Defect in 5-formylTHF metabolism
Treated w/5-methylTHF
5-formylTHF = 5-formyltetrahydrofolate; 5-methylTHF = 5-methyltetrahydrofolate; AR = autosomal recessive; CSF = cerebral spinal fluid; DD = developmental delay; MOI = mode of inheritance
• Loss of function of the proton-coupled folate transporter (PCFT) protein (encoded by
• Loss of function of FOLR1 (encoded by
• No response to folic acid
• Corrects w/5-formylTHF
• Can occur w/isolated macrocytosis w/o anemia
• Defect in remethylation of homocysteine to methionine
• Plasma folate is low but not accompanied by anemia.
• Treated w/betaine
• Defect in 5-formylTHF metabolism
• Treated w/5-methylTHF
## Management
There are no established clinical practice guidelines for
To establish the extent of the disorder and needs in an individual diagnosed with previously untreated
Eval of seizures: type, frequency
Assessment of gait
Assessment for hypotonia, tremor, strabismus, nystagmus
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living;
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
In symptomatic individuals, movement disorders, behavior issues, and developmental delay / intellectual disability may improve with 5-formylTHF treatment depending on the age of the individual and severity of the neurologic deficits. Rarely, seizures may cease completely with 5-formylTHF treatment. Clinical improvement has been reported to be accompanied by improvement in MRI findings [
Symptomatic children treated with 5-formylTHF from a young age can have substantial improvement in their neurologic findings. In particular, treatment of asymptomatic or mildly symptomatic younger sibs at the time of diagnosis of their older sibs can either prevent or completely resolve the neurologic signs of
While there are no established guidelines for the treatment of
5-methyltetrahydrofolate (5-methylTHF) is the major physiologic folate found in blood. It is available as the active isomer in appropriate oral formulations; it is not available in parenteral formulations. It is administered orally at one half the racemic 5-formylTHF dose; however, there is no reported clinical experience using this folate in the treatment of
Clinical observations suggest that normal and supranormal CSF folate levels are more readily achieved with
5-formylTHF = 5-formyltetrahydrofolate; CSF = cerebrospinal fluid;
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Treatment for the neurologic findings (including multidisciplinary care by specialists) as outlined in
Standardized treatment with ASMs by experienced neurologists
5-formylTHF is essential & generally decreases frequency of seizures. In some persons, ASMs can be discontinued when optimal 5-formylTHF dose is achieved (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
CSF folate levels must be monitored closely to ensure that age-relevant physiologic levels are achieved w/5-formylTHF treatment & that there is reliable ongoing adherence.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
5-formylTHF = 5-formyltetrahydrofolate; ASM = anti-seizure medication; CSF = cerebrospinal fluid; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the response to 5-formylTHF targeted therapy and supportive care, and the emergence of new manifestations, the evaluations summarized in this section are recommended.
For affected individuals who are being treated with 5-formylTHF, in the absence of published guidelines, the following schedule for monitoring CSF folate levels is recommended:
A baseline CSF folate level should be obtained at the time of diagnosis.
Once treatment is begun, repeat CSF folate levels should be obtained after two to three weeks to confirm that an adequate therapeutic dose has been achieved, thereby optimizing the clinical outcome.
CSF folate levels should be repeated if there are changes in the individual's clinical status (e.g., developmental delays or regression, new-onset neurologic findings, seizures) or if there are concerns regarding adherence.
Optimally and if feasible, a CSF folate level should be obtained yearly to age five years.
Monitor for new- onset or changes in seizure type & frequency.
Assess for other manifestations such as changes in gait, ataxia, tremor, & other movement disorders.
Folic acid is not used to treat
Clarification of the genetic status of all sibs of a proband is recommended in order to identify as early as possible those who inherited biallelic
See
Search
• Eval of seizures: type, frequency
• Assessment of gait
• Assessment for hypotonia, tremor, strabismus, nystagmus
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Standardized treatment with ASMs by experienced neurologists
• 5-formylTHF is essential & generally decreases frequency of seizures. In some persons, ASMs can be discontinued when optimal 5-formylTHF dose is achieved (see
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• CSF folate levels must be monitored closely to ensure that age-relevant physiologic levels are achieved w/5-formylTHF treatment & that there is reliable ongoing adherence.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• A baseline CSF folate level should be obtained at the time of diagnosis.
• Once treatment is begun, repeat CSF folate levels should be obtained after two to three weeks to confirm that an adequate therapeutic dose has been achieved, thereby optimizing the clinical outcome.
• CSF folate levels should be repeated if there are changes in the individual's clinical status (e.g., developmental delays or regression, new-onset neurologic findings, seizures) or if there are concerns regarding adherence.
• Optimally and if feasible, a CSF folate level should be obtained yearly to age five years.
• Monitor for new- onset or changes in seizure type & frequency.
• Assess for other manifestations such as changes in gait, ataxia, tremor, & other movement disorders.
## Evaluations Following Initial Diagnosis
To establish the extent of the disorder and needs in an individual diagnosed with previously untreated
Eval of seizures: type, frequency
Assessment of gait
Assessment for hypotonia, tremor, strabismus, nystagmus
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living;
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Eval of seizures: type, frequency
• Assessment of gait
• Assessment for hypotonia, tremor, strabismus, nystagmus
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
In symptomatic individuals, movement disorders, behavior issues, and developmental delay / intellectual disability may improve with 5-formylTHF treatment depending on the age of the individual and severity of the neurologic deficits. Rarely, seizures may cease completely with 5-formylTHF treatment. Clinical improvement has been reported to be accompanied by improvement in MRI findings [
Symptomatic children treated with 5-formylTHF from a young age can have substantial improvement in their neurologic findings. In particular, treatment of asymptomatic or mildly symptomatic younger sibs at the time of diagnosis of their older sibs can either prevent or completely resolve the neurologic signs of
While there are no established guidelines for the treatment of
5-methyltetrahydrofolate (5-methylTHF) is the major physiologic folate found in blood. It is available as the active isomer in appropriate oral formulations; it is not available in parenteral formulations. It is administered orally at one half the racemic 5-formylTHF dose; however, there is no reported clinical experience using this folate in the treatment of
Clinical observations suggest that normal and supranormal CSF folate levels are more readily achieved with
5-formylTHF = 5-formyltetrahydrofolate; CSF = cerebrospinal fluid;
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Treatment for the neurologic findings (including multidisciplinary care by specialists) as outlined in
Standardized treatment with ASMs by experienced neurologists
5-formylTHF is essential & generally decreases frequency of seizures. In some persons, ASMs can be discontinued when optimal 5-formylTHF dose is achieved (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
CSF folate levels must be monitored closely to ensure that age-relevant physiologic levels are achieved w/5-formylTHF treatment & that there is reliable ongoing adherence.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
5-formylTHF = 5-formyltetrahydrofolate; ASM = anti-seizure medication; CSF = cerebrospinal fluid; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Standardized treatment with ASMs by experienced neurologists
• 5-formylTHF is essential & generally decreases frequency of seizures. In some persons, ASMs can be discontinued when optimal 5-formylTHF dose is achieved (see
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• CSF folate levels must be monitored closely to ensure that age-relevant physiologic levels are achieved w/5-formylTHF treatment & that there is reliable ongoing adherence.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Targeted Therapy
In symptomatic individuals, movement disorders, behavior issues, and developmental delay / intellectual disability may improve with 5-formylTHF treatment depending on the age of the individual and severity of the neurologic deficits. Rarely, seizures may cease completely with 5-formylTHF treatment. Clinical improvement has been reported to be accompanied by improvement in MRI findings [
Symptomatic children treated with 5-formylTHF from a young age can have substantial improvement in their neurologic findings. In particular, treatment of asymptomatic or mildly symptomatic younger sibs at the time of diagnosis of their older sibs can either prevent or completely resolve the neurologic signs of
While there are no established guidelines for the treatment of
5-methyltetrahydrofolate (5-methylTHF) is the major physiologic folate found in blood. It is available as the active isomer in appropriate oral formulations; it is not available in parenteral formulations. It is administered orally at one half the racemic 5-formylTHF dose; however, there is no reported clinical experience using this folate in the treatment of
Clinical observations suggest that normal and supranormal CSF folate levels are more readily achieved with
5-formylTHF = 5-formyltetrahydrofolate; CSF = cerebrospinal fluid;
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Treatment for the neurologic findings (including multidisciplinary care by specialists) as outlined in
Standardized treatment with ASMs by experienced neurologists
5-formylTHF is essential & generally decreases frequency of seizures. In some persons, ASMs can be discontinued when optimal 5-formylTHF dose is achieved (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
CSF folate levels must be monitored closely to ensure that age-relevant physiologic levels are achieved w/5-formylTHF treatment & that there is reliable ongoing adherence.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
5-formylTHF = 5-formyltetrahydrofolate; ASM = anti-seizure medication; CSF = cerebrospinal fluid; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Standardized treatment with ASMs by experienced neurologists
• 5-formylTHF is essential & generally decreases frequency of seizures. In some persons, ASMs can be discontinued when optimal 5-formylTHF dose is achieved (see
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• CSF folate levels must be monitored closely to ensure that age-relevant physiologic levels are achieved w/5-formylTHF treatment & that there is reliable ongoing adherence.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
##
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the response to 5-formylTHF targeted therapy and supportive care, and the emergence of new manifestations, the evaluations summarized in this section are recommended.
For affected individuals who are being treated with 5-formylTHF, in the absence of published guidelines, the following schedule for monitoring CSF folate levels is recommended:
A baseline CSF folate level should be obtained at the time of diagnosis.
Once treatment is begun, repeat CSF folate levels should be obtained after two to three weeks to confirm that an adequate therapeutic dose has been achieved, thereby optimizing the clinical outcome.
CSF folate levels should be repeated if there are changes in the individual's clinical status (e.g., developmental delays or regression, new-onset neurologic findings, seizures) or if there are concerns regarding adherence.
Optimally and if feasible, a CSF folate level should be obtained yearly to age five years.
Monitor for new- onset or changes in seizure type & frequency.
Assess for other manifestations such as changes in gait, ataxia, tremor, & other movement disorders.
• A baseline CSF folate level should be obtained at the time of diagnosis.
• Once treatment is begun, repeat CSF folate levels should be obtained after two to three weeks to confirm that an adequate therapeutic dose has been achieved, thereby optimizing the clinical outcome.
• CSF folate levels should be repeated if there are changes in the individual's clinical status (e.g., developmental delays or regression, new-onset neurologic findings, seizures) or if there are concerns regarding adherence.
• Optimally and if feasible, a CSF folate level should be obtained yearly to age five years.
• Monitor for new- onset or changes in seizure type & frequency.
• Assess for other manifestations such as changes in gait, ataxia, tremor, & other movement disorders.
## Agents/Circumstances to Avoid
Folic acid is not used to treat
## Evaluation of Relatives at Risk
Clarification of the genetic status of all sibs of a proband is recommended in order to identify as early as possible those who inherited biallelic
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Clarification of the genetic status of all sibs of a proband is recommended in order to identify as early as possible those who inherited biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals known to have an
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Clarification of the genetic status of all sibs of a proband is recommended in order to identify as early as possible those who inherited biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to have an
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Clarification of the genetic status of all sibs of a proband is recommended in order to identify as early as possible those who inherited biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Clarification of the genetic status of all sibs of a proband is recommended in order to identify as early as possible those who inherited biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals known to have an
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to have an
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
FOLR1-Related Cerebral Folate Transport Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FOLR1-Related Cerebral Folate Transport Deficiency (
Folates are essential cofactors for a variety of biological processes such as nucleotide synthesis and repair of DNA, regulation of gene expression, and synthesis of amino acids and neurotransmitters.
The loss of FOLR1 function impairs folate transport across the choroid plexus into the cerebrospinal fluid (CSF) within the cerebral ventricles. This results in folate deficiency in brain tissue nourished by the CSF, where neural stem cells develop into mature brain cells. The brain is also nourished by folates delivered directly from intact blood vessels that are functional in
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
Folates are essential cofactors for a variety of biological processes such as nucleotide synthesis and repair of DNA, regulation of gene expression, and synthesis of amino acids and neurotransmitters.
The loss of FOLR1 function impairs folate transport across the choroid plexus into the cerebrospinal fluid (CSF) within the cerebral ventricles. This results in folate deficiency in brain tissue nourished by the CSF, where neural stem cells develop into mature brain cells. The brain is also nourished by folates delivered directly from intact blood vessels that are functional in
Variants listed in the table have been provided by the author.
## Chapter Notes
Dr Goldman has a long-standing research interest in the mechanisms by which folates are absorbed in the intestine and are transported into and out of systemic tissues and the brain. His laboratory discovered the protein-coupled folate transporter (PCFT; encoded by
Experts in
Dr Goldman is interested in hearing from clinicians treating families with and families affected by
Dr Goldman's research has been supported by grants from the National Institutes of Health.
11 January 2023 (bp) Review posted live
7 June 2023 (idg) Original submission
• 11 January 2023 (bp) Review posted live
• 7 June 2023 (idg) Original submission
## Author Notes
Dr Goldman has a long-standing research interest in the mechanisms by which folates are absorbed in the intestine and are transported into and out of systemic tissues and the brain. His laboratory discovered the protein-coupled folate transporter (PCFT; encoded by
Experts in
Dr Goldman is interested in hearing from clinicians treating families with and families affected by
## Acknowledgments
Dr Goldman's research has been supported by grants from the National Institutes of Health.
## Revision History
11 January 2023 (bp) Review posted live
7 June 2023 (idg) Original submission
• 11 January 2023 (bp) Review posted live
• 7 June 2023 (idg) Original submission
## Key Sections in this
## References
## Literature Cited
|
[] |
11/1/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
fop
|
fop
|
[
"Myositis Ossificans Progressiva",
"Progressive Ossifying Myositis",
"ACVR1-Related Fibrodysplasia Ossificans Progressiva",
"Myositis Ossificans Progressive",
"Progressive Ossifying Myositis",
"ACVR1-Related Fibrodysplasia Ossificans Progressiva",
"Activin receptor type-1",
"ACVR1",
"Fibrodysplasia Ossificans Progressiva"
] |
Fibrodysplasia Ossificans Progressiva
|
Lauren S Akesson, Ravi Savarirayan
|
Summary Fibrodysplasia ossificans progressiva (FOP) is characterized by congenital bilateral hallux valgus malformations and early-onset heterotopic ossification, which may be spontaneous or precipitated by trauma including intramuscular vaccinations. Painful, recurrent soft-tissue swellings (flare-ups) may precede localized heterotopic ossification. Heterotopic ossification can occur at any location, but typically affects regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement as a result of ossification impacting joint mobility. Problems with swallowing and speaking can occur with ossification affecting the jaw, head, and neck, and restriction of the airway and breathing may lead to thoracic insufficiency syndrome. The diagnosis of FOP is established in a proband with heterotopic ossification, hallux valgus malformations, and/or a heterozygous pathogenic variant in FOP is inherited in an autosomal dominant manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a
|
## Diagnosis
There are no formal diagnostic criteria for fibrodysplasia ossificans progressiva (FOP).
FOP
Congenital hallux valgus deformity that is most often bilateral
Progressive heterotopic ossification (extraosseous bone formation) that may manifest as a palpable mass. Ossification is either spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from vaccinations or surgical procedures.
Painful, recurrent soft-tissue swellings (flare-ups) that may precede localized heterotopic ossification. This may occur in the form of scalp nodules in infancy, which may be an early or presenting feature.
Limb reduction defects that may affect the fingers in atypical or nonclassic FOP and may be mistaken for a brachydactyly syndrome in individuals who have not yet developed heterotopic ossifications
Prenatal ultrasound may identify a hallux valgus deformity as early as 23 weeks' gestation [
Radiographs of the halluces demonstrate short, malformed first metatarsals and a single dysplastic phalanx.
Radiographs of affected areas demonstrate heterotopic ossification (extraosseous bone formation).
Note: Individuals with suspected FOP should avoid biopsy, elective surgery, and immunizations until diagnosis is confirmed [
The diagnosis of FOP
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive features described in
When the phenotypic and radiographic findings suggest the diagnosis of FOP, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of FOP has not been considered, including in individuals with atypical phenotypic features and/or the absence of congenital hallux malformation,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fibrodysplasia Ossificans Progressiva
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The pathogenic variant
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Congenital hallux valgus deformity that is most often bilateral
• Progressive heterotopic ossification (extraosseous bone formation) that may manifest as a palpable mass. Ossification is either spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from vaccinations or surgical procedures.
• Painful, recurrent soft-tissue swellings (flare-ups) that may precede localized heterotopic ossification. This may occur in the form of scalp nodules in infancy, which may be an early or presenting feature.
• Limb reduction defects that may affect the fingers in atypical or nonclassic FOP and may be mistaken for a brachydactyly syndrome in individuals who have not yet developed heterotopic ossifications
• Prenatal ultrasound may identify a hallux valgus deformity as early as 23 weeks' gestation [
• Radiographs of the halluces demonstrate short, malformed first metatarsals and a single dysplastic phalanx.
• Radiographs of affected areas demonstrate heterotopic ossification (extraosseous bone formation).
• For an introduction to multigene panels click
## Suggestive Findings
FOP
Congenital hallux valgus deformity that is most often bilateral
Progressive heterotopic ossification (extraosseous bone formation) that may manifest as a palpable mass. Ossification is either spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from vaccinations or surgical procedures.
Painful, recurrent soft-tissue swellings (flare-ups) that may precede localized heterotopic ossification. This may occur in the form of scalp nodules in infancy, which may be an early or presenting feature.
Limb reduction defects that may affect the fingers in atypical or nonclassic FOP and may be mistaken for a brachydactyly syndrome in individuals who have not yet developed heterotopic ossifications
Prenatal ultrasound may identify a hallux valgus deformity as early as 23 weeks' gestation [
Radiographs of the halluces demonstrate short, malformed first metatarsals and a single dysplastic phalanx.
Radiographs of affected areas demonstrate heterotopic ossification (extraosseous bone formation).
Note: Individuals with suspected FOP should avoid biopsy, elective surgery, and immunizations until diagnosis is confirmed [
• Congenital hallux valgus deformity that is most often bilateral
• Progressive heterotopic ossification (extraosseous bone formation) that may manifest as a palpable mass. Ossification is either spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from vaccinations or surgical procedures.
• Painful, recurrent soft-tissue swellings (flare-ups) that may precede localized heterotopic ossification. This may occur in the form of scalp nodules in infancy, which may be an early or presenting feature.
• Limb reduction defects that may affect the fingers in atypical or nonclassic FOP and may be mistaken for a brachydactyly syndrome in individuals who have not yet developed heterotopic ossifications
• Prenatal ultrasound may identify a hallux valgus deformity as early as 23 weeks' gestation [
• Radiographs of the halluces demonstrate short, malformed first metatarsals and a single dysplastic phalanx.
• Radiographs of affected areas demonstrate heterotopic ossification (extraosseous bone formation).
## Establishing the Diagnosis
The diagnosis of FOP
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive features described in
When the phenotypic and radiographic findings suggest the diagnosis of FOP, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of FOP has not been considered, including in individuals with atypical phenotypic features and/or the absence of congenital hallux malformation,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fibrodysplasia Ossificans Progressiva
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The pathogenic variant
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and radiographic findings suggest the diagnosis of FOP, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of FOP has not been considered, including in individuals with atypical phenotypic features and/or the absence of congenital hallux malformation,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fibrodysplasia Ossificans Progressiva
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
The pathogenic variant
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Fibrodysplasia ossificans progressiva (FOP) is characterized by congenital bilateral hallux valgus malformations and early-onset heterotopic ossification, which may be spontaneous or precipitated by trauma, including intramuscular vaccinations [
To date, more than 800 individuals with more than 20 pathogenic variants in
Select Features of Fibrodysplasia Ossificans Progressiva
Hallux valgus, malformed 1st metatarsal, &/or monophalangism
Often 1st clinical feature
Present in 100% of persons w/common
Age dependent
Episodic
May be triggered by soft-tissue injury incl vaccinations
Localized manifestation of soft-tissue swelling
May be an early or presenting feature when observed in neonatal period or infancy
Extraosseous bone formation (abnormal bone formation in soft connective tissues outside of the normal skeleton) may manifest as a palpable hard lump or mass. Onset of ossification in individuals with the most common pathogenic variant (
Heterotopic ossification can be spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from intramuscular vaccinations, falls, and surgical procedures. Painful, recurrent soft-tissue swelling may precede localized heterotopic ossification.
Heterotopic ossification can occur at any location, typically affecting regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement as a result of ossification affecting joint mobility. Ossification of the jaw, head, and neck can affect swallowing and speaking.
Heterotopic ossification occurring in the thoracic region, submandibular region, throat, or other locations near the airway may impact the airway or respiratory function. In addition, costovertebral involvement, ossification of intercostal muscles, paravertebral muscles, and aponeuroses, as well as progressive spinal deformity with kyphoscoliosis may lead to
Heterotopic ossification may be misdiagnosed as tumors or isolated osteochondromas such as those seen in
Soft-tissue swellings (flare-ups) may be spontaneous or follow an injury. They are characterized by painful swellings in soft connective tissue including skeletal muscles, tendons, ligaments, fascia, and aponeuroses. They may precede the development of localized heterotopic ossification.
Scalp nodules occurring in neonates and infants have been described in 40% of individuals from a national disease registry [
Variable
Pelvic radiographs may identify
The
Specific gain-of-function variants at amino acid residue
The penetrance of gain-of-function variants in
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
Based on studies in French [
• Hallux valgus, malformed 1st metatarsal, &/or monophalangism
• Often 1st clinical feature
• Present in 100% of persons w/common
• Age dependent
• Episodic
• May be triggered by soft-tissue injury incl vaccinations
• Localized manifestation of soft-tissue swelling
• May be an early or presenting feature when observed in neonatal period or infancy
• Extraosseous bone formation (abnormal bone formation in soft connective tissues outside of the normal skeleton) may manifest as a palpable hard lump or mass. Onset of ossification in individuals with the most common pathogenic variant (
• Heterotopic ossification can be spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from intramuscular vaccinations, falls, and surgical procedures. Painful, recurrent soft-tissue swelling may precede localized heterotopic ossification.
• Heterotopic ossification can occur at any location, typically affecting regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement as a result of ossification affecting joint mobility. Ossification of the jaw, head, and neck can affect swallowing and speaking.
• Heterotopic ossification occurring in the thoracic region, submandibular region, throat, or other locations near the airway may impact the airway or respiratory function. In addition, costovertebral involvement, ossification of intercostal muscles, paravertebral muscles, and aponeuroses, as well as progressive spinal deformity with kyphoscoliosis may lead to
• Heterotopic ossification may be misdiagnosed as tumors or isolated osteochondromas such as those seen in
• Soft-tissue swellings (flare-ups) may be spontaneous or follow an injury. They are characterized by painful swellings in soft connective tissue including skeletal muscles, tendons, ligaments, fascia, and aponeuroses. They may precede the development of localized heterotopic ossification.
• Scalp nodules occurring in neonates and infants have been described in 40% of individuals from a national disease registry [
• Variable
• Pelvic radiographs may identify
## Clinical Description
Fibrodysplasia ossificans progressiva (FOP) is characterized by congenital bilateral hallux valgus malformations and early-onset heterotopic ossification, which may be spontaneous or precipitated by trauma, including intramuscular vaccinations [
To date, more than 800 individuals with more than 20 pathogenic variants in
Select Features of Fibrodysplasia Ossificans Progressiva
Hallux valgus, malformed 1st metatarsal, &/or monophalangism
Often 1st clinical feature
Present in 100% of persons w/common
Age dependent
Episodic
May be triggered by soft-tissue injury incl vaccinations
Localized manifestation of soft-tissue swelling
May be an early or presenting feature when observed in neonatal period or infancy
Extraosseous bone formation (abnormal bone formation in soft connective tissues outside of the normal skeleton) may manifest as a palpable hard lump or mass. Onset of ossification in individuals with the most common pathogenic variant (
Heterotopic ossification can be spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from intramuscular vaccinations, falls, and surgical procedures. Painful, recurrent soft-tissue swelling may precede localized heterotopic ossification.
Heterotopic ossification can occur at any location, typically affecting regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement as a result of ossification affecting joint mobility. Ossification of the jaw, head, and neck can affect swallowing and speaking.
Heterotopic ossification occurring in the thoracic region, submandibular region, throat, or other locations near the airway may impact the airway or respiratory function. In addition, costovertebral involvement, ossification of intercostal muscles, paravertebral muscles, and aponeuroses, as well as progressive spinal deformity with kyphoscoliosis may lead to
Heterotopic ossification may be misdiagnosed as tumors or isolated osteochondromas such as those seen in
Soft-tissue swellings (flare-ups) may be spontaneous or follow an injury. They are characterized by painful swellings in soft connective tissue including skeletal muscles, tendons, ligaments, fascia, and aponeuroses. They may precede the development of localized heterotopic ossification.
Scalp nodules occurring in neonates and infants have been described in 40% of individuals from a national disease registry [
Variable
Pelvic radiographs may identify
• Hallux valgus, malformed 1st metatarsal, &/or monophalangism
• Often 1st clinical feature
• Present in 100% of persons w/common
• Age dependent
• Episodic
• May be triggered by soft-tissue injury incl vaccinations
• Localized manifestation of soft-tissue swelling
• May be an early or presenting feature when observed in neonatal period or infancy
• Extraosseous bone formation (abnormal bone formation in soft connective tissues outside of the normal skeleton) may manifest as a palpable hard lump or mass. Onset of ossification in individuals with the most common pathogenic variant (
• Heterotopic ossification can be spontaneous or in response to soft-tissue trauma, including iatrogenic trauma from intramuscular vaccinations, falls, and surgical procedures. Painful, recurrent soft-tissue swelling may precede localized heterotopic ossification.
• Heterotopic ossification can occur at any location, typically affecting regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement as a result of ossification affecting joint mobility. Ossification of the jaw, head, and neck can affect swallowing and speaking.
• Heterotopic ossification occurring in the thoracic region, submandibular region, throat, or other locations near the airway may impact the airway or respiratory function. In addition, costovertebral involvement, ossification of intercostal muscles, paravertebral muscles, and aponeuroses, as well as progressive spinal deformity with kyphoscoliosis may lead to
• Heterotopic ossification may be misdiagnosed as tumors or isolated osteochondromas such as those seen in
• Soft-tissue swellings (flare-ups) may be spontaneous or follow an injury. They are characterized by painful swellings in soft connective tissue including skeletal muscles, tendons, ligaments, fascia, and aponeuroses. They may precede the development of localized heterotopic ossification.
• Scalp nodules occurring in neonates and infants have been described in 40% of individuals from a national disease registry [
• Variable
• Pelvic radiographs may identify
## Genotype-Phenotype Correlations
The
Specific gain-of-function variants at amino acid residue
## Penetrance
The penetrance of gain-of-function variants in
## Nomenclature
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
Based on studies in French [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The diagnosis of fibrodysplasia ossificans progressiva (FOP) is often missed, due in part to the rarity of the condition. Nearly 90% of individuals with FOP initially receive a misdiagnosis, with two thirds undergoing unnecessary and potentially dangerous procedures that lead to permanent harm and lifelong disability in as many as 50% [
Disorders that may present with clinical features similar to those of FOP are summarized in
Genes of Interest in the Differential Diagnosis of Fibrodysplasia Ossificans Progressiva
No hallux malformations
No heterotopic ossification
No hallux malformations or inflammatory soft-tissue swellings
Individuals w/POH typically develop ossification w/in superficial dermal layer of the skin (which is unaffected in FOP.
Predominance of membranous rather than endochondral bone formation
No hallux malformations
No heterotopic ossification
AD = autosomal dominant; FOP = fibrodysplasia ossificans progressiva; MOI = mode of inheritance; POH = progressive osseous heteroplasia
Disorders to consider in individuals presenting with an isolated clinical feature characteristic of FOP [
• No hallux malformations
• No heterotopic ossification
• No hallux malformations or inflammatory soft-tissue swellings
• Individuals w/POH typically develop ossification w/in superficial dermal layer of the skin (which is unaffected in FOP.
• Predominance of membranous rather than endochondral bone formation
• No hallux malformations
• No heterotopic ossification
## Management
To establish the extent of disease and needs in an individual diagnosed with fibrodysplasia ossificans progressiva (FOP), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fibrodysplasia Ossificans Progressiva
Note: Further evaluation may be indicated for participation in clinical trials.
Clinical Staging of Fibrodysplasia Ossificans Progressiva
Adapted from
ADL = activities of daily living; CAJIS = cumulative analog joint involvement scale (for FOP)
See
Guidelines for the management of individuals with FOP have been developed by a multidisciplinary team of experts [
Fibrodysplasia Ossificans Progressiva: Targeted Therapy
5 mg orally 1x/day
Adjust dose as needed for younger persons & flare-ups.
BMP = bone morphogenic protein; RAR = retinoic acid receptor
A negative pregnancy test is required before initiating treatment due to fetal toxicity associated with retinoids.
Although there is evidence for efficacy of palovarotene in reducing new heterotopic ossification in FOP, there is a high risk of premature physeal closure in skeletally immature individuals. Thus, palovarotene has not been FDA approved for females age <8 years and males age <10 years, the age at which approximately 80% of bone maturation has been reached (see
Dosage for children is based on age and weight, with modified/increased dose in the event of FOP flare-up (see
Fibrodysplasia Ossificans Progressiva: Recommended Palovarotene Dose
Initiate adjusted daily oral dose with first manifestation of FOP flare-up or high-risk event likely to lead to an FOP flare-up (e.g., surgery, intramuscular immunization; mandibular blocks for dental procedures; muscle fatigue; blunt muscle trauma from bumps, bruises, or falls; or influenza-like viral illnesses).
Symptoms of FOP flare-up include, but are not limited to, localized pain, soft-tissue swelling/inflammation, redness, warmth, decreased joint range of motion, and stiffness.
Complete 12 weeks of adjusted daily oral dose for FOP flare-up even if symptoms resolve earlier; then return to standard daily oral dose for age and weight.
If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
Reduce daily oral dose in those with adverse reactions to palovarotene and for coadministration of moderate CYP3A4 inhibitors. Avoid coadministration with strong CYP3A4 inhibitors and moderate or strong CYP3A4 inducers.
No dosage adjustment is necessary for individuals with impaired kidney function or mild liver impairment. Use of palovarotene in individuals with moderate or severe liver impairment is not recommended.
Refer to the product information for adverse effects (including dose adjustments) and precautions during therapy.
Avoidance of soft-tissue injury and muscle damage to prevent inflammatory soft-tissue swellings and heterotopic ossification is the hallmark of FOP management [
Treatment of Manifestations in Individuals with Fibrodysplasia Ossificans Progressiva
Avoid overstretching of jaw.
Care w/local anesthesia
Modification of activity
Improved household safety (e.g., install handrails, secure loose carpeting, remove objects from walkways, eliminate uneven flooring.)
Use of ambulatory devices
Prompt medical attention
Consider head & neck injuries to be serious until proven otherwise.
Consider prophylactic corticosteroid use.
Preventative dental care from a young age
Consult FOP expert prior to dental procedures.
Dental care may be affected by spontaneous or post-traumatic jaw ankylosis.
Consider corticosteroids for prophylaxis prior to dental & surgical procedures.
If general anesthesia is required, an awake intubation by nasotracheal fiber-optic technique should be performed because of neck malformations, jaw ankylosis, sensitive airway, & risk of an obstructing neck flare-up.
Highly skilled FOP-aware anesthesiologists should be present for all elective intubations.
Singing, swimming, incentive spirometry
Positive pressure ventilation when indicated
Avoid respiratory infections.
Consider subcutaneous vaccination for influenza & pneumococcus in the proband.
Recommend pertussis & influenza vaccination in family members.
Avoid supplemental oxygen, which can suppress respiratory drive.
NSAIDs or COX-2 inhibitors (oral or topical)
Other anti-inflammatory medications including mast cell stabilizers, leukotriene inhibitors
Consider corticosteroids, particularly for flare-ups affecting the submandibular region or jaw, major joints, & after significant soft-tissue trauma.
Consider oral corticosteroids for prophylaxis prior to dental & surgical procedures.
Consider prophylactic treatment to prevent gastrointestinal complications due to NSAIDs or COX-2 inhibitors.
Avoid narcotic analgesia if possible.
No definitive evidence for use of bisphosphonates or imatinib
Fractures usually heal w/minimal heterotopic bone formation.
Avoid open reduction & internal fixation, which can precipitate heterotopic ossification.
Encourage fluid intake (1.5-2 L/day).
Avoid high-protein & high-salt diets.
Elevate legs during sleep & while recumbent.
DVT prophylaxis
Supportive stockings while avoiding traumatic compression
ADL = activities of daily living; DVT = deep vein thrombosis; NSAID = nonsteroidal anti-inflammatory drug; OT = occupational therapy
See
Anti-influenza medication (oseltamivir) at first sign of influenza-like illness, while contacting medical practitioner
Note: Treatments for which no definitive evidence supports their use in FOP include chemotherapy, radiotherapy, bone marrow transplantation, and the chronic use of antiangiogenic agents, calcium binders, colchicine, fluoroquinolone antibiotics, propranolol, mineralization inhibitors, PPAR-gamma antagonists, and TNF-α inhibitors [
Recommended Surveillance for Individuals with Fibrodysplasia Ossificans Progressiva
Clinical eval w/orthopedist &/or clinical geneticist w/experience in managing FOP
Careful eval for scoliosis, which may be progressive
Anthropometric assessment
Nutrition eval to monitor weight & caloric intake
Clinical history & physical exam for jaw ankylosis
Clinical history & physical exam for signs/symptoms of respiratory disease
Pulmonary assessments & sleep assessments
Echocardiogram
Baseline pulmonary function assessment, sleep assessments, & echocardiogram before age 10 yrs (earlier if indicated)
Annual clinical eval w/investigations as clinically indicated to guide specific respiratory therapies, incl positive pressure ventilation
If corticosteroid treatment has been extensive, consider eval for corticosteroid-induced osteopenia/osteoporosis.
Eval for fall risk
Based on
DVT = deep vein thrombosis; NSAID = nonsteroidal anti-inflammatory drug
It is imperative that iatrogenic harm is limited by avoiding procedures that predispose to soft-tissue injury, including intramuscular injections such as vaccinations, dental procedures, procedures related to anesthesia, biopsies, removal of heterotopic bone, and all nonemergent surgical procedures [
Other activities to avoid include soft-tissue injuries, contact sports, overstretching of soft tissues, muscle fatigue, and passive range of motion (caution is required during treatment with physical therapists) [
Falls should be actively avoided. Protective headwear should be considered for children who have upper limb involvement to prevent fall-induced head injury. Mobility aids may be effective in reducing falls in all age groups [
In individuals with thoracic insufficiency syndrome, avoid supplemental oxygen, which can suppress respiratory drive.
Administration of vaccinations must be carefully managed in individuals with FOP. Detailed guidelines are available [
It may be appropriate to clarify the genetic status of apparently asymptomatic young sibs of an affected individual in order to identify individuals at risk of iatrogenic harm (e.g., intramuscular injections) and other sources of trauma that may precipitate heterotopic ossification.
Note: For adult at-risk family members of a proband with classic FOP, molecular genetic testing in the absence of supportive physical examination findings (i.e., hallux deformity and signs of heterotopic ossification) is not usually required. However, for the evaluation of adult family members of a proband with atypical FOP, molecular genetic testing is recommended because manifestations of FOP may not be clinically apparent on physical examination.
See
It is not known whether women with FOP have impaired fertility. Pregnancy in women with FOP is uncommon, as the disease manifestations at reproductive age limit reproductive potential. FOP poses major life-threatening risks to mother and fetus because of potential mechanical restrictions secondary to heterotopic ossification affecting the pelvis and surrounding regions, as well as breathing difficulties in later pregnancy secondary to restrictive chest wall disease. There is an increased risk of thromboembolism exacerbated by immobility. Ideally, pregnancy in a woman with FOP should be provided at a high-risk pregnancy center and follow established guidelines for the management of pregnancy in women with FOP (see
See
Research to develop treatments for FOP has focused on targeted inhibition of the ACVR1 receptor, ACVR1 ligands, BMP pathway signaling, pre-osseous chondrogenic heterotopic ossification, and inflammatory triggers of disease activity.
REGN2477 is an antibody that binds to activin A and blocks its activity. By binding and blocking activin A, REN2477 may prevent the formation and stop the growth of heterotopic ossification in individuals with FOP. REGN2477 is currently in Phase II clinical trials in individuals older than age 18 years.
Sirolimus is an mTOR inhibitor that may reduce heterotopic ossification. Sirolimus is currently in Phase II clinical trials in individuals older than age six years.
Several other agents are currently undergoing safety and tolerability assessment in Phase I clinical trials. Further information on therapies under investigation is available in
Search
• 5 mg orally 1x/day
• Adjust dose as needed for younger persons & flare-ups.
• A negative pregnancy test is required before initiating treatment due to fetal toxicity associated with retinoids.
• Although there is evidence for efficacy of palovarotene in reducing new heterotopic ossification in FOP, there is a high risk of premature physeal closure in skeletally immature individuals. Thus, palovarotene has not been FDA approved for females age <8 years and males age <10 years, the age at which approximately 80% of bone maturation has been reached (see
• Dosage for children is based on age and weight, with modified/increased dose in the event of FOP flare-up (see
• Initiate adjusted daily oral dose with first manifestation of FOP flare-up or high-risk event likely to lead to an FOP flare-up (e.g., surgery, intramuscular immunization; mandibular blocks for dental procedures; muscle fatigue; blunt muscle trauma from bumps, bruises, or falls; or influenza-like viral illnesses).
• Symptoms of FOP flare-up include, but are not limited to, localized pain, soft-tissue swelling/inflammation, redness, warmth, decreased joint range of motion, and stiffness.
• Complete 12 weeks of adjusted daily oral dose for FOP flare-up even if symptoms resolve earlier; then return to standard daily oral dose for age and weight.
• If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
• If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
• If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
• If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
• If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
• If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
• Reduce daily oral dose in those with adverse reactions to palovarotene and for coadministration of moderate CYP3A4 inhibitors. Avoid coadministration with strong CYP3A4 inhibitors and moderate or strong CYP3A4 inducers.
• No dosage adjustment is necessary for individuals with impaired kidney function or mild liver impairment. Use of palovarotene in individuals with moderate or severe liver impairment is not recommended.
• Refer to the product information for adverse effects (including dose adjustments) and precautions during therapy.
• If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
• If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
• If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
• Avoid overstretching of jaw.
• Care w/local anesthesia
• Modification of activity
• Improved household safety (e.g., install handrails, secure loose carpeting, remove objects from walkways, eliminate uneven flooring.)
• Use of ambulatory devices
• Prompt medical attention
• Consider head & neck injuries to be serious until proven otherwise.
• Consider prophylactic corticosteroid use.
• Preventative dental care from a young age
• Consult FOP expert prior to dental procedures.
• Dental care may be affected by spontaneous or post-traumatic jaw ankylosis.
• Consider corticosteroids for prophylaxis prior to dental & surgical procedures.
• If general anesthesia is required, an awake intubation by nasotracheal fiber-optic technique should be performed because of neck malformations, jaw ankylosis, sensitive airway, & risk of an obstructing neck flare-up.
• Highly skilled FOP-aware anesthesiologists should be present for all elective intubations.
• Singing, swimming, incentive spirometry
• Positive pressure ventilation when indicated
• Avoid respiratory infections.
• Consider subcutaneous vaccination for influenza & pneumococcus in the proband.
• Recommend pertussis & influenza vaccination in family members.
• Avoid supplemental oxygen, which can suppress respiratory drive.
• NSAIDs or COX-2 inhibitors (oral or topical)
• Other anti-inflammatory medications including mast cell stabilizers, leukotriene inhibitors
• Consider corticosteroids, particularly for flare-ups affecting the submandibular region or jaw, major joints, & after significant soft-tissue trauma.
• Consider oral corticosteroids for prophylaxis prior to dental & surgical procedures.
• Consider prophylactic treatment to prevent gastrointestinal complications due to NSAIDs or COX-2 inhibitors.
• Avoid narcotic analgesia if possible.
• No definitive evidence for use of bisphosphonates or imatinib
• Fractures usually heal w/minimal heterotopic bone formation.
• Avoid open reduction & internal fixation, which can precipitate heterotopic ossification.
• Encourage fluid intake (1.5-2 L/day).
• Avoid high-protein & high-salt diets.
• Elevate legs during sleep & while recumbent.
• DVT prophylaxis
• Supportive stockings while avoiding traumatic compression
• Clinical eval w/orthopedist &/or clinical geneticist w/experience in managing FOP
• Careful eval for scoliosis, which may be progressive
• Anthropometric assessment
• Nutrition eval to monitor weight & caloric intake
• Clinical history & physical exam for jaw ankylosis
• Clinical history & physical exam for signs/symptoms of respiratory disease
• Pulmonary assessments & sleep assessments
• Echocardiogram
• Baseline pulmonary function assessment, sleep assessments, & echocardiogram before age 10 yrs (earlier if indicated)
• Annual clinical eval w/investigations as clinically indicated to guide specific respiratory therapies, incl positive pressure ventilation
• If corticosteroid treatment has been extensive, consider eval for corticosteroid-induced osteopenia/osteoporosis.
• Eval for fall risk
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with fibrodysplasia ossificans progressiva (FOP), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fibrodysplasia Ossificans Progressiva
Note: Further evaluation may be indicated for participation in clinical trials.
Clinical Staging of Fibrodysplasia Ossificans Progressiva
Adapted from
ADL = activities of daily living; CAJIS = cumulative analog joint involvement scale (for FOP)
See
## Treatment of Manifestations
Guidelines for the management of individuals with FOP have been developed by a multidisciplinary team of experts [
Fibrodysplasia Ossificans Progressiva: Targeted Therapy
5 mg orally 1x/day
Adjust dose as needed for younger persons & flare-ups.
BMP = bone morphogenic protein; RAR = retinoic acid receptor
A negative pregnancy test is required before initiating treatment due to fetal toxicity associated with retinoids.
Although there is evidence for efficacy of palovarotene in reducing new heterotopic ossification in FOP, there is a high risk of premature physeal closure in skeletally immature individuals. Thus, palovarotene has not been FDA approved for females age <8 years and males age <10 years, the age at which approximately 80% of bone maturation has been reached (see
Dosage for children is based on age and weight, with modified/increased dose in the event of FOP flare-up (see
Fibrodysplasia Ossificans Progressiva: Recommended Palovarotene Dose
Initiate adjusted daily oral dose with first manifestation of FOP flare-up or high-risk event likely to lead to an FOP flare-up (e.g., surgery, intramuscular immunization; mandibular blocks for dental procedures; muscle fatigue; blunt muscle trauma from bumps, bruises, or falls; or influenza-like viral illnesses).
Symptoms of FOP flare-up include, but are not limited to, localized pain, soft-tissue swelling/inflammation, redness, warmth, decreased joint range of motion, and stiffness.
Complete 12 weeks of adjusted daily oral dose for FOP flare-up even if symptoms resolve earlier; then return to standard daily oral dose for age and weight.
If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
Reduce daily oral dose in those with adverse reactions to palovarotene and for coadministration of moderate CYP3A4 inhibitors. Avoid coadministration with strong CYP3A4 inhibitors and moderate or strong CYP3A4 inducers.
No dosage adjustment is necessary for individuals with impaired kidney function or mild liver impairment. Use of palovarotene in individuals with moderate or severe liver impairment is not recommended.
Refer to the product information for adverse effects (including dose adjustments) and precautions during therapy.
Avoidance of soft-tissue injury and muscle damage to prevent inflammatory soft-tissue swellings and heterotopic ossification is the hallmark of FOP management [
Treatment of Manifestations in Individuals with Fibrodysplasia Ossificans Progressiva
Avoid overstretching of jaw.
Care w/local anesthesia
Modification of activity
Improved household safety (e.g., install handrails, secure loose carpeting, remove objects from walkways, eliminate uneven flooring.)
Use of ambulatory devices
Prompt medical attention
Consider head & neck injuries to be serious until proven otherwise.
Consider prophylactic corticosteroid use.
Preventative dental care from a young age
Consult FOP expert prior to dental procedures.
Dental care may be affected by spontaneous or post-traumatic jaw ankylosis.
Consider corticosteroids for prophylaxis prior to dental & surgical procedures.
If general anesthesia is required, an awake intubation by nasotracheal fiber-optic technique should be performed because of neck malformations, jaw ankylosis, sensitive airway, & risk of an obstructing neck flare-up.
Highly skilled FOP-aware anesthesiologists should be present for all elective intubations.
Singing, swimming, incentive spirometry
Positive pressure ventilation when indicated
Avoid respiratory infections.
Consider subcutaneous vaccination for influenza & pneumococcus in the proband.
Recommend pertussis & influenza vaccination in family members.
Avoid supplemental oxygen, which can suppress respiratory drive.
NSAIDs or COX-2 inhibitors (oral or topical)
Other anti-inflammatory medications including mast cell stabilizers, leukotriene inhibitors
Consider corticosteroids, particularly for flare-ups affecting the submandibular region or jaw, major joints, & after significant soft-tissue trauma.
Consider oral corticosteroids for prophylaxis prior to dental & surgical procedures.
Consider prophylactic treatment to prevent gastrointestinal complications due to NSAIDs or COX-2 inhibitors.
Avoid narcotic analgesia if possible.
No definitive evidence for use of bisphosphonates or imatinib
Fractures usually heal w/minimal heterotopic bone formation.
Avoid open reduction & internal fixation, which can precipitate heterotopic ossification.
Encourage fluid intake (1.5-2 L/day).
Avoid high-protein & high-salt diets.
Elevate legs during sleep & while recumbent.
DVT prophylaxis
Supportive stockings while avoiding traumatic compression
ADL = activities of daily living; DVT = deep vein thrombosis; NSAID = nonsteroidal anti-inflammatory drug; OT = occupational therapy
See
Anti-influenza medication (oseltamivir) at first sign of influenza-like illness, while contacting medical practitioner
Note: Treatments for which no definitive evidence supports their use in FOP include chemotherapy, radiotherapy, bone marrow transplantation, and the chronic use of antiangiogenic agents, calcium binders, colchicine, fluoroquinolone antibiotics, propranolol, mineralization inhibitors, PPAR-gamma antagonists, and TNF-α inhibitors [
• 5 mg orally 1x/day
• Adjust dose as needed for younger persons & flare-ups.
• A negative pregnancy test is required before initiating treatment due to fetal toxicity associated with retinoids.
• Although there is evidence for efficacy of palovarotene in reducing new heterotopic ossification in FOP, there is a high risk of premature physeal closure in skeletally immature individuals. Thus, palovarotene has not been FDA approved for females age <8 years and males age <10 years, the age at which approximately 80% of bone maturation has been reached (see
• Dosage for children is based on age and weight, with modified/increased dose in the event of FOP flare-up (see
• Initiate adjusted daily oral dose with first manifestation of FOP flare-up or high-risk event likely to lead to an FOP flare-up (e.g., surgery, intramuscular immunization; mandibular blocks for dental procedures; muscle fatigue; blunt muscle trauma from bumps, bruises, or falls; or influenza-like viral illnesses).
• Symptoms of FOP flare-up include, but are not limited to, localized pain, soft-tissue swelling/inflammation, redness, warmth, decreased joint range of motion, and stiffness.
• Complete 12 weeks of adjusted daily oral dose for FOP flare-up even if symptoms resolve earlier; then return to standard daily oral dose for age and weight.
• If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
• If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
• If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
• If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
• If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
• If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
• Reduce daily oral dose in those with adverse reactions to palovarotene and for coadministration of moderate CYP3A4 inhibitors. Avoid coadministration with strong CYP3A4 inhibitors and moderate or strong CYP3A4 inducers.
• No dosage adjustment is necessary for individuals with impaired kidney function or mild liver impairment. Use of palovarotene in individuals with moderate or severe liver impairment is not recommended.
• Refer to the product information for adverse effects (including dose adjustments) and precautions during therapy.
• If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
• If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
• If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
• Avoid overstretching of jaw.
• Care w/local anesthesia
• Modification of activity
• Improved household safety (e.g., install handrails, secure loose carpeting, remove objects from walkways, eliminate uneven flooring.)
• Use of ambulatory devices
• Prompt medical attention
• Consider head & neck injuries to be serious until proven otherwise.
• Consider prophylactic corticosteroid use.
• Preventative dental care from a young age
• Consult FOP expert prior to dental procedures.
• Dental care may be affected by spontaneous or post-traumatic jaw ankylosis.
• Consider corticosteroids for prophylaxis prior to dental & surgical procedures.
• If general anesthesia is required, an awake intubation by nasotracheal fiber-optic technique should be performed because of neck malformations, jaw ankylosis, sensitive airway, & risk of an obstructing neck flare-up.
• Highly skilled FOP-aware anesthesiologists should be present for all elective intubations.
• Singing, swimming, incentive spirometry
• Positive pressure ventilation when indicated
• Avoid respiratory infections.
• Consider subcutaneous vaccination for influenza & pneumococcus in the proband.
• Recommend pertussis & influenza vaccination in family members.
• Avoid supplemental oxygen, which can suppress respiratory drive.
• NSAIDs or COX-2 inhibitors (oral or topical)
• Other anti-inflammatory medications including mast cell stabilizers, leukotriene inhibitors
• Consider corticosteroids, particularly for flare-ups affecting the submandibular region or jaw, major joints, & after significant soft-tissue trauma.
• Consider oral corticosteroids for prophylaxis prior to dental & surgical procedures.
• Consider prophylactic treatment to prevent gastrointestinal complications due to NSAIDs or COX-2 inhibitors.
• Avoid narcotic analgesia if possible.
• No definitive evidence for use of bisphosphonates or imatinib
• Fractures usually heal w/minimal heterotopic bone formation.
• Avoid open reduction & internal fixation, which can precipitate heterotopic ossification.
• Encourage fluid intake (1.5-2 L/day).
• Avoid high-protein & high-salt diets.
• Elevate legs during sleep & while recumbent.
• DVT prophylaxis
• Supportive stockings while avoiding traumatic compression
## Targeted Therapy
Fibrodysplasia Ossificans Progressiva: Targeted Therapy
5 mg orally 1x/day
Adjust dose as needed for younger persons & flare-ups.
BMP = bone morphogenic protein; RAR = retinoic acid receptor
A negative pregnancy test is required before initiating treatment due to fetal toxicity associated with retinoids.
Although there is evidence for efficacy of palovarotene in reducing new heterotopic ossification in FOP, there is a high risk of premature physeal closure in skeletally immature individuals. Thus, palovarotene has not been FDA approved for females age <8 years and males age <10 years, the age at which approximately 80% of bone maturation has been reached (see
Dosage for children is based on age and weight, with modified/increased dose in the event of FOP flare-up (see
Fibrodysplasia Ossificans Progressiva: Recommended Palovarotene Dose
Initiate adjusted daily oral dose with first manifestation of FOP flare-up or high-risk event likely to lead to an FOP flare-up (e.g., surgery, intramuscular immunization; mandibular blocks for dental procedures; muscle fatigue; blunt muscle trauma from bumps, bruises, or falls; or influenza-like viral illnesses).
Symptoms of FOP flare-up include, but are not limited to, localized pain, soft-tissue swelling/inflammation, redness, warmth, decreased joint range of motion, and stiffness.
Complete 12 weeks of adjusted daily oral dose for FOP flare-up even if symptoms resolve earlier; then return to standard daily oral dose for age and weight.
If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
Reduce daily oral dose in those with adverse reactions to palovarotene and for coadministration of moderate CYP3A4 inhibitors. Avoid coadministration with strong CYP3A4 inhibitors and moderate or strong CYP3A4 inducers.
No dosage adjustment is necessary for individuals with impaired kidney function or mild liver impairment. Use of palovarotene in individuals with moderate or severe liver impairment is not recommended.
Refer to the product information for adverse effects (including dose adjustments) and precautions during therapy.
• 5 mg orally 1x/day
• Adjust dose as needed for younger persons & flare-ups.
• A negative pregnancy test is required before initiating treatment due to fetal toxicity associated with retinoids.
• Although there is evidence for efficacy of palovarotene in reducing new heterotopic ossification in FOP, there is a high risk of premature physeal closure in skeletally immature individuals. Thus, palovarotene has not been FDA approved for females age <8 years and males age <10 years, the age at which approximately 80% of bone maturation has been reached (see
• Dosage for children is based on age and weight, with modified/increased dose in the event of FOP flare-up (see
• Initiate adjusted daily oral dose with first manifestation of FOP flare-up or high-risk event likely to lead to an FOP flare-up (e.g., surgery, intramuscular immunization; mandibular blocks for dental procedures; muscle fatigue; blunt muscle trauma from bumps, bruises, or falls; or influenza-like viral illnesses).
• Symptoms of FOP flare-up include, but are not limited to, localized pain, soft-tissue swelling/inflammation, redness, warmth, decreased joint range of motion, and stiffness.
• Complete 12 weeks of adjusted daily oral dose for FOP flare-up even if symptoms resolve earlier; then return to standard daily oral dose for age and weight.
• If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
• If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
• If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
• If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
• If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
• If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
• Reduce daily oral dose in those with adverse reactions to palovarotene and for coadministration of moderate CYP3A4 inhibitors. Avoid coadministration with strong CYP3A4 inhibitors and moderate or strong CYP3A4 inducers.
• No dosage adjustment is necessary for individuals with impaired kidney function or mild liver impairment. Use of palovarotene in individuals with moderate or severe liver impairment is not recommended.
• Refer to the product information for adverse effects (including dose adjustments) and precautions during therapy.
• If original flare-up site worsens or another flare-up starts at a new location during flare-up treatment, restart 12-week flare-up dosing with the weeks 1-4 dose.
• If flare-up symptoms have not resolved after 12 weeks of adjusted daily oral dose, extend weeks 5-12 flare-up dose in four-week intervals, and continue until flare-up symptoms resolve.
• If new flare-up symptoms occur after standard daily dosing is resumed, restart flare-up dosing.
## Supportive Care
Avoidance of soft-tissue injury and muscle damage to prevent inflammatory soft-tissue swellings and heterotopic ossification is the hallmark of FOP management [
Treatment of Manifestations in Individuals with Fibrodysplasia Ossificans Progressiva
Avoid overstretching of jaw.
Care w/local anesthesia
Modification of activity
Improved household safety (e.g., install handrails, secure loose carpeting, remove objects from walkways, eliminate uneven flooring.)
Use of ambulatory devices
Prompt medical attention
Consider head & neck injuries to be serious until proven otherwise.
Consider prophylactic corticosteroid use.
Preventative dental care from a young age
Consult FOP expert prior to dental procedures.
Dental care may be affected by spontaneous or post-traumatic jaw ankylosis.
Consider corticosteroids for prophylaxis prior to dental & surgical procedures.
If general anesthesia is required, an awake intubation by nasotracheal fiber-optic technique should be performed because of neck malformations, jaw ankylosis, sensitive airway, & risk of an obstructing neck flare-up.
Highly skilled FOP-aware anesthesiologists should be present for all elective intubations.
Singing, swimming, incentive spirometry
Positive pressure ventilation when indicated
Avoid respiratory infections.
Consider subcutaneous vaccination for influenza & pneumococcus in the proband.
Recommend pertussis & influenza vaccination in family members.
Avoid supplemental oxygen, which can suppress respiratory drive.
NSAIDs or COX-2 inhibitors (oral or topical)
Other anti-inflammatory medications including mast cell stabilizers, leukotriene inhibitors
Consider corticosteroids, particularly for flare-ups affecting the submandibular region or jaw, major joints, & after significant soft-tissue trauma.
Consider oral corticosteroids for prophylaxis prior to dental & surgical procedures.
Consider prophylactic treatment to prevent gastrointestinal complications due to NSAIDs or COX-2 inhibitors.
Avoid narcotic analgesia if possible.
No definitive evidence for use of bisphosphonates or imatinib
Fractures usually heal w/minimal heterotopic bone formation.
Avoid open reduction & internal fixation, which can precipitate heterotopic ossification.
Encourage fluid intake (1.5-2 L/day).
Avoid high-protein & high-salt diets.
Elevate legs during sleep & while recumbent.
DVT prophylaxis
Supportive stockings while avoiding traumatic compression
ADL = activities of daily living; DVT = deep vein thrombosis; NSAID = nonsteroidal anti-inflammatory drug; OT = occupational therapy
See
Anti-influenza medication (oseltamivir) at first sign of influenza-like illness, while contacting medical practitioner
Note: Treatments for which no definitive evidence supports their use in FOP include chemotherapy, radiotherapy, bone marrow transplantation, and the chronic use of antiangiogenic agents, calcium binders, colchicine, fluoroquinolone antibiotics, propranolol, mineralization inhibitors, PPAR-gamma antagonists, and TNF-α inhibitors [
• Avoid overstretching of jaw.
• Care w/local anesthesia
• Modification of activity
• Improved household safety (e.g., install handrails, secure loose carpeting, remove objects from walkways, eliminate uneven flooring.)
• Use of ambulatory devices
• Prompt medical attention
• Consider head & neck injuries to be serious until proven otherwise.
• Consider prophylactic corticosteroid use.
• Preventative dental care from a young age
• Consult FOP expert prior to dental procedures.
• Dental care may be affected by spontaneous or post-traumatic jaw ankylosis.
• Consider corticosteroids for prophylaxis prior to dental & surgical procedures.
• If general anesthesia is required, an awake intubation by nasotracheal fiber-optic technique should be performed because of neck malformations, jaw ankylosis, sensitive airway, & risk of an obstructing neck flare-up.
• Highly skilled FOP-aware anesthesiologists should be present for all elective intubations.
• Singing, swimming, incentive spirometry
• Positive pressure ventilation when indicated
• Avoid respiratory infections.
• Consider subcutaneous vaccination for influenza & pneumococcus in the proband.
• Recommend pertussis & influenza vaccination in family members.
• Avoid supplemental oxygen, which can suppress respiratory drive.
• NSAIDs or COX-2 inhibitors (oral or topical)
• Other anti-inflammatory medications including mast cell stabilizers, leukotriene inhibitors
• Consider corticosteroids, particularly for flare-ups affecting the submandibular region or jaw, major joints, & after significant soft-tissue trauma.
• Consider oral corticosteroids for prophylaxis prior to dental & surgical procedures.
• Consider prophylactic treatment to prevent gastrointestinal complications due to NSAIDs or COX-2 inhibitors.
• Avoid narcotic analgesia if possible.
• No definitive evidence for use of bisphosphonates or imatinib
• Fractures usually heal w/minimal heterotopic bone formation.
• Avoid open reduction & internal fixation, which can precipitate heterotopic ossification.
• Encourage fluid intake (1.5-2 L/day).
• Avoid high-protein & high-salt diets.
• Elevate legs during sleep & while recumbent.
• DVT prophylaxis
• Supportive stockings while avoiding traumatic compression
## Surveillance
Recommended Surveillance for Individuals with Fibrodysplasia Ossificans Progressiva
Clinical eval w/orthopedist &/or clinical geneticist w/experience in managing FOP
Careful eval for scoliosis, which may be progressive
Anthropometric assessment
Nutrition eval to monitor weight & caloric intake
Clinical history & physical exam for jaw ankylosis
Clinical history & physical exam for signs/symptoms of respiratory disease
Pulmonary assessments & sleep assessments
Echocardiogram
Baseline pulmonary function assessment, sleep assessments, & echocardiogram before age 10 yrs (earlier if indicated)
Annual clinical eval w/investigations as clinically indicated to guide specific respiratory therapies, incl positive pressure ventilation
If corticosteroid treatment has been extensive, consider eval for corticosteroid-induced osteopenia/osteoporosis.
Eval for fall risk
Based on
DVT = deep vein thrombosis; NSAID = nonsteroidal anti-inflammatory drug
• Clinical eval w/orthopedist &/or clinical geneticist w/experience in managing FOP
• Careful eval for scoliosis, which may be progressive
• Anthropometric assessment
• Nutrition eval to monitor weight & caloric intake
• Clinical history & physical exam for jaw ankylosis
• Clinical history & physical exam for signs/symptoms of respiratory disease
• Pulmonary assessments & sleep assessments
• Echocardiogram
• Baseline pulmonary function assessment, sleep assessments, & echocardiogram before age 10 yrs (earlier if indicated)
• Annual clinical eval w/investigations as clinically indicated to guide specific respiratory therapies, incl positive pressure ventilation
• If corticosteroid treatment has been extensive, consider eval for corticosteroid-induced osteopenia/osteoporosis.
• Eval for fall risk
## Agents/Circumstances to Avoid
It is imperative that iatrogenic harm is limited by avoiding procedures that predispose to soft-tissue injury, including intramuscular injections such as vaccinations, dental procedures, procedures related to anesthesia, biopsies, removal of heterotopic bone, and all nonemergent surgical procedures [
Other activities to avoid include soft-tissue injuries, contact sports, overstretching of soft tissues, muscle fatigue, and passive range of motion (caution is required during treatment with physical therapists) [
Falls should be actively avoided. Protective headwear should be considered for children who have upper limb involvement to prevent fall-induced head injury. Mobility aids may be effective in reducing falls in all age groups [
In individuals with thoracic insufficiency syndrome, avoid supplemental oxygen, which can suppress respiratory drive.
Administration of vaccinations must be carefully managed in individuals with FOP. Detailed guidelines are available [
## Evaluation of Relatives at Risk
It may be appropriate to clarify the genetic status of apparently asymptomatic young sibs of an affected individual in order to identify individuals at risk of iatrogenic harm (e.g., intramuscular injections) and other sources of trauma that may precipitate heterotopic ossification.
Note: For adult at-risk family members of a proband with classic FOP, molecular genetic testing in the absence of supportive physical examination findings (i.e., hallux deformity and signs of heterotopic ossification) is not usually required. However, for the evaluation of adult family members of a proband with atypical FOP, molecular genetic testing is recommended because manifestations of FOP may not be clinically apparent on physical examination.
See
## Pregnancy Management
It is not known whether women with FOP have impaired fertility. Pregnancy in women with FOP is uncommon, as the disease manifestations at reproductive age limit reproductive potential. FOP poses major life-threatening risks to mother and fetus because of potential mechanical restrictions secondary to heterotopic ossification affecting the pelvis and surrounding regions, as well as breathing difficulties in later pregnancy secondary to restrictive chest wall disease. There is an increased risk of thromboembolism exacerbated by immobility. Ideally, pregnancy in a woman with FOP should be provided at a high-risk pregnancy center and follow established guidelines for the management of pregnancy in women with FOP (see
See
## Therapies Under Investigation
Research to develop treatments for FOP has focused on targeted inhibition of the ACVR1 receptor, ACVR1 ligands, BMP pathway signaling, pre-osseous chondrogenic heterotopic ossification, and inflammatory triggers of disease activity.
REGN2477 is an antibody that binds to activin A and blocks its activity. By binding and blocking activin A, REN2477 may prevent the formation and stop the growth of heterotopic ossification in individuals with FOP. REGN2477 is currently in Phase II clinical trials in individuals older than age 18 years.
Sirolimus is an mTOR inhibitor that may reduce heterotopic ossification. Sirolimus is currently in Phase II clinical trials in individuals older than age six years.
Several other agents are currently undergoing safety and tolerability assessment in Phase I clinical trials. Further information on therapies under investigation is available in
Search
## Genetic Counseling
Fibrodysplasia ossificans progressiva (FOP) is inherited in an autosomal dominant manner.
Most individuals diagnosed with FOP have the disorder as the result of a
Rarely, an individual diagnosed with FOP has an affected parent.
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the proband most likely has a
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with atypical or non-classic FOP may appear to be negative because of failure to recognize the disorder in other family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic (and germline) mosaicism for the variant and may be mildly/minimally affected. Possible parental mosaicism was reported in the mildly affected father (who had minimal evidence of heterotopic ossification without hallux malformation) of a daughter with classic heterotropic ossification and hallux malformation. The daughter was heterozygous for the common
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of FOP is estimated to be near complete with intrafamilial clinical variability.
If the proband has a known
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with FOP have the disorder as the result of a
• Rarely, an individual diagnosed with FOP has an affected parent.
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the proband most likely has a
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with atypical or non-classic FOP may appear to be negative because of failure to recognize the disorder in other family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic (and germline) mosaicism for the variant and may be mildly/minimally affected. Possible parental mosaicism was reported in the mildly affected father (who had minimal evidence of heterotopic ossification without hallux malformation) of a daughter with classic heterotropic ossification and hallux malformation. The daughter was heterozygous for the common
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of FOP is estimated to be near complete with intrafamilial clinical variability.
• If the proband has a known
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Fibrodysplasia ossificans progressiva (FOP) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with FOP have the disorder as the result of a
Rarely, an individual diagnosed with FOP has an affected parent.
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the proband most likely has a
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with atypical or non-classic FOP may appear to be negative because of failure to recognize the disorder in other family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic (and germline) mosaicism for the variant and may be mildly/minimally affected. Possible parental mosaicism was reported in the mildly affected father (who had minimal evidence of heterotopic ossification without hallux malformation) of a daughter with classic heterotropic ossification and hallux malformation. The daughter was heterozygous for the common
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of FOP is estimated to be near complete with intrafamilial clinical variability.
If the proband has a known
If the parents have not been tested for the
• Most individuals diagnosed with FOP have the disorder as the result of a
• Rarely, an individual diagnosed with FOP has an affected parent.
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the proband most likely has a
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with atypical or non-classic FOP may appear to be negative because of failure to recognize the disorder in other family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic (and germline) mosaicism for the variant and may be mildly/minimally affected. Possible parental mosaicism was reported in the mildly affected father (who had minimal evidence of heterotopic ossification without hallux malformation) of a daughter with classic heterotropic ossification and hallux malformation. The daughter was heterozygous for the common
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of FOP is estimated to be near complete with intrafamilial clinical variability.
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 196217
Winter Springs FL 32719-6217
•
•
•
• PO Box 196217
• Winter Springs FL 32719-6217
•
•
•
•
•
## Molecular Genetics
Fibrodysplasia Ossificans Progressiva: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Fibrodysplasia Ossificans Progressiva (
Notable
Variants listed in the table have been provided by the authors.
Somatic gain-of-function variants in
## Molecular Pathogenesis
Notable
Variants listed in the table have been provided by the authors.
## Cancer and Benign Tumors
Somatic gain-of-function variants in
## Chapter Notes
23 May 2024 (sw) Revision: added
11 May 2023 (sw) Revision: "
11 June 2020 (me) Review posted live
19 February 2020 (la) Original submission
• 23 May 2024 (sw) Revision: added
• 11 May 2023 (sw) Revision: "
• 11 June 2020 (me) Review posted live
• 19 February 2020 (la) Original submission
## Revision History
23 May 2024 (sw) Revision: added
11 May 2023 (sw) Revision: "
11 June 2020 (me) Review posted live
19 February 2020 (la) Original submission
• 23 May 2024 (sw) Revision: added
• 11 May 2023 (sw) Revision: "
• 11 June 2020 (me) Review posted live
• 19 February 2020 (la) Original submission
## Key Sections in this
## References
Kaplan FS, Al Mukaddam M, Baujat G, Brown M, Cali A, Cho T-J, Crowe C, De Cunto C, Delai P, Diecidue R, Di Rocco M, Eekhoff EMW, Friedman C, Grunwald Z, Haga N, Hsiao E, Keen R, Kitterman J, Levy C, Morhart R, Netelenbos C, Scott C, Shore EM, Zasloff M, Zhang K, Pignolo RJ. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP. 2019;1:1-111. Available
• Kaplan FS, Al Mukaddam M, Baujat G, Brown M, Cali A, Cho T-J, Crowe C, De Cunto C, Delai P, Diecidue R, Di Rocco M, Eekhoff EMW, Friedman C, Grunwald Z, Haga N, Hsiao E, Keen R, Kitterman J, Levy C, Morhart R, Netelenbos C, Scott C, Shore EM, Zasloff M, Zhang K, Pignolo RJ. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP. 2019;1:1-111. Available
## Published Guidelines / Consensus Statements
Kaplan FS, Al Mukaddam M, Baujat G, Brown M, Cali A, Cho T-J, Crowe C, De Cunto C, Delai P, Diecidue R, Di Rocco M, Eekhoff EMW, Friedman C, Grunwald Z, Haga N, Hsiao E, Keen R, Kitterman J, Levy C, Morhart R, Netelenbos C, Scott C, Shore EM, Zasloff M, Zhang K, Pignolo RJ. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP. 2019;1:1-111. Available
• Kaplan FS, Al Mukaddam M, Baujat G, Brown M, Cali A, Cho T-J, Crowe C, De Cunto C, Delai P, Diecidue R, Di Rocco M, Eekhoff EMW, Friedman C, Grunwald Z, Haga N, Hsiao E, Keen R, Kitterman J, Levy C, Morhart R, Netelenbos C, Scott C, Shore EM, Zasloff M, Zhang K, Pignolo RJ. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Proc Intl Clin Council FOP. 2019;1:1-111. Available
## Literature Cited
Characteristic features of FOP. A photograph (A) and radiograph (B) of the feet in an affected boy age 15 years with classic FOP show short, malformed halluces with a single, dysplastic phalanx in each great toe. A photograph of his back (C) and a radiograph of his lumbar spine (D) reveal confluent areas (plates) of heterotopic bone (D, arrows).
Reproduced with permission from
|
[] |
11/6/2020
|
23/5/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
foxg1-ndd
|
foxg1-ndd
|
[
"FOXG1-Related Disorder",
"FOXG1-Related Encephalopathy",
"FOXG1-Related Neurodevelopmental Disorder",
"FOXG1-Related Neurodevelopmental Disorder",
"FOXG1-Related Disorder",
"FOXG1-Related Encephalopathy",
"Forkhead box protein G1",
"FOXG1",
"FOXG1 Syndrome"
] |
Knut Brockmann, Martin Staudt
|
Summary The diagnosis of
|
## Diagnosis
Severe developmental delay; absent speech development in most individuals
Severe intellectual disability
Generalized hypotonia of infancy
Infant feeding difficulties and poor weight gain
Hyperkinetic/dyskinetic movement disorder
Epilepsy with a wide range of seizure types including infantile spasms, focal, complex focal, generalized tonic, atonic, myoclonic, and Lennox-Gastaut syndrome
Spasticity
Neurobehavioral/psychiatric manifestations including motor stereotypies, impairment of social interaction, abnormal sleep patterns, unexplained episodes of crying, restlessness, and bruxism
Gastroesophageal reflux and recurrent aspiration
Microcephaly (congenital or postnatal onset)
Short stature in about 50% of individuals
Strabismus and cortical visual impairment
Corpus callosum anomalies with filiform thinning of the rostrum
Thickening of the fornices
Simplified gyral pattern
Enlargement of the inner cerebrospinal fluid spaces
Hypoplasia of the basal ganglia
Hypoplasia of the frontal lobes
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Several additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see
Individuals with whole-gene
• Severe developmental delay; absent speech development in most individuals
• Severe intellectual disability
• Generalized hypotonia of infancy
• Infant feeding difficulties and poor weight gain
• Hyperkinetic/dyskinetic movement disorder
• Epilepsy with a wide range of seizure types including infantile spasms, focal, complex focal, generalized tonic, atonic, myoclonic, and Lennox-Gastaut syndrome
• Spasticity
• Neurobehavioral/psychiatric manifestations including motor stereotypies, impairment of social interaction, abnormal sleep patterns, unexplained episodes of crying, restlessness, and bruxism
• Gastroesophageal reflux and recurrent aspiration
• Microcephaly (congenital or postnatal onset)
• Short stature in about 50% of individuals
• Strabismus and cortical visual impairment
• Corpus callosum anomalies with filiform thinning of the rostrum
• Thickening of the fornices
• Simplified gyral pattern
• Enlargement of the inner cerebrospinal fluid spaces
• Hypoplasia of the basal ganglia
• Hypoplasia of the frontal lobes
## Suggestive Findings
Severe developmental delay; absent speech development in most individuals
Severe intellectual disability
Generalized hypotonia of infancy
Infant feeding difficulties and poor weight gain
Hyperkinetic/dyskinetic movement disorder
Epilepsy with a wide range of seizure types including infantile spasms, focal, complex focal, generalized tonic, atonic, myoclonic, and Lennox-Gastaut syndrome
Spasticity
Neurobehavioral/psychiatric manifestations including motor stereotypies, impairment of social interaction, abnormal sleep patterns, unexplained episodes of crying, restlessness, and bruxism
Gastroesophageal reflux and recurrent aspiration
Microcephaly (congenital or postnatal onset)
Short stature in about 50% of individuals
Strabismus and cortical visual impairment
Corpus callosum anomalies with filiform thinning of the rostrum
Thickening of the fornices
Simplified gyral pattern
Enlargement of the inner cerebrospinal fluid spaces
Hypoplasia of the basal ganglia
Hypoplasia of the frontal lobes
• Severe developmental delay; absent speech development in most individuals
• Severe intellectual disability
• Generalized hypotonia of infancy
• Infant feeding difficulties and poor weight gain
• Hyperkinetic/dyskinetic movement disorder
• Epilepsy with a wide range of seizure types including infantile spasms, focal, complex focal, generalized tonic, atonic, myoclonic, and Lennox-Gastaut syndrome
• Spasticity
• Neurobehavioral/psychiatric manifestations including motor stereotypies, impairment of social interaction, abnormal sleep patterns, unexplained episodes of crying, restlessness, and bruxism
• Gastroesophageal reflux and recurrent aspiration
• Microcephaly (congenital or postnatal onset)
• Short stature in about 50% of individuals
• Strabismus and cortical visual impairment
• Corpus callosum anomalies with filiform thinning of the rostrum
• Thickening of the fornices
• Simplified gyral pattern
• Enlargement of the inner cerebrospinal fluid spaces
• Hypoplasia of the basal ganglia
• Hypoplasia of the frontal lobes
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Several additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see
Individuals with whole-gene
## Option 1
For an introduction to comprehensive genomic testing click
## Option 2
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Several additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see
Individuals with whole-gene
## Clinical Characteristics
Select Features of
Based on
BMI = body mass index; SD = standard deviations
In a study of 83 individuals with age at last follow up ranging from 14 months to 32 years, 21% had some verbal expression. Age at first words was reported in nine individuals, with a mean age of 46 months (range: 21 months to 9 years). Mean number of spoken words in those who had some verbal expression was 19 (range: 2-100 words) [
Several reports have indicated a genotype-phenotype association.
Individuals with truncating pathogenic variants or intragenic deletions show more severe clinical phenotypes than those with missense pathogenic variants [
Of note, three unrelated individuals who developed Lennox-Gastaut syndrome all had a missense pathogenic variant affecting amino acid 187 [
To date, no individuals (e.g., parent) with a pathogenic variant have been reported to be non-penetrant. Thus, penetrance is expected to be complete.
To date, no data on the prevalence of
## Clinical Description
Select Features of
Based on
BMI = body mass index; SD = standard deviations
In a study of 83 individuals with age at last follow up ranging from 14 months to 32 years, 21% had some verbal expression. Age at first words was reported in nine individuals, with a mean age of 46 months (range: 21 months to 9 years). Mean number of spoken words in those who had some verbal expression was 19 (range: 2-100 words) [
## Genotype-Phenotype Correlations
Several reports have indicated a genotype-phenotype association.
Individuals with truncating pathogenic variants or intragenic deletions show more severe clinical phenotypes than those with missense pathogenic variants [
Of note, three unrelated individuals who developed Lennox-Gastaut syndrome all had a missense pathogenic variant affecting amino acid 187 [
## Penetrance
To date, no individuals (e.g., parent) with a pathogenic variant have been reported to be non-penetrant. Thus, penetrance is expected to be complete.
## Nomenclature
## Prevalence
To date, no data on the prevalence of
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Selected Disorders of Interest in the Differential Diagnosis of
Severe DD/ID
Hypotonia
Central visual impairment
Deceleration of growth (weight, height, head circumference) after birth
Predominant severe refractory infantile-onset epilepsy
Neuroimaging may show progressive cerebral atrophy (but not malformations, as characteristically observed in
Global DD
Sleep disturbances
Seizures
Hand stereotypies & loss of purposeful hand skills
Breathing irregularities
Agitation
In females, apparently normal psychomotor development during 1st 6-18 mos of life
Psychomotor regression is characteristically observed.
Gait abnormalities
Absence of hyperkinetic/dyskinetic movement disorder
Neuroimaging is normal.
Severe DD/ID
Severe speech impairment
Acquired microcephaly
Seizures
Unique behavior w/apparent happy demeanor, frequent laughing, smiling, & excitability
Gait ataxia (not hypotonia &/or spasticity as in
Highly characteristic EEG features are noted early in disease course.
Neuroimaging is typically normal.
DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
Individuals with Angelman syndrome typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a
• Severe DD/ID
• Hypotonia
• Central visual impairment
• Deceleration of growth (weight, height, head circumference) after birth
• Predominant severe refractory infantile-onset epilepsy
• Neuroimaging may show progressive cerebral atrophy (but not malformations, as characteristically observed in
• Global DD
• Sleep disturbances
• Seizures
• Hand stereotypies & loss of purposeful hand skills
• Breathing irregularities
• Agitation
• In females, apparently normal psychomotor development during 1st 6-18 mos of life
• Psychomotor regression is characteristically observed.
• Gait abnormalities
• Absence of hyperkinetic/dyskinetic movement disorder
• Neuroimaging is normal.
• Severe DD/ID
• Severe speech impairment
• Acquired microcephaly
• Seizures
• Unique behavior w/apparent happy demeanor, frequent laughing, smiling, & excitability
• Gait ataxia (not hypotonia &/or spasticity as in
• Highly characteristic EEG features are noted early in disease course.
• Neuroimaging is typically normal.
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI
Consider EEG if seizures are a concern.
To incl eval for hyperkinetic/dyskinetic movement disorder
For infants: screening for irritability, episodes of crying, abnormal sleep patterns
For persons age >12 mos: screening for concerns incl sleep disturbances, impairment of social interaction
To incl assessment for feeding difficulties
To incl eval for gastroesophageal reflux
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement &/or fundoplication in persons w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Local: botulinum toxin
Systemic: baclofen, tolperisone, nitrazepam
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Standard therapies for gastroesophageal reflux
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Incidence of constipation has not been reported in individuals with
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, when necessary.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Assessment for gastroesophageal reflux
OT = occupational therapy; PT = physical therapy
Incidence of constipation has not been reported in individuals with
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl eval for hyperkinetic/dyskinetic movement disorder
• For infants: screening for irritability, episodes of crying, abnormal sleep patterns
• For persons age >12 mos: screening for concerns incl sleep disturbances, impairment of social interaction
• To incl assessment for feeding difficulties
• To incl eval for gastroesophageal reflux
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement &/or fundoplication in persons w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support
• Home nursing referral
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Local: botulinum toxin
• Systemic: baclofen, tolperisone, nitrazepam
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Standard therapies for gastroesophageal reflux
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Assessment for gastroesophageal reflux
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI
Consider EEG if seizures are a concern.
To incl eval for hyperkinetic/dyskinetic movement disorder
For infants: screening for irritability, episodes of crying, abnormal sleep patterns
For persons age >12 mos: screening for concerns incl sleep disturbances, impairment of social interaction
To incl assessment for feeding difficulties
To incl eval for gastroesophageal reflux
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement &/or fundoplication in persons w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl eval for hyperkinetic/dyskinetic movement disorder
• For infants: screening for irritability, episodes of crying, abnormal sleep patterns
• For persons age >12 mos: screening for concerns incl sleep disturbances, impairment of social interaction
• To incl assessment for feeding difficulties
• To incl eval for gastroesophageal reflux
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement &/or fundoplication in persons w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Local: botulinum toxin
Systemic: baclofen, tolperisone, nitrazepam
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Standard therapies for gastroesophageal reflux
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Incidence of constipation has not been reported in individuals with
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, when necessary.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Local: botulinum toxin
• Systemic: baclofen, tolperisone, nitrazepam
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Standard therapies for gastroesophageal reflux
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the US; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, when necessary.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Assessment for gastroesophageal reflux
OT = occupational therapy; PT = physical therapy
Incidence of constipation has not been reported in individuals with
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Assessment for gastroesophageal reflux
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most probands reported to date with
Rarely, a proband with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a parent of the proband is known to have the
If the
Individuals with
Each child of an individual with
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Risk to future pregnancies is presumed to be low, as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most probands reported to date with
• Rarely, a proband with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is known to have the
• If the
• Individuals with
• Each child of an individual with
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Most probands reported to date with
Rarely, a proband with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a parent of the proband is known to have the
If the
Individuals with
Each child of an individual with
• Most probands reported to date with
• Rarely, a proband with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is known to have the
• If the
• Individuals with
• Each child of an individual with
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Risk to future pregnancies is presumed to be low, as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
## Molecular Genetics
FOXG1 Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FOXG1 Syndrome (
Note: The pathomechanism of
## Molecular Pathogenesis
Note: The pathomechanism of
## Chapter Notes
KB and MS thank all our colleagues who worked with us in our
This work was supported by funding from the Niedersächsisches Ministerium für Wissenschaft und Kultur, grant no. 74ZN1284 (to KB).
1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
6 June 2024 (sw) Review posted live
13 November 2023 (kb) Original submission
• 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 6 June 2024 (sw) Review posted live
• 13 November 2023 (kb) Original submission
## Acknowledgments
KB and MS thank all our colleagues who worked with us in our
This work was supported by funding from the Niedersächsisches Ministerium für Wissenschaft und Kultur, grant no. 74ZN1284 (to KB).
## Revision History
1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
6 June 2024 (sw) Review posted live
13 November 2023 (kb) Original submission
• 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 6 June 2024 (sw) Review posted live
• 13 November 2023 (kb) Original submission
## References
## Literature Cited
|
[] |
6/6/2024
|
1/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
foxp1
|
foxp1
|
[
"FOXP1 Haploinsufficiency",
"FOXP1-Related Neurodevelopmental Disorder",
"FOXP1 Haploinsufficiency",
"FOXP1-Related Neurodevelopmental Disorder",
"Forkhead box protein P1",
"FOXP1",
"FOXP1 Syndrome"
] |
FOXP1 Syndrome
|
Gudrun Rappold, Paige Siper, Ana Kostic, Ruth Braden, Angela Morgan, Saskia Koene, Alexander Kolevzon
|
Summary FOXP1 syndrome is characterized by delays in early motor and language milestones, mild-to-severe intellectual deficits, speech and language impairment in all individuals regardless of level of cognitive abilities, and behavior abnormalities (including autism spectrum disorder or autistic features, attention-deficit/hyperactivity disorder, anxiety, repetitive behaviors, sleep disturbances, and sensory symptoms). Other common findings are oromotor dysfunction (contributing to speech and feeding difficulties), refractive errors, strabismus, cardiac abnormalities, renal abnormalities, cryptorchidism, hypertonia, hearing loss, and epilepsy. To date, more than 200 individuals have been identified with FOXP1 syndrome. The diagnosis of FOXP1 syndrome is established in a proband with a heterozygous pathogenic variant in FOXP1 syndrome is an autosomal dominant disorder typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for FOXP1 syndrome have been published.
FOXP1 syndrome should be considered in a proband with the following clinical findings, imaging findings, and family history.
Generalized hypotonia of infancy
Infant feeding issues
Mild-to-severe intellectual disability
Speech and language disorder
Delays in early motor and language milestones
Behavior abnormalities:
Attention-deficit/hyperactivity disorder
Anxiety, combined with other clinical signs
Autism spectrum disorder or autistic features
Repetitive behaviors
Strabismus, refractive errors
Cryptorchidism
Congenital abnormalities of the heart and/or kidneys
The diagnosis of FOXP1 syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in FOXP1 Syndrome
See
See
Additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
S Koene, unpublished data
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
There are three reports of complex rearrangements including inversions and translocations involving the
• Generalized hypotonia of infancy
• Infant feeding issues
• Mild-to-severe intellectual disability
• Speech and language disorder
• Delays in early motor and language milestones
• Behavior abnormalities:
• Attention-deficit/hyperactivity disorder
• Anxiety, combined with other clinical signs
• Autism spectrum disorder or autistic features
• Repetitive behaviors
• Attention-deficit/hyperactivity disorder
• Anxiety, combined with other clinical signs
• Autism spectrum disorder or autistic features
• Repetitive behaviors
• Strabismus, refractive errors
• Cryptorchidism
• Congenital abnormalities of the heart and/or kidneys
• Attention-deficit/hyperactivity disorder
• Anxiety, combined with other clinical signs
• Autism spectrum disorder or autistic features
• Repetitive behaviors
## Suggestive Findings
FOXP1 syndrome should be considered in a proband with the following clinical findings, imaging findings, and family history.
Generalized hypotonia of infancy
Infant feeding issues
Mild-to-severe intellectual disability
Speech and language disorder
Delays in early motor and language milestones
Behavior abnormalities:
Attention-deficit/hyperactivity disorder
Anxiety, combined with other clinical signs
Autism spectrum disorder or autistic features
Repetitive behaviors
Strabismus, refractive errors
Cryptorchidism
Congenital abnormalities of the heart and/or kidneys
• Generalized hypotonia of infancy
• Infant feeding issues
• Mild-to-severe intellectual disability
• Speech and language disorder
• Delays in early motor and language milestones
• Behavior abnormalities:
• Attention-deficit/hyperactivity disorder
• Anxiety, combined with other clinical signs
• Autism spectrum disorder or autistic features
• Repetitive behaviors
• Attention-deficit/hyperactivity disorder
• Anxiety, combined with other clinical signs
• Autism spectrum disorder or autistic features
• Repetitive behaviors
• Strabismus, refractive errors
• Cryptorchidism
• Congenital abnormalities of the heart and/or kidneys
• Attention-deficit/hyperactivity disorder
• Anxiety, combined with other clinical signs
• Autism spectrum disorder or autistic features
• Repetitive behaviors
## Establishing the Diagnosis
The diagnosis of FOXP1 syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in FOXP1 Syndrome
See
See
Additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
S Koene, unpublished data
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
There are three reports of complex rearrangements including inversions and translocations involving the
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in FOXP1 Syndrome
See
See
Additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
S Koene, unpublished data
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
There are three reports of complex rearrangements including inversions and translocations involving the
## Clinical Characteristics
FOXP1 syndrome is characterized by mild-to-severe intellectual disability, speech and language impairment in all individuals despite level of cognitive abilities, behavior abnormalities (including autism spectrum disorder or autistic features, attention-deficit/hyperactivity disorder, anxiety, repetitive behaviors, and sensory symptoms), and dysmorphic features.
To date, more than 200 individuals have been identified with a pathogenic variant in
FOXP1 Syndrome: Frequency of Select Features
Adapted from
CAKUT = congenital anomalies of the kidney and urinary tract
The speech difficulties lead listeners to presume expression of language (vocabulary, grammar) is more affected than understanding, but this is not the case.
Development and maintenance of friendships is an area of particular challenge.
Despite certain social communication strengths, repetitive behaviors, restricted interests, and sensory symptoms are highly prevalent even in those who do not meet DSM-5 criteria for ASD. Specifically, long-standing restricted interests are common and can be all encompassing in their intensity (e.g., collecting objects of interest).
Sensory manifestations are characterized by frequent sensory seeking (finger picking is also common), tactile hyporeactivity (i.e., high pain threshold), and auditory hyperreactvity. Repetitive behaviors and sensory manifestations are present in the majority of individuals with FOXP1 syndrome regardless of the diagnosis of ASD.
Behavioral problems include hyperactivity, attention problems, impulsivity, aggression, anxiety, mood lability, obsessions, and compulsions. Attention-deficit/hyperactivity disorder (ADHD) is present in the majority of individuals, often combined with hyperactivity and inattention.
Aggressive behavior is common, often emerging during early childhood and likely due to low frustration tolerance and communication challenges. In most individuals, hyperactivity and aggressive behavior appear to improve with age.
Hypotonia, seen in half of affected individuals, can be either generalized or axial. Some individuals have peripheral hypertonia and axial hypertonia. In the latter instance, movement disorder / gait disturbance can include the presence of spastic contractures. Muscle spasms have also been reported.
Swallowing problems may also result from esophageal achalasia, resulting from failure of the lower esophageal sphincter to relax after swallowing [
No genotype-phenotype correlations have been identified.
FOXP1 syndrome may be referred to as "
FOXP1 syndrome is considered rare. Approximately 200 individuals have been identified in the medical literature and by the
According to the
## Clinical Description
FOXP1 syndrome is characterized by mild-to-severe intellectual disability, speech and language impairment in all individuals despite level of cognitive abilities, behavior abnormalities (including autism spectrum disorder or autistic features, attention-deficit/hyperactivity disorder, anxiety, repetitive behaviors, and sensory symptoms), and dysmorphic features.
To date, more than 200 individuals have been identified with a pathogenic variant in
FOXP1 Syndrome: Frequency of Select Features
Adapted from
CAKUT = congenital anomalies of the kidney and urinary tract
The speech difficulties lead listeners to presume expression of language (vocabulary, grammar) is more affected than understanding, but this is not the case.
Development and maintenance of friendships is an area of particular challenge.
Despite certain social communication strengths, repetitive behaviors, restricted interests, and sensory symptoms are highly prevalent even in those who do not meet DSM-5 criteria for ASD. Specifically, long-standing restricted interests are common and can be all encompassing in their intensity (e.g., collecting objects of interest).
Sensory manifestations are characterized by frequent sensory seeking (finger picking is also common), tactile hyporeactivity (i.e., high pain threshold), and auditory hyperreactvity. Repetitive behaviors and sensory manifestations are present in the majority of individuals with FOXP1 syndrome regardless of the diagnosis of ASD.
Behavioral problems include hyperactivity, attention problems, impulsivity, aggression, anxiety, mood lability, obsessions, and compulsions. Attention-deficit/hyperactivity disorder (ADHD) is present in the majority of individuals, often combined with hyperactivity and inattention.
Aggressive behavior is common, often emerging during early childhood and likely due to low frustration tolerance and communication challenges. In most individuals, hyperactivity and aggressive behavior appear to improve with age.
Hypotonia, seen in half of affected individuals, can be either generalized or axial. Some individuals have peripheral hypertonia and axial hypertonia. In the latter instance, movement disorder / gait disturbance can include the presence of spastic contractures. Muscle spasms have also been reported.
Swallowing problems may also result from esophageal achalasia, resulting from failure of the lower esophageal sphincter to relax after swallowing [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
FOXP1 syndrome may be referred to as "
## Prevalence
FOXP1 syndrome is considered rare. Approximately 200 individuals have been identified in the medical literature and by the
According to the
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Hearing impairment occurs more frequently in individuals with extended 3p deletions that include
## Differential Diagnosis
Because the phenotypic features associated with FOXP1 syndrome are not sufficient to diagnose this condition, all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See
## Management
No clinical practice guidelines for FOXP1 syndrome have been published. Management recommendations below are based on information in the current literature and the authors' clinical experience.
To establish the extent of disease and needs in an individual diagnosed with FOXP1 syndrome, the evaluations summarized in
FOXP1 Syndrome: Recommended Evaluations Following Initial Diagnosis
Evaluate events suggestive of seizures; consider EEG if seizures are a concern.
Evaluate for abnormalities of tone (i.e., hypotonia & spasticity).
Perform neurologic exam to evaluate for focal &/or other abnormalities that may warrant brain MRI.
Gross motor & fine motor skills;
Spasticity, joint contractures, scoliosis;
Mobility, ADL, & need for adaptive devices;
Need for ongoing PT therapy (to improve gross motor skills) &/or ongoing OT therapy (to improve fine motor skills, sensory processing).
Evaluate oral motor function incl drooling.
Evaluate speech production & receptive/expressive language in all persons, regardless of age.
To pinpoint specific diagnoses & make recommendations for targeted therapies
To screen for behavior concerns incl ADHD, impulsivity, anxiety, sleep disturbances, &/or findings suggestive of ASD
To evaluate risk of aspiration & nutritional status
To assess for feeding challenges relative to developmental stage (e.g., breast/bottle feeding in infancy; transition to chewable solids in toddlers)
Community or
Social work involvement for parental support;
Home nursing referral;
Early intervention referral;
Case management support referral.
* = for all individuals; ** = based on concern
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CAKUT = congenital anomalies of the kidney and urinary tract; MOI = mode of inheritance; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathology/pathologist; UTI = urinary tract infection
Gold-standard autism diagnostic assessments such as the Autism Diagnostic Observation Schedule, 2nd Edition (ADOS
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for FOXP1 syndrome.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatrics, developmental medicine or neurodevelopment, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, psychology, ophthalmology, and medical genetics (see
FOXP1 Syndrome: Treatment of Manifestations
Speech & language therapy tailored to child's specific profile & developmental age.
Consider early reading & spelling support as age appropriate.
Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Connect to parent advocacy group.
ASM = anti-seizure medication; OT = occupational therapy/therapist; PT = physical therapy/therapist
Occupational therapy with the use of sensory-based therapies may be acceptable as one of the components of a comprehensive treatment plan. However, parents should be informed that the amount of research regarding the effectiveness of sensory integration therapy is limited and inconclusive [
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
See NICE guidelines on
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
In terms of verbal development, difficulties with motor planning (apraxia) and execution (dysarthria) is severe in the early years of life, and intensive evidence-based motor speech therapies should be applied [
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician, neurologist, or psychiatrist may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a neurologist, developmental specialist, psychologist, or psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
FOXP1 Syndrome: Recommended Surveillance
Assessment of ongoing therapy initiated w/early interventional services
Referral to AAC specialist overtime if warranted
Eval for speech disorder subtype over time
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathologist
See
Search
Icahn School of Medicine at Mount Sinai is currently recruiting for an observational clinical trial on FOXP1 syndrome (
• Evaluate events suggestive of seizures; consider EEG if seizures are a concern.
• Evaluate for abnormalities of tone (i.e., hypotonia & spasticity).
• Perform neurologic exam to evaluate for focal &/or other abnormalities that may warrant brain MRI.
• Gross motor & fine motor skills;
• Spasticity, joint contractures, scoliosis;
• Mobility, ADL, & need for adaptive devices;
• Need for ongoing PT therapy (to improve gross motor skills) &/or ongoing OT therapy (to improve fine motor skills, sensory processing).
• Evaluate oral motor function incl drooling.
• Evaluate speech production & receptive/expressive language in all persons, regardless of age.
• To pinpoint specific diagnoses & make recommendations for targeted therapies
• To screen for behavior concerns incl ADHD, impulsivity, anxiety, sleep disturbances, &/or findings suggestive of ASD
• To evaluate risk of aspiration & nutritional status
• To assess for feeding challenges relative to developmental stage (e.g., breast/bottle feeding in infancy; transition to chewable solids in toddlers)
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Early intervention referral;
• Case management support referral.
• Speech & language therapy tailored to child's specific profile & developmental age.
• Consider early reading & spelling support as age appropriate.
• Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Connect to parent advocacy group.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• Assessment of ongoing therapy initiated w/early interventional services
• Referral to AAC specialist overtime if warranted
• Eval for speech disorder subtype over time
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with FOXP1 syndrome, the evaluations summarized in
FOXP1 Syndrome: Recommended Evaluations Following Initial Diagnosis
Evaluate events suggestive of seizures; consider EEG if seizures are a concern.
Evaluate for abnormalities of tone (i.e., hypotonia & spasticity).
Perform neurologic exam to evaluate for focal &/or other abnormalities that may warrant brain MRI.
Gross motor & fine motor skills;
Spasticity, joint contractures, scoliosis;
Mobility, ADL, & need for adaptive devices;
Need for ongoing PT therapy (to improve gross motor skills) &/or ongoing OT therapy (to improve fine motor skills, sensory processing).
Evaluate oral motor function incl drooling.
Evaluate speech production & receptive/expressive language in all persons, regardless of age.
To pinpoint specific diagnoses & make recommendations for targeted therapies
To screen for behavior concerns incl ADHD, impulsivity, anxiety, sleep disturbances, &/or findings suggestive of ASD
To evaluate risk of aspiration & nutritional status
To assess for feeding challenges relative to developmental stage (e.g., breast/bottle feeding in infancy; transition to chewable solids in toddlers)
Community or
Social work involvement for parental support;
Home nursing referral;
Early intervention referral;
Case management support referral.
* = for all individuals; ** = based on concern
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CAKUT = congenital anomalies of the kidney and urinary tract; MOI = mode of inheritance; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathology/pathologist; UTI = urinary tract infection
Gold-standard autism diagnostic assessments such as the Autism Diagnostic Observation Schedule, 2nd Edition (ADOS
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Evaluate events suggestive of seizures; consider EEG if seizures are a concern.
• Evaluate for abnormalities of tone (i.e., hypotonia & spasticity).
• Perform neurologic exam to evaluate for focal &/or other abnormalities that may warrant brain MRI.
• Gross motor & fine motor skills;
• Spasticity, joint contractures, scoliosis;
• Mobility, ADL, & need for adaptive devices;
• Need for ongoing PT therapy (to improve gross motor skills) &/or ongoing OT therapy (to improve fine motor skills, sensory processing).
• Evaluate oral motor function incl drooling.
• Evaluate speech production & receptive/expressive language in all persons, regardless of age.
• To pinpoint specific diagnoses & make recommendations for targeted therapies
• To screen for behavior concerns incl ADHD, impulsivity, anxiety, sleep disturbances, &/or findings suggestive of ASD
• To evaluate risk of aspiration & nutritional status
• To assess for feeding challenges relative to developmental stage (e.g., breast/bottle feeding in infancy; transition to chewable solids in toddlers)
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Early intervention referral;
• Case management support referral.
## Treatment of Manifestations
There is no cure for FOXP1 syndrome.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatrics, developmental medicine or neurodevelopment, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, psychology, ophthalmology, and medical genetics (see
FOXP1 Syndrome: Treatment of Manifestations
Speech & language therapy tailored to child's specific profile & developmental age.
Consider early reading & spelling support as age appropriate.
Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Connect to parent advocacy group.
ASM = anti-seizure medication; OT = occupational therapy/therapist; PT = physical therapy/therapist
Occupational therapy with the use of sensory-based therapies may be acceptable as one of the components of a comprehensive treatment plan. However, parents should be informed that the amount of research regarding the effectiveness of sensory integration therapy is limited and inconclusive [
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
See NICE guidelines on
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
In terms of verbal development, difficulties with motor planning (apraxia) and execution (dysarthria) is severe in the early years of life, and intensive evidence-based motor speech therapies should be applied [
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician, neurologist, or psychiatrist may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a neurologist, developmental specialist, psychologist, or psychiatrist.
• Speech & language therapy tailored to child's specific profile & developmental age.
• Consider early reading & spelling support as age appropriate.
• Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Connect to parent advocacy group.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
In terms of verbal development, difficulties with motor planning (apraxia) and execution (dysarthria) is severe in the early years of life, and intensive evidence-based motor speech therapies should be applied [
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician, neurologist, or psychiatrist may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a neurologist, developmental specialist, psychologist, or psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
FOXP1 Syndrome: Recommended Surveillance
Assessment of ongoing therapy initiated w/early interventional services
Referral to AAC specialist overtime if warranted
Eval for speech disorder subtype over time
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathologist
• Assessment of ongoing therapy initiated w/early interventional services
• Referral to AAC specialist overtime if warranted
• Eval for speech disorder subtype over time
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
Icahn School of Medicine at Mount Sinai is currently recruiting for an observational clinical trial on FOXP1 syndrome (
## Genetic Counseling
FOXP1 syndrome is an autosomal dominant disorder typically caused by a
Most probands reported to date with FOXP1 syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a
Rarely, a parent of an individual with FOXP1 syndrome has somatic and germline mosaicism for the
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the proband has a complex chromosomal rearrangement involving
If the proband has a genetic alteration involving
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is known to have the
If one of the parents has a chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Risk to future offspring of the parents of the proband is presumed to be low, as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most probands reported to date with FOXP1 syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a
• Rarely, a parent of an individual with FOXP1 syndrome has somatic and germline mosaicism for the
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the proband has a complex chromosomal rearrangement involving
• If the proband has a genetic alteration involving
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is known to have the
• If one of the parents has a chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
FOXP1 syndrome is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Most probands reported to date with FOXP1 syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a
Rarely, a parent of an individual with FOXP1 syndrome has somatic and germline mosaicism for the
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the proband has a complex chromosomal rearrangement involving
If the proband has a genetic alteration involving
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is known to have the
If one of the parents has a chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
If the
• Most probands reported to date with FOXP1 syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a
• Rarely, a parent of an individual with FOXP1 syndrome has somatic and germline mosaicism for the
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the proband has a complex chromosomal rearrangement involving
• If the proband has a genetic alteration involving
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is known to have the
• If one of the parents has a chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Risk to future offspring of the parents of the proband is presumed to be low, as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Speaking out for People with Intellectual and Developmental Disabilities
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• Speaking out for People with Intellectual and Developmental Disabilities
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## Molecular Genetics
FOXP1 Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FOXP1 Syndrome (
FOXP1 syndrome is caused by defects in
The phenotypic spectra of FOXP1 and
## Molecular Pathogenesis
FOXP1 syndrome is caused by defects in
The phenotypic spectra of FOXP1 and
## Chapter Notes
Prof Gudrun Rappold (
Dr Saskia Koene (
Dr Ruth Braden (
Contact Dr Saskia Koene (
We acknowledge the involvement of Dr Henning Fröhlich and Prof Maja Hempel in this project. Research support is from the Deutsche Forschungsgemeinschaft and the Medical Faculty of the University of Heidelberg.
We acknowledge individuals with FOXP1 syndrome and their families for their generous contributions to our research, and the
21 September 2023 (bp) Review posted live
26 August 2022 (gr) Original submission
• 21 September 2023 (bp) Review posted live
• 26 August 2022 (gr) Original submission
## Author Notes
Prof Gudrun Rappold (
Dr Saskia Koene (
Dr Ruth Braden (
Contact Dr Saskia Koene (
## Acknowledgments
We acknowledge the involvement of Dr Henning Fröhlich and Prof Maja Hempel in this project. Research support is from the Deutsche Forschungsgemeinschaft and the Medical Faculty of the University of Heidelberg.
We acknowledge individuals with FOXP1 syndrome and their families for their generous contributions to our research, and the
## Revision History
21 September 2023 (bp) Review posted live
26 August 2022 (gr) Original submission
• 21 September 2023 (bp) Review posted live
• 26 August 2022 (gr) Original submission
## References
## Literature Cited
|
[] |
21/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
foxp2-sl-dis
|
foxp2-sl-dis
|
[
"FOXP2-Only-Related Disorders",
"FOXP2-Plus-Related Disorders",
"Forkhead box protein P2",
"FOXP2",
"FOXP2-Related Speech and Language Disorder"
] |
Angela Morgan, Simon E Fisher, Ingrid Scheffer, Michael Hildebrand
|
Summary The diagnosis of
|
This chapter addresses the core phenotype (speech and language disorder) and additional (variable) findings associated with intragenic
## Diagnosis
No consensus clinical diagnostic criteria for
Children with CAS have difficulties in automatically and accurately sequencing speech sounds into words with the correct prosody.
The diagnosis of CAS is made by assessment by a speech-language pathologist (also known as a speech and language therapist in the UK or speech pathologist in Australia). CAS is challenging to diagnose in a child younger than age three years; speech development is delayed in these children, and thus key manifestations are typically not seen or able to be elicited until the child has acquired sufficient speech to complete the verbal assessment tasks.
Delayed speech development
Poor oral-motor function (e.g., excessive drooling, early feeding difficulties)
Oral-motor difficulties and/or oral-motor dyspraxia
Dysarthria
Receptive and expressive language impairment
Low average IQ, typically with poorer verbal IQ compared to nonverbal IQ (and average nonverbal IQ reported in some)
Reading and spelling impairment
Fine and gross motor impairment
Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. This percentage is an estimate derived from data regarding intragenic deletion and duplications as well as whole gene deletions from the Human Gene Mutation Database [
• Children with CAS have difficulties in automatically and accurately sequencing speech sounds into words with the correct prosody.
• The diagnosis of CAS is made by assessment by a speech-language pathologist (also known as a speech and language therapist in the UK or speech pathologist in Australia). CAS is challenging to diagnose in a child younger than age three years; speech development is delayed in these children, and thus key manifestations are typically not seen or able to be elicited until the child has acquired sufficient speech to complete the verbal assessment tasks.
• Delayed speech development
• Poor oral-motor function (e.g., excessive drooling, early feeding difficulties)
• Oral-motor difficulties and/or oral-motor dyspraxia
• Dysarthria
• Receptive and expressive language impairment
• Low average IQ, typically with poorer verbal IQ compared to nonverbal IQ (and average nonverbal IQ reported in some)
• Reading and spelling impairment
• Fine and gross motor impairment
## Suggestive Findings
Children with CAS have difficulties in automatically and accurately sequencing speech sounds into words with the correct prosody.
The diagnosis of CAS is made by assessment by a speech-language pathologist (also known as a speech and language therapist in the UK or speech pathologist in Australia). CAS is challenging to diagnose in a child younger than age three years; speech development is delayed in these children, and thus key manifestations are typically not seen or able to be elicited until the child has acquired sufficient speech to complete the verbal assessment tasks.
Delayed speech development
Poor oral-motor function (e.g., excessive drooling, early feeding difficulties)
Oral-motor difficulties and/or oral-motor dyspraxia
Dysarthria
Receptive and expressive language impairment
Low average IQ, typically with poorer verbal IQ compared to nonverbal IQ (and average nonverbal IQ reported in some)
Reading and spelling impairment
Fine and gross motor impairment
Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.
• Children with CAS have difficulties in automatically and accurately sequencing speech sounds into words with the correct prosody.
• The diagnosis of CAS is made by assessment by a speech-language pathologist (also known as a speech and language therapist in the UK or speech pathologist in Australia). CAS is challenging to diagnose in a child younger than age three years; speech development is delayed in these children, and thus key manifestations are typically not seen or able to be elicited until the child has acquired sufficient speech to complete the verbal assessment tasks.
• Delayed speech development
• Poor oral-motor function (e.g., excessive drooling, early feeding difficulties)
• Oral-motor difficulties and/or oral-motor dyspraxia
• Dysarthria
• Receptive and expressive language impairment
• Low average IQ, typically with poorer verbal IQ compared to nonverbal IQ (and average nonverbal IQ reported in some)
• Reading and spelling impairment
• Fine and gross motor impairment
## Clinical Findings
Children with CAS have difficulties in automatically and accurately sequencing speech sounds into words with the correct prosody.
The diagnosis of CAS is made by assessment by a speech-language pathologist (also known as a speech and language therapist in the UK or speech pathologist in Australia). CAS is challenging to diagnose in a child younger than age three years; speech development is delayed in these children, and thus key manifestations are typically not seen or able to be elicited until the child has acquired sufficient speech to complete the verbal assessment tasks.
• Children with CAS have difficulties in automatically and accurately sequencing speech sounds into words with the correct prosody.
• The diagnosis of CAS is made by assessment by a speech-language pathologist (also known as a speech and language therapist in the UK or speech pathologist in Australia). CAS is challenging to diagnose in a child younger than age three years; speech development is delayed in these children, and thus key manifestations are typically not seen or able to be elicited until the child has acquired sufficient speech to complete the verbal assessment tasks.
## Additional Clinical Findings
Delayed speech development
Poor oral-motor function (e.g., excessive drooling, early feeding difficulties)
Oral-motor difficulties and/or oral-motor dyspraxia
Dysarthria
Receptive and expressive language impairment
Low average IQ, typically with poorer verbal IQ compared to nonverbal IQ (and average nonverbal IQ reported in some)
Reading and spelling impairment
Fine and gross motor impairment
• Delayed speech development
• Poor oral-motor function (e.g., excessive drooling, early feeding difficulties)
• Oral-motor difficulties and/or oral-motor dyspraxia
• Dysarthria
• Receptive and expressive language impairment
• Low average IQ, typically with poorer verbal IQ compared to nonverbal IQ (and average nonverbal IQ reported in some)
• Reading and spelling impairment
• Fine and gross motor impairment
## Family History
Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. This percentage is an estimate derived from data regarding intragenic deletion and duplications as well as whole gene deletions from the Human Gene Mutation Database [
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. This percentage is an estimate derived from data regarding intragenic deletion and duplications as well as whole gene deletions from the Human Gene Mutation Database [
## Clinical Characteristics
Available evidence to date suggests that
The interactions between these communication disorder subtypes are not well understood. Language and literacy difficulties may be influenced by or even result from CAS, or these phenotypes may actually be features of the same broad communication disorder.
Additional findings in
In
Sleep issues are present in some.
To date,
In the first decade of life, speech is highly unintelligible, even to close friends and family. Although speech development and intelligibility improve over time, speech never develops to the same level as age-matched peers, and intelligibility may remain reduced in adulthood [
Although CAS comprises certain core features, it is important to note that the severity and features of CAS change across the life span [
Inconsistent speech errors (e.g., producing the same syllable or word differently across repetitions of the same word, such as "ubella," "umbrella," and "umbarella" for umbrella)
Lengthened and disrupted coarticulatory transitions (e.g., oral groping behaviors during speech; difficulty sequencing phonemes and syllables; difficulty maintaining syllable integrity; hypernasality, thought to be due to incoordination of the velum for denoting oral-nasal contrasts; slowed and disrupted diadochokinetic sequences, e.g., when asked to repeat "pa-ta-ka")
Inappropriate prosody (e.g., lexical stress errors, equal stress across words giving a robotic-sounding presentation)
In addition, children with CAS tend to lag behind their peers in acquiring the sounds of their language system; hence, their phonetic inventory may be reduced for the child's age. Children with CAS may use a more restricted range of consonants and vowels than age-matched peers. For example, they will simplify syllable shapes, reducing a consonant-consonant-vowel (CCV) shape (e.g., "sta") or a consonant-consonant-consonant-vowel (CCCV) shape ("stra") to a consonant-vowel (CV) shape ("sa").
Although CAS is distinct from other speech disorders (e.g., stuttering, phonologic disorder) and language disorders (e.g., developmental language disorder), these additional diagnoses can co-occur with CAS [
The specific genetic alteration responsible for
Of note, large copy number abnormalities and more complex variants (including deletions, translocations, and inversions) affecting one allele also lead to speech and language issues as well as other features similar to
The penetrance for
Prior to the discovery of causative pathogenic variants in
"Speech and language impairment" is a synonymous term for "speech and language disorder." The term "speech and language delay" should be avoided unless there is a clear clinical justification for use of this term, which implies a child will "catch up" to peers.
The population prevalence of CAS has not been determined by any epidemiologic study. The most commonly referenced estimate of prevalence is 1-2:1,000 [
In a cohort with a severe speech disorder, one of 49 individuals had a confirmed
Three recent studies performed molecular genetic testing on probands clinically diagnosed with CAS [
• Inconsistent speech errors (e.g., producing the same syllable or word differently across repetitions of the same word, such as "ubella," "umbrella," and "umbarella" for umbrella)
• Lengthened and disrupted coarticulatory transitions (e.g., oral groping behaviors during speech; difficulty sequencing phonemes and syllables; difficulty maintaining syllable integrity; hypernasality, thought to be due to incoordination of the velum for denoting oral-nasal contrasts; slowed and disrupted diadochokinetic sequences, e.g., when asked to repeat "pa-ta-ka")
• Inappropriate prosody (e.g., lexical stress errors, equal stress across words giving a robotic-sounding presentation)
## Clinical Description
Available evidence to date suggests that
The interactions between these communication disorder subtypes are not well understood. Language and literacy difficulties may be influenced by or even result from CAS, or these phenotypes may actually be features of the same broad communication disorder.
Additional findings in
In
Sleep issues are present in some.
To date,
In the first decade of life, speech is highly unintelligible, even to close friends and family. Although speech development and intelligibility improve over time, speech never develops to the same level as age-matched peers, and intelligibility may remain reduced in adulthood [
Although CAS comprises certain core features, it is important to note that the severity and features of CAS change across the life span [
Inconsistent speech errors (e.g., producing the same syllable or word differently across repetitions of the same word, such as "ubella," "umbrella," and "umbarella" for umbrella)
Lengthened and disrupted coarticulatory transitions (e.g., oral groping behaviors during speech; difficulty sequencing phonemes and syllables; difficulty maintaining syllable integrity; hypernasality, thought to be due to incoordination of the velum for denoting oral-nasal contrasts; slowed and disrupted diadochokinetic sequences, e.g., when asked to repeat "pa-ta-ka")
Inappropriate prosody (e.g., lexical stress errors, equal stress across words giving a robotic-sounding presentation)
In addition, children with CAS tend to lag behind their peers in acquiring the sounds of their language system; hence, their phonetic inventory may be reduced for the child's age. Children with CAS may use a more restricted range of consonants and vowels than age-matched peers. For example, they will simplify syllable shapes, reducing a consonant-consonant-vowel (CCV) shape (e.g., "sta") or a consonant-consonant-consonant-vowel (CCCV) shape ("stra") to a consonant-vowel (CV) shape ("sa").
Although CAS is distinct from other speech disorders (e.g., stuttering, phonologic disorder) and language disorders (e.g., developmental language disorder), these additional diagnoses can co-occur with CAS [
• Inconsistent speech errors (e.g., producing the same syllable or word differently across repetitions of the same word, such as "ubella," "umbrella," and "umbarella" for umbrella)
• Lengthened and disrupted coarticulatory transitions (e.g., oral groping behaviors during speech; difficulty sequencing phonemes and syllables; difficulty maintaining syllable integrity; hypernasality, thought to be due to incoordination of the velum for denoting oral-nasal contrasts; slowed and disrupted diadochokinetic sequences, e.g., when asked to repeat "pa-ta-ka")
• Inappropriate prosody (e.g., lexical stress errors, equal stress across words giving a robotic-sounding presentation)
## Genotype-Phenotype Correlations
The specific genetic alteration responsible for
Of note, large copy number abnormalities and more complex variants (including deletions, translocations, and inversions) affecting one allele also lead to speech and language issues as well as other features similar to
## Penetrance
The penetrance for
## Nomenclature
Prior to the discovery of causative pathogenic variants in
"Speech and language impairment" is a synonymous term for "speech and language disorder." The term "speech and language delay" should be avoided unless there is a clear clinical justification for use of this term, which implies a child will "catch up" to peers.
## Prevalence
The population prevalence of CAS has not been determined by any epidemiologic study. The most commonly referenced estimate of prevalence is 1-2:1,000 [
In a cohort with a severe speech disorder, one of 49 individuals had a confirmed
Three recent studies performed molecular genetic testing on probands clinically diagnosed with CAS [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Large copy number variants (i.e., contiguous gene deletions), structural variants (i.e., translocations or inversions), or maternal uniparental disomy of chromosome 7 involving
Like children with
In addition to CAS, clinical features reported in
Oral-motor deficits (commonly reported) [
"Global" developmental delay (presumably involving speech, cognitive, gross, and fine motor abilities) [
Autism spectrum disorder (ASD) [
Facial dysmorphology [
• Oral-motor deficits (commonly reported) [
• "Global" developmental delay (presumably involving speech, cognitive, gross, and fine motor abilities) [
• Autism spectrum disorder (ASD) [
• Facial dysmorphology [
## Differential Diagnosis
The prelinguistic developmental history of children with childhood apraxia of speech (CAS) (e.g., restricted babbling or feeding difficulties) is very similar to that seen in other neurodevelopmental speech or language conditions (e.g., developmental language disorder, phonologic disorder) or even other neurodevelopmental disorders in which language impairment may occur such as autism spectrum disorder. Hence, early signs are not usually sufficiently discriminating to enable a differential diagnosis prior to a child gaining some speech production abilities.
While CAS is rare, it may also be observed in a range of other conditions. The following chromosomal and single-gene disorders may be considered in the differential diagnosis.
Single-Gene Disorders with Childhood Apraxia of Speech in the Differential Diagnosis of
Nearly all persons age >1 yr display impaired verbal language skills (either absent or restricted speech).
CAS seen in more than half of persons w/verbal impairment.
DD/ID
Other common findings are recognizable facial features in some persons, behavioral findings, feeding difficulties in infancy, structural cardiac defects, & seizures.
Delayed speech acquisition
Expressive language deficits w/CAS & dysarthria
DD/ID
Macrocephaly, characteristic facial features (prominent forehead, hypertelorism, hypotonia, joint laxity)
Severity of neurologic deficits & presence of nonneurologic features are variable.
Speech disorder incl CAS
Mild to severely affected receptive & expressive language
~50% of affected females remain nonverbal after age 5 yrs (
DD/ID
Hypotonia that can be assoc w/feeding difficulty in infancy
Behavioral issues (e.g., ASD, ADHD, self-injurious behavior, poor impulse control, & aggression)
CAS & dysarthria (Prevalence of motor speech disorder is high; in 1 study ~25% of children had CAS.
Expressive/receptive language impairment
Life-threatening complications in untreated infants
If lactose-restricted diet is provided during 1st 10 days of life, neonatal signs usually quickly resolve & neonatal death is prevented; however, despite adequate treatment from an early age, affected children are at ↑ risk for DD & abnormalities of motor function.
Severe speech disorders incl dysarthria & speech dyspraxia, & both receptive & expressive language delay/regression.
More mildly affected persons may display subtly impaired intelligibility of conversational speech.
Majority of affected persons are minimally verbal & rely on alternate communication methods.
Verbal persons have speech disorder incl CAS.
Severe expressive & receptive language impairment
Moderate-to-severe ID, vision, GI function, sleep issues
ASD present in 30% of affected persons
Mainly truncating variants reported
Delayed speech & language
Expressive language is more severely affected than receptive language.
Most affected persons are unable to speak.
CAS
ID, delayed motor skills (severely delayed walking; some persons never walk), hypotonia, feeding difficulties, dysphagia
Infants: hypersomnolence, low body temperature, apnea, slow breathing
Recurrent seizures, heart abnormalities, urogenital, GI, & skeletal anomalies, hormone disorders
Delayed speech in early years
CAS, receptive & expressive language impairments across domains of function
Mild motor DD & hypotonia, ID
ADHD
Refractive errors & strabismus
Speech & language delay
CAS
DD (precedes seizure onset), ID, ASD, variable epilepsy phenotypes
Males are overrepresented.
Behavioral issues are more common in males.
Absent to severely delayed speech
CAS
Dysarthria & verbal dyspraxia w/phoneme imprecision
Hypernasality, high-pitched voice
Severe receptive & expressive language impairment across all domains of function
Craniofacial features
Low birth weight, normal head circumference, & short stature
Bone age delay that normalizes between ages 6-12 yrs
Skeletal anomalies
ID that is typically mild to moderate
Delayed speech
CAS
ID/DD, fine & gross motor delay
ASD, ADHD, or other behavioral findings
Musculoskeletal findings
ID
Variable manifestation of seizures, tremor, dystonia
24 families reported
AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; AR = autosomal recessive; ASD = autism spectrum disorder; CAS = childhood apraxia of speech; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; NDD = neurodevelopmental disorder
A heterozygous intragenic pathogenic variant in
Author, personal observation;
• Nearly all persons age >1 yr display impaired verbal language skills (either absent or restricted speech).
• CAS seen in more than half of persons w/verbal impairment.
• DD/ID
• Other common findings are recognizable facial features in some persons, behavioral findings, feeding difficulties in infancy, structural cardiac defects, & seizures.
• Delayed speech acquisition
• Expressive language deficits w/CAS & dysarthria
• DD/ID
• Macrocephaly, characteristic facial features (prominent forehead, hypertelorism, hypotonia, joint laxity)
• Severity of neurologic deficits & presence of nonneurologic features are variable.
• Speech disorder incl CAS
• Mild to severely affected receptive & expressive language
• ~50% of affected females remain nonverbal after age 5 yrs (
• DD/ID
• Hypotonia that can be assoc w/feeding difficulty in infancy
• Behavioral issues (e.g., ASD, ADHD, self-injurious behavior, poor impulse control, & aggression)
• CAS & dysarthria (Prevalence of motor speech disorder is high; in 1 study ~25% of children had CAS.
• Expressive/receptive language impairment
• Life-threatening complications in untreated infants
• If lactose-restricted diet is provided during 1st 10 days of life, neonatal signs usually quickly resolve & neonatal death is prevented; however, despite adequate treatment from an early age, affected children are at ↑ risk for DD & abnormalities of motor function.
• Severe speech disorders incl dysarthria & speech dyspraxia, & both receptive & expressive language delay/regression.
• More mildly affected persons may display subtly impaired intelligibility of conversational speech.
• Majority of affected persons are minimally verbal & rely on alternate communication methods.
• Verbal persons have speech disorder incl CAS.
• Severe expressive & receptive language impairment
• Moderate-to-severe ID, vision, GI function, sleep issues
• ASD present in 30% of affected persons
• Mainly truncating variants reported
• Delayed speech & language
• Expressive language is more severely affected than receptive language.
• Most affected persons are unable to speak.
• CAS
• ID, delayed motor skills (severely delayed walking; some persons never walk), hypotonia, feeding difficulties, dysphagia
• Infants: hypersomnolence, low body temperature, apnea, slow breathing
• Recurrent seizures, heart abnormalities, urogenital, GI, & skeletal anomalies, hormone disorders
• Delayed speech in early years
• CAS, receptive & expressive language impairments across domains of function
• Mild motor DD & hypotonia, ID
• ADHD
• Refractive errors & strabismus
• Speech & language delay
• CAS
• DD (precedes seizure onset), ID, ASD, variable epilepsy phenotypes
• Males are overrepresented.
• Behavioral issues are more common in males.
• Absent to severely delayed speech
• CAS
• Dysarthria & verbal dyspraxia w/phoneme imprecision
• Hypernasality, high-pitched voice
• Severe receptive & expressive language impairment across all domains of function
• Craniofacial features
• Low birth weight, normal head circumference, & short stature
• Bone age delay that normalizes between ages 6-12 yrs
• Skeletal anomalies
• ID that is typically mild to moderate
• Delayed speech
• CAS
• ID/DD, fine & gross motor delay
• ASD, ADHD, or other behavioral findings
• Musculoskeletal findings
• ID
• Variable manifestation of seizures, tremor, dystonia
• 24 families reported
## Management
No clinical practice guidelines for
To establish the extent of disease and management needs for an individual with
Detailed developmental history including early oral-motor and feeding abilities, speech sound development, motor milestones, and cognitive development
Family history of speech disorder
Oral-facial structural examination to determine if any structural abnormalities are present
Speech sound assessment including a test of single words, sounds in isolation, and connected speech to determine the child's phonetic inventory (i.e., has the child acquired age-appropriate speech sounds) and to determine if the child has phonologic errors, apraxic errors, dysfluency (stuttering), dysarthric errors, or a combination of these speech disorder diagnoses. The presence of resonance or nasality deficits signals the need to consider whether structurally based velopharyngeal port incompetence is present by referral to an ear, nose, and throat specialist and possibly videopalatography.
Assessment of oral-motor function including:
Examination of facial asymmetry, reduced or increased oral-facial tone, and/or poor coordination of neuromuscular oral movements (e.g., "try to lick your nose with your tongue," "move your tongue quickly side to side," "blow a kiss" [lip protrusion], "smile" [lip retraction], etc.)
Examination for evidence of oral-motor dyspraxia (i.e., can the individual perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
Language assessment to determine the presence of receptive and/or expressive language impairments across the domains of semantics, syntax, and morphology
Literacy assessment or preliteracy (phonologic awareness) for evidence of reading and spelling difficulties so that appropriate support can be arranged
Additional evaluations include the following:
Referral to a neuropsychologist or clinical psychologist to determine the extent of any coexisting cognitive and learning impairments and to assess for the presence of behaviors associated with autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, or depression
Referral to a physical therapist if gross motor movement difficulties are reported and to an occupational therapist if fine motor movement difficulties are observed
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of
Assessment of the need for family support (see
There is no cure for
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields.
No single recommended treatment exists. The optimal approach should be determined based on the individual's presentation, but guidance on CAS therapies is as follows [
Consider evaluation for nonverbal support or alternative means of communication (e.g.,
AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
In terms of verbal development, difficulties with motor planning (apraxia) are severe in the early years of life, and intensive evidence-based motor speech therapies should be applied [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about anxiety can be addressed by a developmental specialist or psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended:
Routine care by a general pediatrician
Follow-up evaluations with standardized tests by a speech-language pathologist
Review educational progress/needs
Review mental health if anxiety and/or depression have been issues or have emerged as issues
It is appropriate to clarify the genetic status of apparently asymptomatic sibs of an affected individual by molecular genetic testing for the
See
Search
• Detailed developmental history including early oral-motor and feeding abilities, speech sound development, motor milestones, and cognitive development
• Family history of speech disorder
• Oral-facial structural examination to determine if any structural abnormalities are present
• Speech sound assessment including a test of single words, sounds in isolation, and connected speech to determine the child's phonetic inventory (i.e., has the child acquired age-appropriate speech sounds) and to determine if the child has phonologic errors, apraxic errors, dysfluency (stuttering), dysarthric errors, or a combination of these speech disorder diagnoses. The presence of resonance or nasality deficits signals the need to consider whether structurally based velopharyngeal port incompetence is present by referral to an ear, nose, and throat specialist and possibly videopalatography.
• Assessment of oral-motor function including:
• Examination of facial asymmetry, reduced or increased oral-facial tone, and/or poor coordination of neuromuscular oral movements (e.g., "try to lick your nose with your tongue," "move your tongue quickly side to side," "blow a kiss" [lip protrusion], "smile" [lip retraction], etc.)
• Examination for evidence of oral-motor dyspraxia (i.e., can the individual perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
• Examination of facial asymmetry, reduced or increased oral-facial tone, and/or poor coordination of neuromuscular oral movements (e.g., "try to lick your nose with your tongue," "move your tongue quickly side to side," "blow a kiss" [lip protrusion], "smile" [lip retraction], etc.)
• Examination for evidence of oral-motor dyspraxia (i.e., can the individual perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
• Language assessment to determine the presence of receptive and/or expressive language impairments across the domains of semantics, syntax, and morphology
• Literacy assessment or preliteracy (phonologic awareness) for evidence of reading and spelling difficulties so that appropriate support can be arranged
• Examination of facial asymmetry, reduced or increased oral-facial tone, and/or poor coordination of neuromuscular oral movements (e.g., "try to lick your nose with your tongue," "move your tongue quickly side to side," "blow a kiss" [lip protrusion], "smile" [lip retraction], etc.)
• Examination for evidence of oral-motor dyspraxia (i.e., can the individual perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
• Referral to a neuropsychologist or clinical psychologist to determine the extent of any coexisting cognitive and learning impairments and to assess for the presence of behaviors associated with autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, or depression
• Referral to a physical therapist if gross motor movement difficulties are reported and to an occupational therapist if fine motor movement difficulties are observed
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of
• Assessment of the need for family support (see
• Consider evaluation for nonverbal support or alternative means of communication (e.g.,
• AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
• In terms of verbal development, difficulties with motor planning (apraxia) are severe in the early years of life, and intensive evidence-based motor speech therapies should be applied [
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• Routine care by a general pediatrician
• Follow-up evaluations with standardized tests by a speech-language pathologist
• Review educational progress/needs
• Review mental health if anxiety and/or depression have been issues or have emerged as issues
## Evaluations Following Initial Diagnosis
To establish the extent of disease and management needs for an individual with
Detailed developmental history including early oral-motor and feeding abilities, speech sound development, motor milestones, and cognitive development
Family history of speech disorder
Oral-facial structural examination to determine if any structural abnormalities are present
Speech sound assessment including a test of single words, sounds in isolation, and connected speech to determine the child's phonetic inventory (i.e., has the child acquired age-appropriate speech sounds) and to determine if the child has phonologic errors, apraxic errors, dysfluency (stuttering), dysarthric errors, or a combination of these speech disorder diagnoses. The presence of resonance or nasality deficits signals the need to consider whether structurally based velopharyngeal port incompetence is present by referral to an ear, nose, and throat specialist and possibly videopalatography.
Assessment of oral-motor function including:
Examination of facial asymmetry, reduced or increased oral-facial tone, and/or poor coordination of neuromuscular oral movements (e.g., "try to lick your nose with your tongue," "move your tongue quickly side to side," "blow a kiss" [lip protrusion], "smile" [lip retraction], etc.)
Examination for evidence of oral-motor dyspraxia (i.e., can the individual perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
Language assessment to determine the presence of receptive and/or expressive language impairments across the domains of semantics, syntax, and morphology
Literacy assessment or preliteracy (phonologic awareness) for evidence of reading and spelling difficulties so that appropriate support can be arranged
Additional evaluations include the following:
Referral to a neuropsychologist or clinical psychologist to determine the extent of any coexisting cognitive and learning impairments and to assess for the presence of behaviors associated with autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, or depression
Referral to a physical therapist if gross motor movement difficulties are reported and to an occupational therapist if fine motor movement difficulties are observed
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of
Assessment of the need for family support (see
• Detailed developmental history including early oral-motor and feeding abilities, speech sound development, motor milestones, and cognitive development
• Family history of speech disorder
• Oral-facial structural examination to determine if any structural abnormalities are present
• Speech sound assessment including a test of single words, sounds in isolation, and connected speech to determine the child's phonetic inventory (i.e., has the child acquired age-appropriate speech sounds) and to determine if the child has phonologic errors, apraxic errors, dysfluency (stuttering), dysarthric errors, or a combination of these speech disorder diagnoses. The presence of resonance or nasality deficits signals the need to consider whether structurally based velopharyngeal port incompetence is present by referral to an ear, nose, and throat specialist and possibly videopalatography.
• Assessment of oral-motor function including:
• Examination of facial asymmetry, reduced or increased oral-facial tone, and/or poor coordination of neuromuscular oral movements (e.g., "try to lick your nose with your tongue," "move your tongue quickly side to side," "blow a kiss" [lip protrusion], "smile" [lip retraction], etc.)
• Examination for evidence of oral-motor dyspraxia (i.e., can the individual perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
• Examination of facial asymmetry, reduced or increased oral-facial tone, and/or poor coordination of neuromuscular oral movements (e.g., "try to lick your nose with your tongue," "move your tongue quickly side to side," "blow a kiss" [lip protrusion], "smile" [lip retraction], etc.)
• Examination for evidence of oral-motor dyspraxia (i.e., can the individual perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
• Language assessment to determine the presence of receptive and/or expressive language impairments across the domains of semantics, syntax, and morphology
• Literacy assessment or preliteracy (phonologic awareness) for evidence of reading and spelling difficulties so that appropriate support can be arranged
• Examination of facial asymmetry, reduced or increased oral-facial tone, and/or poor coordination of neuromuscular oral movements (e.g., "try to lick your nose with your tongue," "move your tongue quickly side to side," "blow a kiss" [lip protrusion], "smile" [lip retraction], etc.)
• Examination for evidence of oral-motor dyspraxia (i.e., can the individual perform oral movements on command in isolation [e.g., "bite" or "blow"] or in sequence [e.g., "kiss and blow"; "kiss, blow, and bite"])
• Referral to a neuropsychologist or clinical psychologist to determine the extent of any coexisting cognitive and learning impairments and to assess for the presence of behaviors associated with autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, or depression
• Referral to a physical therapist if gross motor movement difficulties are reported and to an occupational therapist if fine motor movement difficulties are observed
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of
• Assessment of the need for family support (see
## Treatment of Manifestations
There is no cure for
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields.
No single recommended treatment exists. The optimal approach should be determined based on the individual's presentation, but guidance on CAS therapies is as follows [
Consider evaluation for nonverbal support or alternative means of communication (e.g.,
AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
In terms of verbal development, difficulties with motor planning (apraxia) are severe in the early years of life, and intensive evidence-based motor speech therapies should be applied [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about anxiety can be addressed by a developmental specialist or psychiatrist.
• Consider evaluation for nonverbal support or alternative means of communication (e.g.,
• AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
• In terms of verbal development, difficulties with motor planning (apraxia) are severe in the early years of life, and intensive evidence-based motor speech therapies should be applied [
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Vocational opportunities and programming including vocational rehabilitation should be considered early with a focus on achievement of meaningful employment
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about anxiety can be addressed by a developmental specialist or psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended:
Routine care by a general pediatrician
Follow-up evaluations with standardized tests by a speech-language pathologist
Review educational progress/needs
Review mental health if anxiety and/or depression have been issues or have emerged as issues
• Routine care by a general pediatrician
• Follow-up evaluations with standardized tests by a speech-language pathologist
• Review educational progress/needs
• Review mental health if anxiety and/or depression have been issues or have emerged as issues
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic sibs of an affected individual by molecular genetic testing for the
See
## Therapies Under Investigation
Search
## Genetic Counseling
About half of individuals diagnosed with
About half of individuals diagnosed with
If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband has the
The penetrance of
If the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• About half of individuals diagnosed with
• About half of individuals diagnosed with
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the
• The penetrance of
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with
## Mode of Inheritance
## Risk to Family Members
About half of individuals diagnosed with
About half of individuals diagnosed with
If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband has the
The penetrance of
If the
• About half of individuals diagnosed with
• About half of individuals diagnosed with
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the
• The penetrance of
• If the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
FOXP2-Related Speech and Language Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FOXP2-Related Speech and Language Disorder (
Other pathogenic missense variants may be associated with dominant-negative effects, which to date have not been demonstrated in published reports.
## Molecular Pathogenesis
Other pathogenic missense variants may be associated with dominant-negative effects, which to date have not been demonstrated in published reports.
## Chapter Notes
Angela T Morgan is a speech pathologist with more than 25 years of experience in speech phenotyping in genetic conditions. She works closely with the coauthors of this review both in identifying genes that cause severe speech disorder and in characterizing speech and language in known genetic conditions.
University of Melbourne
Murdoch Children's Research Institute
Prof Morgan (
Prof Morgan (
Contact Dr Simon Fisher (
Thank you sincerely to the families who have taken part in our research. Thank you to Dr Christiane Zweier and Prof Faraneh Vargha-Khadem for past collaborative work in phenotyping individuals with
26 January 2023 (bp) Comprehensive update posted live
2 February 2017 (am) Revision: based on
23 June 2016 (bp) Review posted live
4 August 2015 (am, msh) Original submission
• University of Melbourne
• Murdoch Children's Research Institute
• 26 January 2023 (bp) Comprehensive update posted live
• 2 February 2017 (am) Revision: based on
• 23 June 2016 (bp) Review posted live
• 4 August 2015 (am, msh) Original submission
## Author Notes
Angela T Morgan is a speech pathologist with more than 25 years of experience in speech phenotyping in genetic conditions. She works closely with the coauthors of this review both in identifying genes that cause severe speech disorder and in characterizing speech and language in known genetic conditions.
University of Melbourne
Murdoch Children's Research Institute
Prof Morgan (
Prof Morgan (
Contact Dr Simon Fisher (
• University of Melbourne
• Murdoch Children's Research Institute
## Acknowledgments
Thank you sincerely to the families who have taken part in our research. Thank you to Dr Christiane Zweier and Prof Faraneh Vargha-Khadem for past collaborative work in phenotyping individuals with
## Revision History
26 January 2023 (bp) Comprehensive update posted live
2 February 2017 (am) Revision: based on
23 June 2016 (bp) Review posted live
4 August 2015 (am, msh) Original submission
• 26 January 2023 (bp) Comprehensive update posted live
• 2 February 2017 (am) Revision: based on
• 23 June 2016 (bp) Review posted live
• 4 August 2015 (am, msh) Original submission
## References
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"SJ Turner, MS Hildebrand, S Block, J Damiano, M Fahey, S Reilly, M Bahlo, IE Scheffer, AT Morgan. Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria.. Am J Med Genet A. 2013;161A:2321-6",
"F Vargha-Khadem, DG Gadian, A Copp, M Mishkin. FOXP2 and the neuroanatomy of speech and language.. Nat Rev Neurosci. 2005;6:131-8",
"F Vargha-Khadem, K Watkins, K Alcock, P Fletcher, R Passingham. Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder.. Proc Natl Acad Sci U S A. 1995;92:930-3",
"F Vargha-Khadem, KE Watkins, CJ Price, J Ashburner, KJ Alcock, A Connelly, RS Frackowiak, KJ Friston, ME Pembrey, M Mishkin, DG Gadian, RE Passingham. Neural basis of an inherited speech and language disorder.. Proc Natl Acad Sci U S A. 1998;95:12695-700",
"SC Vernes, J Nicod, FM Elahi, JA Coventry, N Kenny, AM Coupe, LE Bird, KE Davies, SE Fisher. Functional genetic analysis of mutations implicated in a human speech and language disorder.. Hum Mol Genet. 2006;15:3154-67",
"KE Watkins, NF Dronkers, F Vargha-Khadem. Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia.. Brain. 2002;125:452-64",
"S Zeesman, MJ Nowaczyk, I Teshima, W Roberts, JO Cardy, J Brian, L Senman, L Feuk, LR Osborne, SW Scherer. Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2.. Am J Med Genet A. 2006;140:509-14",
"O Zilina, T Reimand, P Zjablovskaja, K Männik, M Männamaa, A Traat, H Puusepp-Benazzouz, A Kurg, K Ounap. Maternally and paternally inherited deletion of 7q31 involving the FOXP2 gene in two families.. Am J Med Genet A. 2012;158A:254-6"
] |
23/6/2016
|
26/1/2023
|
2/2/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
fragilex
|
fragilex
|
[
"Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)",
"Fragile X Syndrome (FXS)",
"FMR1 Primary Ovarian Insufficiency (FXPOI)",
"Fragile X messenger ribonucleoprotein 1",
"FMR1",
"FMR1 Disorders"
] |
Jessica Ezzell Hunter, Elizabeth Berry-Kravis, Heather Hipp, Peter K Todd
|
Summary Fragile X syndrome occurs in individuals with an FXTAS occurs in individuals who have an FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population. The diagnosis of an
|
Fragile X syndrome (FXS)
Fragile X-associated tremor/ataxia syndrome (FXTAS)
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• Fragile X syndrome (FXS)
• Fragile X-associated tremor/ataxia syndrome (FXTAS)
## Diagnosis
Males and females with intellectual disability or developmental delay of unknown cause
Males with unexplained autism spectrum disorder and females with unexplained autism spectrum disorder and the presence of an additional indicator: phenotype compatible with FXS; family history of X-linked neurodevelopmental disorders; or premature ovarian failure, ataxia, or tremors in close relatives
Males and females who are experiencing late-onset intention tremor and cerebellar ataxia of unknown cause. Men and women with dementia may also be considered, if ataxia, parkinsonism, or tremor are also present.
Males and females with multiple system atrophy, cerebellar subtype (especially if a prolonged course)
The diagnosis of an
Stability of alleles of fewer than 90 repeats is heavily influenced by the number of AGG interspersions within the CGG repeat sequence, both with respect to risk for size change in intermediate alleles and small premutations and expansion to a full mutation in premutation alleles larger than about 60 repeats [
See
Alleles of this size have little meiotic or mitotic instability and are typically transmitted without any increase or decrease in repeat number. However, some instability in normal repeats has been reported, with alleles that contain no AGG interspersions having a greater likelihood to be unstable [
The population distribution of
Intermediate alleles do not cause FXS. However, about 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother [
Historically, the largest repeat included in the intermediate range has been 54; the use of 54 as the upper limit for normal alleles is a conservative estimate reflecting observations that transmission of alleles with 54 or fewer repeats from mothers to their offspring has not resulted in an affected individual to date. The conservative nature of the estimate also reflects potential imprecision (usually stated as ±2-3 repeats) in laboratory measurement of repeat number during diagnostic testing; however, to date no transmission of alleles with 55 or fewer repeats is known to have resulted in an affected individual [
Note: Clinical laboratories performing
Alleles of this size are not associated with FXS but do convey increased risk for FXTAS and FXPOI (
Note: The upper limit of the premutation range is sometimes noted as approximately 230. Both numbers (200 and 230) are estimates derived from Southern blot analysis, in which repeat size can only be roughly estimated.
The clinical criteria for diagnosis of
Three levels are used to indicate the confidence of a diagnosis of FXTAS in individuals with an
MRI white matter lesions in cerebral white matter
Moderate-to-severe generalized brain atrophy
MRI white matter lesions in the splenium of the corpus callosum
Intention tremor
Cerebellar gait ataxia
Parkinsonism
Moderate-to-severe short-term memory deficiency
Executive function deficit
Neuropathy in lower extremities
Diagnostic criteria are based on hypergonadotropic hypogonadism in women younger than age 40 who carry a premutation allele. POI is diagnosed when a woman has (1) experienced four to six months of amenorrhea (absent menses) and (2) has two serum menopausal level FSH values obtained at least one month apart [
See
Note: PCR with newer and more sensitive assays is now adequate for diagnosis and size determination for the premutation, as well as for identification of the full mutation. Southern blot is currently only used to determine the methylation status for the full mutation and the X-inactivation ratio for females with a premutation or full mutation. As PCR methods for determining methylation gain acceptance in diagnostic testing, the need for Southern blot analysis for determination of methylation of the full mutation and activation ratios of women may decrease [
Fewer than 1% of individuals with FXS have a sequence variant, a partial deletion, or a full deletion of
When no CGG repeat expansion is detected but FXS is still suspected, the options are either a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis, targeted analysis for pathogenic variants using PCR, and in some instances Southern blot analysis cannot detect an exon or whole-gene deletion on the X chromosome in heterozygous females.
As newer and more sensitive PCR methods gain acceptance in diagnostic testing, the need for Southern blot analysis may decrease [
Methylation status can be determined by either Southern blot or methylation-specific PCR; the latter may offer a more rapid test turnaround time [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Note: (1) If the clinical phenotype is strongly suggestive of FXS and molecular genetic testing of DNA extracted from leukocytes is normal, molecular genetic testing of a second tissue type (e.g., skin fibroblasts) should be considered as mosaicism has been reported [
• Males and females with intellectual disability or developmental delay of unknown cause
• Males with unexplained autism spectrum disorder and females with unexplained autism spectrum disorder and the presence of an additional indicator: phenotype compatible with FXS; family history of X-linked neurodevelopmental disorders; or premature ovarian failure, ataxia, or tremors in close relatives
• Males and females who are experiencing late-onset intention tremor and cerebellar ataxia of unknown cause. Men and women with dementia may also be considered, if ataxia, parkinsonism, or tremor are also present.
• Males and females with multiple system atrophy, cerebellar subtype (especially if a prolonged course)
• Alleles of this size have little meiotic or mitotic instability and are typically transmitted without any increase or decrease in repeat number. However, some instability in normal repeats has been reported, with alleles that contain no AGG interspersions having a greater likelihood to be unstable [
• The population distribution of
• Intermediate alleles do not cause FXS. However, about 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother [
• Historically, the largest repeat included in the intermediate range has been 54; the use of 54 as the upper limit for normal alleles is a conservative estimate reflecting observations that transmission of alleles with 54 or fewer repeats from mothers to their offspring has not resulted in an affected individual to date. The conservative nature of the estimate also reflects potential imprecision (usually stated as ±2-3 repeats) in laboratory measurement of repeat number during diagnostic testing; however, to date no transmission of alleles with 55 or fewer repeats is known to have resulted in an affected individual [
• Note: Clinical laboratories performing
• Alleles of this size are not associated with FXS but do convey increased risk for FXTAS and FXPOI (
• Note: The upper limit of the premutation range is sometimes noted as approximately 230. Both numbers (200 and 230) are estimates derived from Southern blot analysis, in which repeat size can only be roughly estimated.
•
• MRI white matter lesions in cerebral white matter
• Moderate-to-severe generalized brain atrophy
• MRI white matter lesions in the splenium of the corpus callosum
• MRI white matter lesions in cerebral white matter
• Moderate-to-severe generalized brain atrophy
• MRI white matter lesions in the splenium of the corpus callosum
• MRI white matter lesions in cerebral white matter
• Moderate-to-severe generalized brain atrophy
• MRI white matter lesions in the splenium of the corpus callosum
•
• Intention tremor
• Cerebellar gait ataxia
• Intention tremor
• Cerebellar gait ataxia
•
• Parkinsonism
• Moderate-to-severe short-term memory deficiency
• Executive function deficit
• Neuropathy in lower extremities
• Parkinsonism
• Moderate-to-severe short-term memory deficiency
• Executive function deficit
• Neuropathy in lower extremities
• Intention tremor
• Cerebellar gait ataxia
• Parkinsonism
• Moderate-to-severe short-term memory deficiency
• Executive function deficit
• Neuropathy in lower extremities
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Males and females with intellectual disability or developmental delay of unknown cause
Males with unexplained autism spectrum disorder and females with unexplained autism spectrum disorder and the presence of an additional indicator: phenotype compatible with FXS; family history of X-linked neurodevelopmental disorders; or premature ovarian failure, ataxia, or tremors in close relatives
Males and females who are experiencing late-onset intention tremor and cerebellar ataxia of unknown cause. Men and women with dementia may also be considered, if ataxia, parkinsonism, or tremor are also present.
Males and females with multiple system atrophy, cerebellar subtype (especially if a prolonged course)
• Males and females with intellectual disability or developmental delay of unknown cause
• Males with unexplained autism spectrum disorder and females with unexplained autism spectrum disorder and the presence of an additional indicator: phenotype compatible with FXS; family history of X-linked neurodevelopmental disorders; or premature ovarian failure, ataxia, or tremors in close relatives
• Males and females who are experiencing late-onset intention tremor and cerebellar ataxia of unknown cause. Men and women with dementia may also be considered, if ataxia, parkinsonism, or tremor are also present.
• Males and females with multiple system atrophy, cerebellar subtype (especially if a prolonged course)
## Establishing the Diagnosis
The diagnosis of an
Stability of alleles of fewer than 90 repeats is heavily influenced by the number of AGG interspersions within the CGG repeat sequence, both with respect to risk for size change in intermediate alleles and small premutations and expansion to a full mutation in premutation alleles larger than about 60 repeats [
See
Alleles of this size have little meiotic or mitotic instability and are typically transmitted without any increase or decrease in repeat number. However, some instability in normal repeats has been reported, with alleles that contain no AGG interspersions having a greater likelihood to be unstable [
The population distribution of
Intermediate alleles do not cause FXS. However, about 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother [
Historically, the largest repeat included in the intermediate range has been 54; the use of 54 as the upper limit for normal alleles is a conservative estimate reflecting observations that transmission of alleles with 54 or fewer repeats from mothers to their offspring has not resulted in an affected individual to date. The conservative nature of the estimate also reflects potential imprecision (usually stated as ±2-3 repeats) in laboratory measurement of repeat number during diagnostic testing; however, to date no transmission of alleles with 55 or fewer repeats is known to have resulted in an affected individual [
Note: Clinical laboratories performing
Alleles of this size are not associated with FXS but do convey increased risk for FXTAS and FXPOI (
Note: The upper limit of the premutation range is sometimes noted as approximately 230. Both numbers (200 and 230) are estimates derived from Southern blot analysis, in which repeat size can only be roughly estimated.
• Alleles of this size have little meiotic or mitotic instability and are typically transmitted without any increase or decrease in repeat number. However, some instability in normal repeats has been reported, with alleles that contain no AGG interspersions having a greater likelihood to be unstable [
• The population distribution of
• Intermediate alleles do not cause FXS. However, about 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother [
• Historically, the largest repeat included in the intermediate range has been 54; the use of 54 as the upper limit for normal alleles is a conservative estimate reflecting observations that transmission of alleles with 54 or fewer repeats from mothers to their offspring has not resulted in an affected individual to date. The conservative nature of the estimate also reflects potential imprecision (usually stated as ±2-3 repeats) in laboratory measurement of repeat number during diagnostic testing; however, to date no transmission of alleles with 55 or fewer repeats is known to have resulted in an affected individual [
• Note: Clinical laboratories performing
• Alleles of this size are not associated with FXS but do convey increased risk for FXTAS and FXPOI (
• Note: The upper limit of the premutation range is sometimes noted as approximately 230. Both numbers (200 and 230) are estimates derived from Southern blot analysis, in which repeat size can only be roughly estimated.
## Allele Size
Stability of alleles of fewer than 90 repeats is heavily influenced by the number of AGG interspersions within the CGG repeat sequence, both with respect to risk for size change in intermediate alleles and small premutations and expansion to a full mutation in premutation alleles larger than about 60 repeats [
See
Alleles of this size have little meiotic or mitotic instability and are typically transmitted without any increase or decrease in repeat number. However, some instability in normal repeats has been reported, with alleles that contain no AGG interspersions having a greater likelihood to be unstable [
The population distribution of
Intermediate alleles do not cause FXS. However, about 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother [
Historically, the largest repeat included in the intermediate range has been 54; the use of 54 as the upper limit for normal alleles is a conservative estimate reflecting observations that transmission of alleles with 54 or fewer repeats from mothers to their offspring has not resulted in an affected individual to date. The conservative nature of the estimate also reflects potential imprecision (usually stated as ±2-3 repeats) in laboratory measurement of repeat number during diagnostic testing; however, to date no transmission of alleles with 55 or fewer repeats is known to have resulted in an affected individual [
Note: Clinical laboratories performing
Alleles of this size are not associated with FXS but do convey increased risk for FXTAS and FXPOI (
Note: The upper limit of the premutation range is sometimes noted as approximately 230. Both numbers (200 and 230) are estimates derived from Southern blot analysis, in which repeat size can only be roughly estimated.
• Alleles of this size have little meiotic or mitotic instability and are typically transmitted without any increase or decrease in repeat number. However, some instability in normal repeats has been reported, with alleles that contain no AGG interspersions having a greater likelihood to be unstable [
• The population distribution of
• Intermediate alleles do not cause FXS. However, about 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother [
• Historically, the largest repeat included in the intermediate range has been 54; the use of 54 as the upper limit for normal alleles is a conservative estimate reflecting observations that transmission of alleles with 54 or fewer repeats from mothers to their offspring has not resulted in an affected individual to date. The conservative nature of the estimate also reflects potential imprecision (usually stated as ±2-3 repeats) in laboratory measurement of repeat number during diagnostic testing; however, to date no transmission of alleles with 55 or fewer repeats is known to have resulted in an affected individual [
• Note: Clinical laboratories performing
• Alleles of this size are not associated with FXS but do convey increased risk for FXTAS and FXPOI (
• Note: The upper limit of the premutation range is sometimes noted as approximately 230. Both numbers (200 and 230) are estimates derived from Southern blot analysis, in which repeat size can only be roughly estimated.
## Clinical Criteria
The clinical criteria for diagnosis of
Three levels are used to indicate the confidence of a diagnosis of FXTAS in individuals with an
MRI white matter lesions in cerebral white matter
Moderate-to-severe generalized brain atrophy
MRI white matter lesions in the splenium of the corpus callosum
Intention tremor
Cerebellar gait ataxia
Parkinsonism
Moderate-to-severe short-term memory deficiency
Executive function deficit
Neuropathy in lower extremities
Diagnostic criteria are based on hypergonadotropic hypogonadism in women younger than age 40 who carry a premutation allele. POI is diagnosed when a woman has (1) experienced four to six months of amenorrhea (absent menses) and (2) has two serum menopausal level FSH values obtained at least one month apart [
See
•
• MRI white matter lesions in cerebral white matter
• Moderate-to-severe generalized brain atrophy
• MRI white matter lesions in the splenium of the corpus callosum
• MRI white matter lesions in cerebral white matter
• Moderate-to-severe generalized brain atrophy
• MRI white matter lesions in the splenium of the corpus callosum
• MRI white matter lesions in cerebral white matter
• Moderate-to-severe generalized brain atrophy
• MRI white matter lesions in the splenium of the corpus callosum
•
• Intention tremor
• Cerebellar gait ataxia
• Intention tremor
• Cerebellar gait ataxia
•
• Parkinsonism
• Moderate-to-severe short-term memory deficiency
• Executive function deficit
• Neuropathy in lower extremities
• Parkinsonism
• Moderate-to-severe short-term memory deficiency
• Executive function deficit
• Neuropathy in lower extremities
• Intention tremor
• Cerebellar gait ataxia
• Parkinsonism
• Moderate-to-severe short-term memory deficiency
• Executive function deficit
• Neuropathy in lower extremities
## FXTAS
Three levels are used to indicate the confidence of a diagnosis of FXTAS in individuals with an
MRI white matter lesions in cerebral white matter
Moderate-to-severe generalized brain atrophy
MRI white matter lesions in the splenium of the corpus callosum
Intention tremor
Cerebellar gait ataxia
Parkinsonism
Moderate-to-severe short-term memory deficiency
Executive function deficit
Neuropathy in lower extremities
•
• MRI white matter lesions in cerebral white matter
• Moderate-to-severe generalized brain atrophy
• MRI white matter lesions in the splenium of the corpus callosum
• MRI white matter lesions in cerebral white matter
• Moderate-to-severe generalized brain atrophy
• MRI white matter lesions in the splenium of the corpus callosum
• MRI white matter lesions in cerebral white matter
• Moderate-to-severe generalized brain atrophy
• MRI white matter lesions in the splenium of the corpus callosum
•
• Intention tremor
• Cerebellar gait ataxia
• Intention tremor
• Cerebellar gait ataxia
•
• Parkinsonism
• Moderate-to-severe short-term memory deficiency
• Executive function deficit
• Neuropathy in lower extremities
• Parkinsonism
• Moderate-to-severe short-term memory deficiency
• Executive function deficit
• Neuropathy in lower extremities
• Intention tremor
• Cerebellar gait ataxia
• Parkinsonism
• Moderate-to-severe short-term memory deficiency
• Executive function deficit
• Neuropathy in lower extremities
## FXPOI
Diagnostic criteria are based on hypergonadotropic hypogonadism in women younger than age 40 who carry a premutation allele. POI is diagnosed when a woman has (1) experienced four to six months of amenorrhea (absent menses) and (2) has two serum menopausal level FSH values obtained at least one month apart [
See
## Targeted Analysis for Pathogenic Variants
Note: PCR with newer and more sensitive assays is now adequate for diagnosis and size determination for the premutation, as well as for identification of the full mutation. Southern blot is currently only used to determine the methylation status for the full mutation and the X-inactivation ratio for females with a premutation or full mutation. As PCR methods for determining methylation gain acceptance in diagnostic testing, the need for Southern blot analysis for determination of methylation of the full mutation and activation ratios of women may decrease [
## Additional Testing
Fewer than 1% of individuals with FXS have a sequence variant, a partial deletion, or a full deletion of
When no CGG repeat expansion is detected but FXS is still suspected, the options are either a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Sequence analysis, targeted analysis for pathogenic variants using PCR, and in some instances Southern blot analysis cannot detect an exon or whole-gene deletion on the X chromosome in heterozygous females.
As newer and more sensitive PCR methods gain acceptance in diagnostic testing, the need for Southern blot analysis may decrease [
Methylation status can be determined by either Southern blot or methylation-specific PCR; the latter may offer a more rapid test turnaround time [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Note: (1) If the clinical phenotype is strongly suggestive of FXS and molecular genetic testing of DNA extracted from leukocytes is normal, molecular genetic testing of a second tissue type (e.g., skin fibroblasts) should be considered as mosaicism has been reported [
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
The phenotypic features of males with fragile X syndrome (FXS) vary in relation to puberty [
Sit alone (10 months)
Walk (20.6 months)
First clear words (20 months)
The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the full mutation, but with lower frequency and milder involvement [
FXTAS is characterized by late-onset progressive cerebellar ataxia and intention tremor in persons who have an
Onset is typically between ages 60 and 65 years. The age of onset and progression of symptoms of FXTAS vary significantly among individuals. Both age of onset and disease severity are related to repeat length, sex, and other features.
The first sign of FXTAS is typically tremor followed by ataxia and cognitive impairment [
Ataxia can lead to gait and postural instability with most individuals needing a walking aid within ten years of diagnosis.
Cognitive impairment typically starts with executive function impairment and expands to other domains such as working memory and information processing speed. Almost half of individuals with FXTAS meet criteria for dementia.
Other findings include short-term memory loss, parkinsonism, peripheral neuropathy and neuropathic pain, lower-limb proximal muscle weakness, and autonomic dysfunction [
Psychiatric disorders are common and include anxiety, irritability, agitation, hostility, obsessive-compulsive disorder, apathy, and depression [
Both males and females with a premutation are at risk for FXTAS. Increasing premutation repeat lengths correlate with increasing likelihood of developing FXTAS [
Risk for FXTAS by Age in Males with an
Adapted from
FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population [
Ovarian insufficiency has occurred as early as age 11 years and can present with primary amenorrhea and delayed puberty.
Women with FXPOI have high rates of infertility and menopausal-type symptoms, including vasomotor symptoms, mood changes, and vaginal dryness.
In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
Women with FXPOI are at risk of long-term health sequelae from a hypoestrogenic environment. These include osteoporosis and cardiovascular disease.
Women with POI (including those with FXPOI) are at increased risk of developing thyroid disease.
The earlier findings that alleles in the high normal and intermediate range conferred an increased risk for FXPOI [
Women with full-mutation alleles are not at increased risk for FXPOI, nor do they have signs of diminished ovarian reserve [
In addition to FXTAS and FXPOI, the following have been reported in the literature (see
The term "fragile X-associated neuropsychiatric disorders" (FXAND) has been proposed to promote research into fully characterizing neuropsychiatric outcomes associated with the premutation allele [
Elevated rates of neurologic findings, such as tremor and ataxia, have been reported in individuals with premutations who do not meet diagnostic criteria of FXTAS. A study of 110 daughters of men with FXTAS demonstrated an increased incidence of neurologic and psychiatric symptoms compared to controls, providing more evidence for such an association [
The phenotype of males with an
Types of
At risk for FXPOI & FXTAS
Potential ↑ risk of other fragile X-assoc disorders
ID, if present, is typically high functioning.
May have anxiety &/or behavioral issues even w/out ID
ID = intellectual disability
Both males and females with premutations have been reported to have slightly elevated rates of some manifestations of fragile X syndrome, such as facial features, behavioral problems, learning disabilities, ADHD, and anxiety [
For FXTAS, repeat size is correlated with severity: higher repeat size is associated with greater motor impairment (tremor, ataxia, and parkinsonism), more severe peripheral neuropathy, higher number of intranuclear inclusions in the brain, MRI abnormalities (reduced cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity), and earlier age of onset [
It is estimated that 21% of women who carry a premutation develop FXPOI [
Additional studies indicate other vulnerabilities for the mid-repeat ranges of the premutation in women, such as an increased risk of psychological symptoms [
Odds Ratios for FXPOI by Premutation Size
Approximately 50% of females who have a full
Although some data suggest that individuals with repeat size mosaicism or methylation mosaicism perform at a higher intellectual level than those with completely methylated full mutations, such individuals are usually intellectually disabled.
Rarely, individuals with methylation mosaicism or completely unmethylated full mutations and normal intellect have been reported. The milder phenotype appears to be related to
Fragile X syndrome (FXS) is a trinucleotide repeat disorder that may demonstrate anticipation in some families. Typically, anticipation occurs when less severely affected individuals with a premutation or mosaic mutation transmit unstable
The impact of AGG interruptions on clinical outcomes in individuals with a premutation is unknown. Conflicting results regarding AGG interruptions and FXPOI have been published [
Fragile X syndrome has also been referred to as FXS, fragile X mental retardation, marker X syndrome, and Martin-Bell syndrome.
The prevalence of females with FXS is presumed to be approximately one half the male prevalence due to reduced penetrance.
FXS is the most common known single-gene cause of autism spectrum disorder (ASD) and accounts for about 2%-3% of all ASD cases [
An estimated 2%-4% of men with adult-onset cerebellar ataxia who represent simplex cases (i.e., a single occurrence in a family) have a premutation in
• Sit alone (10 months)
• Walk (20.6 months)
• First clear words (20 months)
• Sit alone (10 months)
• Walk (20.6 months)
• First clear words (20 months)
• Sit alone (10 months)
• Walk (20.6 months)
• First clear words (20 months)
• Ataxia can lead to gait and postural instability with most individuals needing a walking aid within ten years of diagnosis.
• Cognitive impairment typically starts with executive function impairment and expands to other domains such as working memory and information processing speed. Almost half of individuals with FXTAS meet criteria for dementia.
• Ovarian insufficiency has occurred as early as age 11 years and can present with primary amenorrhea and delayed puberty.
• Women with FXPOI have high rates of infertility and menopausal-type symptoms, including vasomotor symptoms, mood changes, and vaginal dryness.
• In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
• The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
• In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
• The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
• Women with FXPOI are at risk of long-term health sequelae from a hypoestrogenic environment. These include osteoporosis and cardiovascular disease.
• Women with POI (including those with FXPOI) are at increased risk of developing thyroid disease.
• In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
• The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
• The term "fragile X-associated neuropsychiatric disorders" (FXAND) has been proposed to promote research into fully characterizing neuropsychiatric outcomes associated with the premutation allele [
• Elevated rates of neurologic findings, such as tremor and ataxia, have been reported in individuals with premutations who do not meet diagnostic criteria of FXTAS. A study of 110 daughters of men with FXTAS demonstrated an increased incidence of neurologic and psychiatric symptoms compared to controls, providing more evidence for such an association [
• At risk for FXPOI & FXTAS
• Potential ↑ risk of other fragile X-assoc disorders
• ID, if present, is typically high functioning.
• May have anxiety &/or behavioral issues even w/out ID
• For FXTAS, repeat size is correlated with severity: higher repeat size is associated with greater motor impairment (tremor, ataxia, and parkinsonism), more severe peripheral neuropathy, higher number of intranuclear inclusions in the brain, MRI abnormalities (reduced cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity), and earlier age of onset [
• It is estimated that 21% of women who carry a premutation develop FXPOI [
• Additional studies indicate other vulnerabilities for the mid-repeat ranges of the premutation in women, such as an increased risk of psychological symptoms [
## Clinical Description
The phenotypic features of males with fragile X syndrome (FXS) vary in relation to puberty [
Sit alone (10 months)
Walk (20.6 months)
First clear words (20 months)
The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the full mutation, but with lower frequency and milder involvement [
FXTAS is characterized by late-onset progressive cerebellar ataxia and intention tremor in persons who have an
Onset is typically between ages 60 and 65 years. The age of onset and progression of symptoms of FXTAS vary significantly among individuals. Both age of onset and disease severity are related to repeat length, sex, and other features.
The first sign of FXTAS is typically tremor followed by ataxia and cognitive impairment [
Ataxia can lead to gait and postural instability with most individuals needing a walking aid within ten years of diagnosis.
Cognitive impairment typically starts with executive function impairment and expands to other domains such as working memory and information processing speed. Almost half of individuals with FXTAS meet criteria for dementia.
Other findings include short-term memory loss, parkinsonism, peripheral neuropathy and neuropathic pain, lower-limb proximal muscle weakness, and autonomic dysfunction [
Psychiatric disorders are common and include anxiety, irritability, agitation, hostility, obsessive-compulsive disorder, apathy, and depression [
Both males and females with a premutation are at risk for FXTAS. Increasing premutation repeat lengths correlate with increasing likelihood of developing FXTAS [
Risk for FXTAS by Age in Males with an
Adapted from
FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population [
Ovarian insufficiency has occurred as early as age 11 years and can present with primary amenorrhea and delayed puberty.
Women with FXPOI have high rates of infertility and menopausal-type symptoms, including vasomotor symptoms, mood changes, and vaginal dryness.
In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
Women with FXPOI are at risk of long-term health sequelae from a hypoestrogenic environment. These include osteoporosis and cardiovascular disease.
Women with POI (including those with FXPOI) are at increased risk of developing thyroid disease.
The earlier findings that alleles in the high normal and intermediate range conferred an increased risk for FXPOI [
Women with full-mutation alleles are not at increased risk for FXPOI, nor do they have signs of diminished ovarian reserve [
In addition to FXTAS and FXPOI, the following have been reported in the literature (see
The term "fragile X-associated neuropsychiatric disorders" (FXAND) has been proposed to promote research into fully characterizing neuropsychiatric outcomes associated with the premutation allele [
Elevated rates of neurologic findings, such as tremor and ataxia, have been reported in individuals with premutations who do not meet diagnostic criteria of FXTAS. A study of 110 daughters of men with FXTAS demonstrated an increased incidence of neurologic and psychiatric symptoms compared to controls, providing more evidence for such an association [
• Sit alone (10 months)
• Walk (20.6 months)
• First clear words (20 months)
• Sit alone (10 months)
• Walk (20.6 months)
• First clear words (20 months)
• Sit alone (10 months)
• Walk (20.6 months)
• First clear words (20 months)
• Ataxia can lead to gait and postural instability with most individuals needing a walking aid within ten years of diagnosis.
• Cognitive impairment typically starts with executive function impairment and expands to other domains such as working memory and information processing speed. Almost half of individuals with FXTAS meet criteria for dementia.
• Ovarian insufficiency has occurred as early as age 11 years and can present with primary amenorrhea and delayed puberty.
• Women with FXPOI have high rates of infertility and menopausal-type symptoms, including vasomotor symptoms, mood changes, and vaginal dryness.
• In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
• The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
• In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
• The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
• Women with FXPOI are at risk of long-term health sequelae from a hypoestrogenic environment. These include osteoporosis and cardiovascular disease.
• Women with POI (including those with FXPOI) are at increased risk of developing thyroid disease.
• In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
• The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
• The term "fragile X-associated neuropsychiatric disorders" (FXAND) has been proposed to promote research into fully characterizing neuropsychiatric outcomes associated with the premutation allele [
• Elevated rates of neurologic findings, such as tremor and ataxia, have been reported in individuals with premutations who do not meet diagnostic criteria of FXTAS. A study of 110 daughters of men with FXTAS demonstrated an increased incidence of neurologic and psychiatric symptoms compared to controls, providing more evidence for such an association [
## Males with Fragile X Syndrome (Full-Mutation Alleles)
The phenotypic features of males with fragile X syndrome (FXS) vary in relation to puberty [
Sit alone (10 months)
Walk (20.6 months)
First clear words (20 months)
• Sit alone (10 months)
• Walk (20.6 months)
• First clear words (20 months)
• Sit alone (10 months)
• Walk (20.6 months)
• First clear words (20 months)
• Sit alone (10 months)
• Walk (20.6 months)
• First clear words (20 months)
## Females with FXS (Heterozygous for Full-Mutation Alleles)
The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the full mutation, but with lower frequency and milder involvement [
## Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
FXTAS is characterized by late-onset progressive cerebellar ataxia and intention tremor in persons who have an
Onset is typically between ages 60 and 65 years. The age of onset and progression of symptoms of FXTAS vary significantly among individuals. Both age of onset and disease severity are related to repeat length, sex, and other features.
The first sign of FXTAS is typically tremor followed by ataxia and cognitive impairment [
Ataxia can lead to gait and postural instability with most individuals needing a walking aid within ten years of diagnosis.
Cognitive impairment typically starts with executive function impairment and expands to other domains such as working memory and information processing speed. Almost half of individuals with FXTAS meet criteria for dementia.
Other findings include short-term memory loss, parkinsonism, peripheral neuropathy and neuropathic pain, lower-limb proximal muscle weakness, and autonomic dysfunction [
Psychiatric disorders are common and include anxiety, irritability, agitation, hostility, obsessive-compulsive disorder, apathy, and depression [
Both males and females with a premutation are at risk for FXTAS. Increasing premutation repeat lengths correlate with increasing likelihood of developing FXTAS [
Risk for FXTAS by Age in Males with an
Adapted from
• Ataxia can lead to gait and postural instability with most individuals needing a walking aid within ten years of diagnosis.
• Cognitive impairment typically starts with executive function impairment and expands to other domains such as working memory and information processing speed. Almost half of individuals with FXTAS meet criteria for dementia.
## Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)
FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population [
Ovarian insufficiency has occurred as early as age 11 years and can present with primary amenorrhea and delayed puberty.
Women with FXPOI have high rates of infertility and menopausal-type symptoms, including vasomotor symptoms, mood changes, and vaginal dryness.
In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
Women with FXPOI are at risk of long-term health sequelae from a hypoestrogenic environment. These include osteoporosis and cardiovascular disease.
Women with POI (including those with FXPOI) are at increased risk of developing thyroid disease.
The earlier findings that alleles in the high normal and intermediate range conferred an increased risk for FXPOI [
Women with full-mutation alleles are not at increased risk for FXPOI, nor do they have signs of diminished ovarian reserve [
• Ovarian insufficiency has occurred as early as age 11 years and can present with primary amenorrhea and delayed puberty.
• Women with FXPOI have high rates of infertility and menopausal-type symptoms, including vasomotor symptoms, mood changes, and vaginal dryness.
• In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
• The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
• In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
• The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
• Women with FXPOI are at risk of long-term health sequelae from a hypoestrogenic environment. These include osteoporosis and cardiovascular disease.
• Women with POI (including those with FXPOI) are at increased risk of developing thyroid disease.
• In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
• The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [
## Other Fragile X-Associated Phenotypes
In addition to FXTAS and FXPOI, the following have been reported in the literature (see
The term "fragile X-associated neuropsychiatric disorders" (FXAND) has been proposed to promote research into fully characterizing neuropsychiatric outcomes associated with the premutation allele [
Elevated rates of neurologic findings, such as tremor and ataxia, have been reported in individuals with premutations who do not meet diagnostic criteria of FXTAS. A study of 110 daughters of men with FXTAS demonstrated an increased incidence of neurologic and psychiatric symptoms compared to controls, providing more evidence for such an association [
• The term "fragile X-associated neuropsychiatric disorders" (FXAND) has been proposed to promote research into fully characterizing neuropsychiatric outcomes associated with the premutation allele [
• Elevated rates of neurologic findings, such as tremor and ataxia, have been reported in individuals with premutations who do not meet diagnostic criteria of FXTAS. A study of 110 daughters of men with FXTAS demonstrated an increased incidence of neurologic and psychiatric symptoms compared to controls, providing more evidence for such an association [
## Genotype-Phenotype Correlations
The phenotype of males with an
Types of
At risk for FXPOI & FXTAS
Potential ↑ risk of other fragile X-assoc disorders
ID, if present, is typically high functioning.
May have anxiety &/or behavioral issues even w/out ID
ID = intellectual disability
Both males and females with premutations have been reported to have slightly elevated rates of some manifestations of fragile X syndrome, such as facial features, behavioral problems, learning disabilities, ADHD, and anxiety [
For FXTAS, repeat size is correlated with severity: higher repeat size is associated with greater motor impairment (tremor, ataxia, and parkinsonism), more severe peripheral neuropathy, higher number of intranuclear inclusions in the brain, MRI abnormalities (reduced cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity), and earlier age of onset [
It is estimated that 21% of women who carry a premutation develop FXPOI [
Additional studies indicate other vulnerabilities for the mid-repeat ranges of the premutation in women, such as an increased risk of psychological symptoms [
Odds Ratios for FXPOI by Premutation Size
Approximately 50% of females who have a full
Although some data suggest that individuals with repeat size mosaicism or methylation mosaicism perform at a higher intellectual level than those with completely methylated full mutations, such individuals are usually intellectually disabled.
Rarely, individuals with methylation mosaicism or completely unmethylated full mutations and normal intellect have been reported. The milder phenotype appears to be related to
• At risk for FXPOI & FXTAS
• Potential ↑ risk of other fragile X-assoc disorders
• ID, if present, is typically high functioning.
• May have anxiety &/or behavioral issues even w/out ID
• For FXTAS, repeat size is correlated with severity: higher repeat size is associated with greater motor impairment (tremor, ataxia, and parkinsonism), more severe peripheral neuropathy, higher number of intranuclear inclusions in the brain, MRI abnormalities (reduced cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity), and earlier age of onset [
• It is estimated that 21% of women who carry a premutation develop FXPOI [
• Additional studies indicate other vulnerabilities for the mid-repeat ranges of the premutation in women, such as an increased risk of psychological symptoms [
## Anticipation
Fragile X syndrome (FXS) is a trinucleotide repeat disorder that may demonstrate anticipation in some families. Typically, anticipation occurs when less severely affected individuals with a premutation or mosaic mutation transmit unstable
The impact of AGG interruptions on clinical outcomes in individuals with a premutation is unknown. Conflicting results regarding AGG interruptions and FXPOI have been published [
## Nomenclature
Fragile X syndrome has also been referred to as FXS, fragile X mental retardation, marker X syndrome, and Martin-Bell syndrome.
## Prevalence
The prevalence of females with FXS is presumed to be approximately one half the male prevalence due to reduced penetrance.
FXS is the most common known single-gene cause of autism spectrum disorder (ASD) and accounts for about 2%-3% of all ASD cases [
An estimated 2%-4% of men with adult-onset cerebellar ataxia who represent simplex cases (i.e., a single occurrence in a family) have a premutation in
## Genetically Related (Allelic) Disorders
No phenotypes other than FXS, FXTAS, FXPOI, and the other fragile X-associated phenotypes discussed in this
## Differential Diagnosis
Because chromosome abnormalities and copy number variants have been identified as frequently or more frequently than
Conditions to be considered in the differential diagnosis of FXS include those summarized in
Disorders to Consider in the Differential Diagnosis of Fragile X Syndrome
Typical facial appearance
Mild-to-severe learning disability
Behavior problems
Seizures
Overgrowth
Congenital cardiac anomalies
Neonatal jaundice
Renal anomalies
Scoliosis
A small subset of those w/FXS have the hyperphagia & obesity characteristic of PWS
DD & cognitive impairment
Temper tantrums, stubbornness, manipulative behavior, & obsessive-compulsive traits
Hypogonadism (genital hypoplasia, incomplete puberty &, in most, infertility)
Characteristic PWS facial appearance
Short stature
AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; AR = autosomal recessive; DD = developmental delay; FXS = fragile X syndrome; MOI = mode of inheritance; Mu = multifactorial; XL = X-linked
PWS is caused by an absence of expression of imprinted genes in the paternally derived PWS/Angelman syndrome (AS) region (i.e., 15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect).
The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.
PWS is characterized by severe infantile hypotonia and feeding difficulties, followed by early-childhood onset of excessive eating and development of morbid obesity unless controlled.
See OMIM
See OMIM
FRAXA and FRAXE are distinct fragile sites, albeit in close proximity on the X chromosome. The genes spanning the two fragile sites are designated
• Typical facial appearance
• Mild-to-severe learning disability
• Behavior problems
• Seizures
• Overgrowth
• Congenital cardiac anomalies
• Neonatal jaundice
• Renal anomalies
• Scoliosis
• A small subset of those w/FXS have the hyperphagia & obesity characteristic of PWS
• DD & cognitive impairment
• Temper tantrums, stubbornness, manipulative behavior, & obsessive-compulsive traits
• Hypogonadism (genital hypoplasia, incomplete puberty &, in most, infertility)
• Characteristic PWS facial appearance
• Short stature
## Management
To establish the extent of disease and needs in an individual diagnosed with an
Fragile X Syndrome: Recommended Evaluations Following Initial Diagnosis
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
ASD = autism spectrum disorder; OCD = obsessive-compulsive disorder; OT = occupational therapy; PT = physical therapy
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Recommended Evaluations Following Initial Diagnosis
OT = occupational therapy; PT = physical therapy
DXA = dual-energy x-ray absorptiometry
No specific treatment is available. Supportive and symptom-based therapy for children and adults with fragile X syndrome (FXS) is currently provided by the Fragile X Clinical and Research Consortium (FXCRC). The National Fragile X Foundation has established and collaborates with the FXCRC, which currently consists of 32 clinics that specialize in FXS, performing evaluations and providing recommendations to local practitioners on management of a child or adult with FXS. The providers at the FXCRC clinics have generated and continue to update FXS treatment guidelines and recommendations (see
Treatment is typically a dual approach: psychopharmacologic treatment of symptoms as needed in conjunction with therapeutic services, such as behavioral intervention, speech and language therapy, occupational therapy, and individualized educational support.
Medications used to treat symptoms in FXS are often the same medications used in the general population. However, individuals with FXS are more sensitive to the adverse effects of psychotropic medications. Thus, these medications should start at low doses and gradually increase to the optimal dosage to avoid adverse effects.
Early educational intervention, special education, and vocational training should be aimed specifically at the known impediments to learning. Parents and teachers of children with FXS have recognized the need for individual attention, small class size, and the avoidance of sudden change. More specific guidelines are available through education resources (see
Routine medical management of strabismus, otitis media, gastroesophageal reflux, cardiac issues, musculoskeletal concerns, and seizures is appropriate.
The following information represents typical management recommendations for individuals with DD/ID in the United States; standard recommendations may vary from country to country. In terms of specific elements to consider in developmental and educational evaluations of individuals with FXS, expert consensus documents written by members of the FXCRC provide general guidelines as well as specific recommendations at each age level from preschool to high school and transition programs. These are posted on the National Fragile X Foundation
IEP services:
An IEP provides specially designed instruction and related services for those who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
No specific treatment is available. Treatment of FXTAS is currently symptomatic and supportive and should be tailored to the individual. Current recommendations are based on anecdotal evidence in individuals with FXTAS and evidence from disorders that are similar to FXTAS.
Treatment should be multidisciplinary and include medications; specialty care in neurology and psychiatry; and therapy such as psychological counseling, speech therapy, occupational therapy, physical therapy, and gait training.
Treatment of Manifestations in Individuals with FXTAS
No specific treatment is available. Gynecologic or reproductive endocrinologic evaluation can provide appropriate treatment and counseling for reproductive considerations and hormone replacement.
Treatment of Manifestations in Individuals with FXPOI
Women who are not preventing pregnancy should be referred for genetic counseling to discuss the risks of transmission of the premutation or full mutation to a child.
If women do not wish to conceive, reliable contraception is necessary. This includes long-acting contraceptives (e.g., intrauterine device or implant), tubal ligation, or vasectomy. Combined contraceptives (e.g., oral contraceptives, vaginal ring) may have a higher failure rate.
For women who desire fertility treatment to increase the chance of conception, both donor oocyte and donor embryo in vitro fertilization (IVF) are reasonable options. IVF in women with POI using autologous oocytes has very low success rates.
HRT can reverse the negative effects of a hypoestrogenic environment on bone mineral density. It can be administered through many routes, but transdermal estradiol with cyclic progesterone (or a progestin-releasing intrauterine device) mimics physiologic hormone levels.
There is evidence from smaller trials that this physiologic replacement is superior to combined contraception for bone mineral density [
Recommended Surveillance for Individuals with Fragile X Syndrome
Recommended Surveillance for Individuals with FXTAS
CV = cardiovascular
Montreal Cognitive Assessment (MOCA) survey is a screening instrument for mild cognitive impairment.
Recommended Surveillance for Individuals with FXPOI
DXA = dual-energy x-ray absorptiometry
Typical and atypical antipsychotics with significant anti-dopaminergic effects, which can exacerbate parkinsonism
Metoclopramide, which can exacerbate parkinsonism
Anticholinergic agents, which can exacerbate cognitive complaints
Excessive alcohol, which can increase cerebellar dysfunction and postural instability
Agents with known cerebellar toxicity or side effects (use with caution)
See
Women with FXPOI who conceive have not been reported to have more pregnancy-related complications [
There are multiple ongoing trials of medication for behavior or drugs targeting the underlying neurobiological mechanism of fragile X syndrome (FXS) based on animal model studies. For example:
Metformin is a drug that is widely used to treat type 2 diabetes and has been shown to improve outcomes (including circadian rhythm and memory) in mouse and fly models of FXS [
Mavoglurant targets neural plasticity through negatively regulating mGluR5 signaling that becomes enhanced in the absence of FMRP in FXS. Efficacy is being tested by assessing language outcomes following an intensive language intervention in young children with FXS [
Additional interventions under investigation for FXS include behavioral therapies, such as behavior analytic treatment to address disruptive behaviors and social gaze training to improve social gaze and shape social skills.
Allopregnanolone is a naturally occurring neurosteroid that has shown promise in ameliorating the neuronal impairments of FXTAS in animal models [
Search
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• IEP services:
• An IEP provides specially designed instruction and related services for those who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services for those who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services for those who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Women who are not preventing pregnancy should be referred for genetic counseling to discuss the risks of transmission of the premutation or full mutation to a child.
• If women do not wish to conceive, reliable contraception is necessary. This includes long-acting contraceptives (e.g., intrauterine device or implant), tubal ligation, or vasectomy. Combined contraceptives (e.g., oral contraceptives, vaginal ring) may have a higher failure rate.
• For women who desire fertility treatment to increase the chance of conception, both donor oocyte and donor embryo in vitro fertilization (IVF) are reasonable options. IVF in women with POI using autologous oocytes has very low success rates.
• HRT can reverse the negative effects of a hypoestrogenic environment on bone mineral density. It can be administered through many routes, but transdermal estradiol with cyclic progesterone (or a progestin-releasing intrauterine device) mimics physiologic hormone levels.
• There is evidence from smaller trials that this physiologic replacement is superior to combined contraception for bone mineral density [
• Typical and atypical antipsychotics with significant anti-dopaminergic effects, which can exacerbate parkinsonism
• Metoclopramide, which can exacerbate parkinsonism
• Anticholinergic agents, which can exacerbate cognitive complaints
• Excessive alcohol, which can increase cerebellar dysfunction and postural instability
• Agents with known cerebellar toxicity or side effects (use with caution)
• Metformin is a drug that is widely used to treat type 2 diabetes and has been shown to improve outcomes (including circadian rhythm and memory) in mouse and fly models of FXS [
• Mavoglurant targets neural plasticity through negatively regulating mGluR5 signaling that becomes enhanced in the absence of FMRP in FXS. Efficacy is being tested by assessing language outcomes following an intensive language intervention in young children with FXS [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with an
Fragile X Syndrome: Recommended Evaluations Following Initial Diagnosis
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
ASD = autism spectrum disorder; OCD = obsessive-compulsive disorder; OT = occupational therapy; PT = physical therapy
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Recommended Evaluations Following Initial Diagnosis
OT = occupational therapy; PT = physical therapy
DXA = dual-energy x-ray absorptiometry
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
## Treatment of Manifestations – FXS
No specific treatment is available. Supportive and symptom-based therapy for children and adults with fragile X syndrome (FXS) is currently provided by the Fragile X Clinical and Research Consortium (FXCRC). The National Fragile X Foundation has established and collaborates with the FXCRC, which currently consists of 32 clinics that specialize in FXS, performing evaluations and providing recommendations to local practitioners on management of a child or adult with FXS. The providers at the FXCRC clinics have generated and continue to update FXS treatment guidelines and recommendations (see
Treatment is typically a dual approach: psychopharmacologic treatment of symptoms as needed in conjunction with therapeutic services, such as behavioral intervention, speech and language therapy, occupational therapy, and individualized educational support.
Medications used to treat symptoms in FXS are often the same medications used in the general population. However, individuals with FXS are more sensitive to the adverse effects of psychotropic medications. Thus, these medications should start at low doses and gradually increase to the optimal dosage to avoid adverse effects.
Early educational intervention, special education, and vocational training should be aimed specifically at the known impediments to learning. Parents and teachers of children with FXS have recognized the need for individual attention, small class size, and the avoidance of sudden change. More specific guidelines are available through education resources (see
Routine medical management of strabismus, otitis media, gastroesophageal reflux, cardiac issues, musculoskeletal concerns, and seizures is appropriate.
The following information represents typical management recommendations for individuals with DD/ID in the United States; standard recommendations may vary from country to country. In terms of specific elements to consider in developmental and educational evaluations of individuals with FXS, expert consensus documents written by members of the FXCRC provide general guidelines as well as specific recommendations at each age level from preschool to high school and transition programs. These are posted on the National Fragile X Foundation
IEP services:
An IEP provides specially designed instruction and related services for those who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• IEP services:
• An IEP provides specially designed instruction and related services for those who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services for those who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services for those who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability (DD/ID) Management Issues
The following information represents typical management recommendations for individuals with DD/ID in the United States; standard recommendations may vary from country to country. In terms of specific elements to consider in developmental and educational evaluations of individuals with FXS, expert consensus documents written by members of the FXCRC provide general guidelines as well as specific recommendations at each age level from preschool to high school and transition programs. These are posted on the National Fragile X Foundation
IEP services:
An IEP provides specially designed instruction and related services for those who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services for those who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services for those who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services for those who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
## Treatment of Manifestations – FXTAS and FXPOI
No specific treatment is available. Treatment of FXTAS is currently symptomatic and supportive and should be tailored to the individual. Current recommendations are based on anecdotal evidence in individuals with FXTAS and evidence from disorders that are similar to FXTAS.
Treatment should be multidisciplinary and include medications; specialty care in neurology and psychiatry; and therapy such as psychological counseling, speech therapy, occupational therapy, physical therapy, and gait training.
Treatment of Manifestations in Individuals with FXTAS
No specific treatment is available. Gynecologic or reproductive endocrinologic evaluation can provide appropriate treatment and counseling for reproductive considerations and hormone replacement.
Treatment of Manifestations in Individuals with FXPOI
Women who are not preventing pregnancy should be referred for genetic counseling to discuss the risks of transmission of the premutation or full mutation to a child.
If women do not wish to conceive, reliable contraception is necessary. This includes long-acting contraceptives (e.g., intrauterine device or implant), tubal ligation, or vasectomy. Combined contraceptives (e.g., oral contraceptives, vaginal ring) may have a higher failure rate.
For women who desire fertility treatment to increase the chance of conception, both donor oocyte and donor embryo in vitro fertilization (IVF) are reasonable options. IVF in women with POI using autologous oocytes has very low success rates.
HRT can reverse the negative effects of a hypoestrogenic environment on bone mineral density. It can be administered through many routes, but transdermal estradiol with cyclic progesterone (or a progestin-releasing intrauterine device) mimics physiologic hormone levels.
There is evidence from smaller trials that this physiologic replacement is superior to combined contraception for bone mineral density [
• Women who are not preventing pregnancy should be referred for genetic counseling to discuss the risks of transmission of the premutation or full mutation to a child.
• If women do not wish to conceive, reliable contraception is necessary. This includes long-acting contraceptives (e.g., intrauterine device or implant), tubal ligation, or vasectomy. Combined contraceptives (e.g., oral contraceptives, vaginal ring) may have a higher failure rate.
• For women who desire fertility treatment to increase the chance of conception, both donor oocyte and donor embryo in vitro fertilization (IVF) are reasonable options. IVF in women with POI using autologous oocytes has very low success rates.
• HRT can reverse the negative effects of a hypoestrogenic environment on bone mineral density. It can be administered through many routes, but transdermal estradiol with cyclic progesterone (or a progestin-releasing intrauterine device) mimics physiologic hormone levels.
• There is evidence from smaller trials that this physiologic replacement is superior to combined contraception for bone mineral density [
## FXTAS
No specific treatment is available. Treatment of FXTAS is currently symptomatic and supportive and should be tailored to the individual. Current recommendations are based on anecdotal evidence in individuals with FXTAS and evidence from disorders that are similar to FXTAS.
Treatment should be multidisciplinary and include medications; specialty care in neurology and psychiatry; and therapy such as psychological counseling, speech therapy, occupational therapy, physical therapy, and gait training.
Treatment of Manifestations in Individuals with FXTAS
## FXPO
No specific treatment is available. Gynecologic or reproductive endocrinologic evaluation can provide appropriate treatment and counseling for reproductive considerations and hormone replacement.
Treatment of Manifestations in Individuals with FXPOI
Women who are not preventing pregnancy should be referred for genetic counseling to discuss the risks of transmission of the premutation or full mutation to a child.
If women do not wish to conceive, reliable contraception is necessary. This includes long-acting contraceptives (e.g., intrauterine device or implant), tubal ligation, or vasectomy. Combined contraceptives (e.g., oral contraceptives, vaginal ring) may have a higher failure rate.
For women who desire fertility treatment to increase the chance of conception, both donor oocyte and donor embryo in vitro fertilization (IVF) are reasonable options. IVF in women with POI using autologous oocytes has very low success rates.
HRT can reverse the negative effects of a hypoestrogenic environment on bone mineral density. It can be administered through many routes, but transdermal estradiol with cyclic progesterone (or a progestin-releasing intrauterine device) mimics physiologic hormone levels.
There is evidence from smaller trials that this physiologic replacement is superior to combined contraception for bone mineral density [
• Women who are not preventing pregnancy should be referred for genetic counseling to discuss the risks of transmission of the premutation or full mutation to a child.
• If women do not wish to conceive, reliable contraception is necessary. This includes long-acting contraceptives (e.g., intrauterine device or implant), tubal ligation, or vasectomy. Combined contraceptives (e.g., oral contraceptives, vaginal ring) may have a higher failure rate.
• For women who desire fertility treatment to increase the chance of conception, both donor oocyte and donor embryo in vitro fertilization (IVF) are reasonable options. IVF in women with POI using autologous oocytes has very low success rates.
• HRT can reverse the negative effects of a hypoestrogenic environment on bone mineral density. It can be administered through many routes, but transdermal estradiol with cyclic progesterone (or a progestin-releasing intrauterine device) mimics physiologic hormone levels.
• There is evidence from smaller trials that this physiologic replacement is superior to combined contraception for bone mineral density [
## Surveillance
Recommended Surveillance for Individuals with Fragile X Syndrome
Recommended Surveillance for Individuals with FXTAS
CV = cardiovascular
Montreal Cognitive Assessment (MOCA) survey is a screening instrument for mild cognitive impairment.
Recommended Surveillance for Individuals with FXPOI
DXA = dual-energy x-ray absorptiometry
## Agents/Circumstances to Avoid
Typical and atypical antipsychotics with significant anti-dopaminergic effects, which can exacerbate parkinsonism
Metoclopramide, which can exacerbate parkinsonism
Anticholinergic agents, which can exacerbate cognitive complaints
Excessive alcohol, which can increase cerebellar dysfunction and postural instability
Agents with known cerebellar toxicity or side effects (use with caution)
• Typical and atypical antipsychotics with significant anti-dopaminergic effects, which can exacerbate parkinsonism
• Metoclopramide, which can exacerbate parkinsonism
• Anticholinergic agents, which can exacerbate cognitive complaints
• Excessive alcohol, which can increase cerebellar dysfunction and postural instability
• Agents with known cerebellar toxicity or side effects (use with caution)
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Women with FXPOI who conceive have not been reported to have more pregnancy-related complications [
## Therapies Under Investigation
There are multiple ongoing trials of medication for behavior or drugs targeting the underlying neurobiological mechanism of fragile X syndrome (FXS) based on animal model studies. For example:
Metformin is a drug that is widely used to treat type 2 diabetes and has been shown to improve outcomes (including circadian rhythm and memory) in mouse and fly models of FXS [
Mavoglurant targets neural plasticity through negatively regulating mGluR5 signaling that becomes enhanced in the absence of FMRP in FXS. Efficacy is being tested by assessing language outcomes following an intensive language intervention in young children with FXS [
Additional interventions under investigation for FXS include behavioral therapies, such as behavior analytic treatment to address disruptive behaviors and social gaze training to improve social gaze and shape social skills.
Allopregnanolone is a naturally occurring neurosteroid that has shown promise in ameliorating the neuronal impairments of FXTAS in animal models [
Search
• Metformin is a drug that is widely used to treat type 2 diabetes and has been shown to improve outcomes (including circadian rhythm and memory) in mouse and fly models of FXS [
• Mavoglurant targets neural plasticity through negatively regulating mGluR5 signaling that becomes enhanced in the absence of FMRP in FXS. Efficacy is being tested by assessing language outcomes following an intensive language intervention in young children with FXS [
## Genetic Counseling
If a male proband has an
If a male proband has a premutation, the mother is heterozygous for an intermediate allele (~45-54 CGG repeats) or premutation allele.
If the mother of the proband is heterozygous for an
Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
A female proband may have inherited an
Molecular genetic testing of the father (if the proband is heterozygous for a premutation) and the mother is recommended.
If the mother of the proband is heterozygous for an
If the father of the proband is hemizygous for a premutation (i.e., a "transmitting male"), he will transmit it to all of his daughters and none of his sons.
For sibs who inherit an
Risk for an
~16% of maternal transmissions of an intermediate allele may result in a minor variation (i.e., 1 or 2 CGG repeats) in repeat size.
Intermediate alleles of ~50-54 repeats may be more unstable than alleles of <50 repeats.
In general, the risk of a maternal premutation becoming a full mutation on transmission to offspring correlates w/number of CGG repeats in the premutation.
For premutations w/<100 repeats, the interruption of the CGG repeats by occasional AGG repeats may help evaluate risk of expansion.
Premutations transmitted by the father may result in small ↑s in trinucleotide repeat number, but not in full mutations.
Premutations transmitted from father to daughter may often regress slightly in repeat number.
FXPOI = fragile X-associated primary ovarian insufficiency; FXS = fragile X syndrome; FXTAS = fragile X-associated tremor/ataxia syndrome; ID = intellectual disability
Intermediate alleles may infrequently contract by a few repeats, and rarely by sufficiently large number of repeats to be in the normal range [
Rarely, contraction of trinucleotide repeat number occurs, though this appears to be more frequent in paternal transmissions than maternal transmissions, with the highest frequency of contractions in the 70-90 repeat range [
The physical and behavioral features seen in males with fragile X syndrome have been reported in females heterozygous for the full mutation, but with lower frequency and milder involvement.
The maternal aunts (and their offspring) of a proband with fragile X syndrome may be at risk of being heterozygotes or being affected (depending on their sex and family relationship).
Newborn screening for FXS has been piloted, but is not currently standard practice [
Note: The diagnosis of FXPOI does not eliminate the possibility of subsequent conception. There are reports of women who carry a premutation having a child with fragile X syndrome after being diagnosed with FXPOI [
For additional information regarding genetic counseling and cascade testing see
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are known to have an
Once an expanded (or altered)
If a woman with an
Women who are heterozygous for a premutation who do not have primary ovarian insufficiency have better success rates. However, they tend to need higher gonadotropin stimulation with fewer oocytes retrieved than unaffected women [
Importantly, PGT cannot currently be used in clinical practice to determine if a premutation has expanded into the full mutation range, though there are research initiatives in progress to reliably determine repeat expansion from an embryo biopsy [
In addition, PGT is considered a screening test. The trophectoderm layer, which is biopsied for the testing, is at risk of mosaicism [
CVS can be used for prenatal testing to determine the presence of a premutation or full mutation during pregnancy. Follow-up amniocentesis may be needed to confirm the methylation status of a full-mutation allele, given that the methylation status of
Full phenotypic information for fetuses diagnosed prenatally with a premutation is difficult to determine, given the variable expressivity of FXPOI and FXTAS. The same unknowns are present when a female fetus is found to have a full mutation, given the variable phenotype [
• If a male proband has an
• If a male proband has a premutation, the mother is heterozygous for an intermediate allele (~45-54 CGG repeats) or premutation allele.
• If the mother of the proband is heterozygous for an
• Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
• Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
• Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
• ~16% of maternal transmissions of an intermediate allele may result in a minor variation (i.e., 1 or 2 CGG repeats) in repeat size.
• Intermediate alleles of ~50-54 repeats may be more unstable than alleles of <50 repeats.
• In general, the risk of a maternal premutation becoming a full mutation on transmission to offspring correlates w/number of CGG repeats in the premutation.
• For premutations w/<100 repeats, the interruption of the CGG repeats by occasional AGG repeats may help evaluate risk of expansion.
• Premutations transmitted by the father may result in small ↑s in trinucleotide repeat number, but not in full mutations.
• Premutations transmitted from father to daughter may often regress slightly in repeat number.
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are known to have an
## Mode of Inheritance
## Risk to Family Members
If a male proband has an
If a male proband has a premutation, the mother is heterozygous for an intermediate allele (~45-54 CGG repeats) or premutation allele.
If the mother of the proband is heterozygous for an
Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
A female proband may have inherited an
Molecular genetic testing of the father (if the proband is heterozygous for a premutation) and the mother is recommended.
If the mother of the proband is heterozygous for an
If the father of the proband is hemizygous for a premutation (i.e., a "transmitting male"), he will transmit it to all of his daughters and none of his sons.
For sibs who inherit an
Risk for an
~16% of maternal transmissions of an intermediate allele may result in a minor variation (i.e., 1 or 2 CGG repeats) in repeat size.
Intermediate alleles of ~50-54 repeats may be more unstable than alleles of <50 repeats.
In general, the risk of a maternal premutation becoming a full mutation on transmission to offspring correlates w/number of CGG repeats in the premutation.
For premutations w/<100 repeats, the interruption of the CGG repeats by occasional AGG repeats may help evaluate risk of expansion.
Premutations transmitted by the father may result in small ↑s in trinucleotide repeat number, but not in full mutations.
Premutations transmitted from father to daughter may often regress slightly in repeat number.
FXPOI = fragile X-associated primary ovarian insufficiency; FXS = fragile X syndrome; FXTAS = fragile X-associated tremor/ataxia syndrome; ID = intellectual disability
Intermediate alleles may infrequently contract by a few repeats, and rarely by sufficiently large number of repeats to be in the normal range [
Rarely, contraction of trinucleotide repeat number occurs, though this appears to be more frequent in paternal transmissions than maternal transmissions, with the highest frequency of contractions in the 70-90 repeat range [
The physical and behavioral features seen in males with fragile X syndrome have been reported in females heterozygous for the full mutation, but with lower frequency and milder involvement.
The maternal aunts (and their offspring) of a proband with fragile X syndrome may be at risk of being heterozygotes or being affected (depending on their sex and family relationship).
Newborn screening for FXS has been piloted, but is not currently standard practice [
• If a male proband has an
• If a male proband has a premutation, the mother is heterozygous for an intermediate allele (~45-54 CGG repeats) or premutation allele.
• If the mother of the proband is heterozygous for an
• Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
• Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
• Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
• ~16% of maternal transmissions of an intermediate allele may result in a minor variation (i.e., 1 or 2 CGG repeats) in repeat size.
• Intermediate alleles of ~50-54 repeats may be more unstable than alleles of <50 repeats.
• In general, the risk of a maternal premutation becoming a full mutation on transmission to offspring correlates w/number of CGG repeats in the premutation.
• For premutations w/<100 repeats, the interruption of the CGG repeats by occasional AGG repeats may help evaluate risk of expansion.
• Premutations transmitted by the father may result in small ↑s in trinucleotide repeat number, but not in full mutations.
• Premutations transmitted from father to daughter may often regress slightly in repeat number.
## Parents of a Male Proband
If a male proband has an
If a male proband has a premutation, the mother is heterozygous for an intermediate allele (~45-54 CGG repeats) or premutation allele.
If the mother of the proband is heterozygous for an
Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
• If a male proband has an
• If a male proband has a premutation, the mother is heterozygous for an intermediate allele (~45-54 CGG repeats) or premutation allele.
• If the mother of the proband is heterozygous for an
• Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
• Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
• Note: If the mother of the proband is heterozygous for a premutation: (1) her father may be hemizygous for a premutation (i.e., a "transmitting male") and may be at risk for FXTAS or (2) her mother may be heterozygous for an intermediate or premutation allele.
## Parents of a Female Proband
A female proband may have inherited an
Molecular genetic testing of the father (if the proband is heterozygous for a premutation) and the mother is recommended.
## Sibs of a Proband
If the mother of the proband is heterozygous for an
If the father of the proband is hemizygous for a premutation (i.e., a "transmitting male"), he will transmit it to all of his daughters and none of his sons.
For sibs who inherit an
Risk for an
~16% of maternal transmissions of an intermediate allele may result in a minor variation (i.e., 1 or 2 CGG repeats) in repeat size.
Intermediate alleles of ~50-54 repeats may be more unstable than alleles of <50 repeats.
In general, the risk of a maternal premutation becoming a full mutation on transmission to offspring correlates w/number of CGG repeats in the premutation.
For premutations w/<100 repeats, the interruption of the CGG repeats by occasional AGG repeats may help evaluate risk of expansion.
Premutations transmitted by the father may result in small ↑s in trinucleotide repeat number, but not in full mutations.
Premutations transmitted from father to daughter may often regress slightly in repeat number.
FXPOI = fragile X-associated primary ovarian insufficiency; FXS = fragile X syndrome; FXTAS = fragile X-associated tremor/ataxia syndrome; ID = intellectual disability
Intermediate alleles may infrequently contract by a few repeats, and rarely by sufficiently large number of repeats to be in the normal range [
Rarely, contraction of trinucleotide repeat number occurs, though this appears to be more frequent in paternal transmissions than maternal transmissions, with the highest frequency of contractions in the 70-90 repeat range [
The physical and behavioral features seen in males with fragile X syndrome have been reported in females heterozygous for the full mutation, but with lower frequency and milder involvement.
• ~16% of maternal transmissions of an intermediate allele may result in a minor variation (i.e., 1 or 2 CGG repeats) in repeat size.
• Intermediate alleles of ~50-54 repeats may be more unstable than alleles of <50 repeats.
• In general, the risk of a maternal premutation becoming a full mutation on transmission to offspring correlates w/number of CGG repeats in the premutation.
• For premutations w/<100 repeats, the interruption of the CGG repeats by occasional AGG repeats may help evaluate risk of expansion.
• Premutations transmitted by the father may result in small ↑s in trinucleotide repeat number, but not in full mutations.
• Premutations transmitted from father to daughter may often regress slightly in repeat number.
## Offspring of an Individual with a Premutation
## Offspring of an Individual with a Full Mutation
## Other Family Members
The maternal aunts (and their offspring) of a proband with fragile X syndrome may be at risk of being heterozygotes or being affected (depending on their sex and family relationship).
## Population-Based Fragile X Syndrome Screening
Newborn screening for FXS has been piloted, but is not currently standard practice [
## Related Genetic Counseling Issues
Note: The diagnosis of FXPOI does not eliminate the possibility of subsequent conception. There are reports of women who carry a premutation having a child with fragile X syndrome after being diagnosed with FXPOI [
For additional information regarding genetic counseling and cascade testing see
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are known to have an
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are known to have an
## Prenatal Testing and Preimplantation Genetic Testing
Once an expanded (or altered)
If a woman with an
Women who are heterozygous for a premutation who do not have primary ovarian insufficiency have better success rates. However, they tend to need higher gonadotropin stimulation with fewer oocytes retrieved than unaffected women [
Importantly, PGT cannot currently be used in clinical practice to determine if a premutation has expanded into the full mutation range, though there are research initiatives in progress to reliably determine repeat expansion from an embryo biopsy [
In addition, PGT is considered a screening test. The trophectoderm layer, which is biopsied for the testing, is at risk of mosaicism [
CVS can be used for prenatal testing to determine the presence of a premutation or full mutation during pregnancy. Follow-up amniocentesis may be needed to confirm the methylation status of a full-mutation allele, given that the methylation status of
Full phenotypic information for fetuses diagnosed prenatally with a premutation is difficult to determine, given the variable expressivity of FXPOI and FXTAS. The same unknowns are present when a female fetus is found to have a full mutation, given the variable phenotype [
## Preimplantation Genetic Testing
If a woman with an
Women who are heterozygous for a premutation who do not have primary ovarian insufficiency have better success rates. However, they tend to need higher gonadotropin stimulation with fewer oocytes retrieved than unaffected women [
## Interpretation of Preimplantation and Prenatal Genetic Test Results
Importantly, PGT cannot currently be used in clinical practice to determine if a premutation has expanded into the full mutation range, though there are research initiatives in progress to reliably determine repeat expansion from an embryo biopsy [
In addition, PGT is considered a screening test. The trophectoderm layer, which is biopsied for the testing, is at risk of mosaicism [
CVS can be used for prenatal testing to determine the presence of a premutation or full mutation during pregnancy. Follow-up amniocentesis may be needed to confirm the methylation status of a full-mutation allele, given that the methylation status of
Full phenotypic information for fetuses diagnosed prenatally with a premutation is difficult to determine, given the variable expressivity of FXPOI and FXTAS. The same unknowns are present when a female fetus is found to have a full mutation, given the variable phenotype [
## Resources
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## Molecular Genetics
FMR1 Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FMR1 Disorders (
Full-mutation alleles are associated with aberrant hypermethylation of the CGG expansion resulting in decrease or silencing of
Premutation alleles are not associated with hypermethylation but are associated with increased mRNA levels. The pathogenic mechanism behind premutation-associated outcomes (FXTAS, FXPOI, and other fragile X-associated outcomes) is thought to be due to toxicity from elevated levels of
## Molecular Pathogenesis
Full-mutation alleles are associated with aberrant hypermethylation of the CGG expansion resulting in decrease or silencing of
Premutation alleles are not associated with hypermethylation but are associated with increased mRNA levels. The pathogenic mechanism behind premutation-associated outcomes (FXTAS, FXPOI, and other fragile X-associated outcomes) is thought to be due to toxicity from elevated levels of
## Chapter Notes
Elizabeth Berry-Kravis, MD, PhD (2019-present)Heather Hipp, MD (2019-present)Jessica Ezzell Hunter, PhD (2019-present)Robert A Saul, MD, FACMG; Greenwood Genetics Center (1998-2019)Jack C Tarleton, PhD, FACMG; Fullerton Genetics Center, Asheville (1998-2019)Peter K Todd, MD, PhD (2019-present)
16 May 2024 (ma) Revision: added
21 November 2019 (ha) Comprehensive update posted live
28 October 2010 (me) Comprehensive update posted live
20 December 2007 (me) Comprehensive update posted live
24 May 2005 (rs/jt) Comprehensive update: change in scope of
13 September 2004 (me) Comprehensive update posted live
22 November 2002 (me) Comprehensive update posted live
26 May 2000 (me) Comprehensive update posted live
16 June 1998 (pb) Review posted live
May 1996 (jt) Original submission
• 16 May 2024 (ma) Revision: added
• 21 November 2019 (ha) Comprehensive update posted live
• 28 October 2010 (me) Comprehensive update posted live
• 20 December 2007 (me) Comprehensive update posted live
• 24 May 2005 (rs/jt) Comprehensive update: change in scope of
• 13 September 2004 (me) Comprehensive update posted live
• 22 November 2002 (me) Comprehensive update posted live
• 26 May 2000 (me) Comprehensive update posted live
• 16 June 1998 (pb) Review posted live
• May 1996 (jt) Original submission
## Author History
Elizabeth Berry-Kravis, MD, PhD (2019-present)Heather Hipp, MD (2019-present)Jessica Ezzell Hunter, PhD (2019-present)Robert A Saul, MD, FACMG; Greenwood Genetics Center (1998-2019)Jack C Tarleton, PhD, FACMG; Fullerton Genetics Center, Asheville (1998-2019)Peter K Todd, MD, PhD (2019-present)
## Revision History
16 May 2024 (ma) Revision: added
21 November 2019 (ha) Comprehensive update posted live
28 October 2010 (me) Comprehensive update posted live
20 December 2007 (me) Comprehensive update posted live
24 May 2005 (rs/jt) Comprehensive update: change in scope of
13 September 2004 (me) Comprehensive update posted live
22 November 2002 (me) Comprehensive update posted live
26 May 2000 (me) Comprehensive update posted live
16 June 1998 (pb) Review posted live
May 1996 (jt) Original submission
• 16 May 2024 (ma) Revision: added
• 21 November 2019 (ha) Comprehensive update posted live
• 28 October 2010 (me) Comprehensive update posted live
• 20 December 2007 (me) Comprehensive update posted live
• 24 May 2005 (rs/jt) Comprehensive update: change in scope of
• 13 September 2004 (me) Comprehensive update posted live
• 22 November 2002 (me) Comprehensive update posted live
• 26 May 2000 (me) Comprehensive update posted live
• 16 June 1998 (pb) Review posted live
• May 1996 (jt) Original submission
## References
Biancalana V, Glaeser D, McQuaid S, Steinbach P. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. Eur J Hum Genet. 2015;23:417-25
Chitayat D, Wyatt PR, et al. Fragile X testing in obstetrics and gynaecology in Canada. J Obstet Gynaecol Can. 2008;30:837-41.
Committee on Genetics. Committee opinion no. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129:e41-55.
Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL, McConkie-Rosell A. Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors. J Genet Couns. 2012;21:752-60.
Hersh JH, Saul RA, Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127:994-1006
Moeschler JB, Shevell M, et al. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014; 134:e903-18
Monaghan KG, Lyon E, Spector EB. ACMG standards and guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med
National Fragile X Foundation. Consensus documents on treatments and interventions for fragile X. Available
Schaefer GB, Mendelsohn NJ, et al. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15:399-407
Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7:584-7.
Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97:189-94.
• Biancalana V, Glaeser D, McQuaid S, Steinbach P. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. Eur J Hum Genet. 2015;23:417-25
• Chitayat D, Wyatt PR, et al. Fragile X testing in obstetrics and gynaecology in Canada. J Obstet Gynaecol Can. 2008;30:837-41.
• Committee on Genetics. Committee opinion no. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129:e41-55.
• Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL, McConkie-Rosell A. Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors. J Genet Couns. 2012;21:752-60.
• Hersh JH, Saul RA, Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127:994-1006
• Moeschler JB, Shevell M, et al. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014; 134:e903-18
• Monaghan KG, Lyon E, Spector EB. ACMG standards and guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med
• National Fragile X Foundation. Consensus documents on treatments and interventions for fragile X. Available
• Schaefer GB, Mendelsohn NJ, et al. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15:399-407
• Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7:584-7.
• Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97:189-94.
## Published Guidelines / Consensus Statements
Biancalana V, Glaeser D, McQuaid S, Steinbach P. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. Eur J Hum Genet. 2015;23:417-25
Chitayat D, Wyatt PR, et al. Fragile X testing in obstetrics and gynaecology in Canada. J Obstet Gynaecol Can. 2008;30:837-41.
Committee on Genetics. Committee opinion no. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129:e41-55.
Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL, McConkie-Rosell A. Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors. J Genet Couns. 2012;21:752-60.
Hersh JH, Saul RA, Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127:994-1006
Moeschler JB, Shevell M, et al. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014; 134:e903-18
Monaghan KG, Lyon E, Spector EB. ACMG standards and guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med
National Fragile X Foundation. Consensus documents on treatments and interventions for fragile X. Available
Schaefer GB, Mendelsohn NJ, et al. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15:399-407
Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7:584-7.
Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97:189-94.
• Biancalana V, Glaeser D, McQuaid S, Steinbach P. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. Eur J Hum Genet. 2015;23:417-25
• Chitayat D, Wyatt PR, et al. Fragile X testing in obstetrics and gynaecology in Canada. J Obstet Gynaecol Can. 2008;30:837-41.
• Committee on Genetics. Committee opinion no. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129:e41-55.
• Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL, McConkie-Rosell A. Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors. J Genet Couns. 2012;21:752-60.
• Hersh JH, Saul RA, Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127:994-1006
• Moeschler JB, Shevell M, et al. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014; 134:e903-18
• Monaghan KG, Lyon E, Spector EB. ACMG standards and guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med
• National Fragile X Foundation. Consensus documents on treatments and interventions for fragile X. Available
• Schaefer GB, Mendelsohn NJ, et al. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15:399-407
• Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. 2005;7:584-7.
• Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97:189-94.
## Literature Cited
|
[] |
16/6/1998
|
21/11/2019
|
16/5/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
friedreich
|
friedreich
|
[
"FRDA",
"FRDA",
"Frataxin, mitochondrial",
"FXN",
"Friedreich Ataxia"
] |
Friedreich Ataxia
|
Sanjay I Bidichandani, Martin B Delatycki, Marek Napierala, Antoine Duquette
|
Summary Typical Friedreich ataxia (FRDA) is characterized by progressive ataxia with onset from early childhood to early adulthood with mean age at onset from 10 to 15 years (range: age two years to the eighth decade). Ataxia, manifesting initially as poor balance when walking, is typically followed by upper-limb ataxia, dysarthria, dysphagia, peripheral motor and sensory neuropathy, spasticity, autonomic disturbance, and often abnormal eye movements and optic atrophy. Hypertrophic cardiomyopathy is present in about two thirds of individuals; occasionally it is diagnosed prior to the onset of ataxia. Diabetes mellitus and impaired glucose tolerance can also occur. Among individuals with FRDA, about 75% have "typical Friedreich ataxia" and about 25% of individuals with biallelic The diagnosis of Friedreich ataxia is established in a proband with suggestive findings and biallelic pathogenic variants in FRDA is inherited in an autosomal recessive manner. If both parents are heterozygous for a pathogenic variant in
|
## Diagnosis
No consensus diagnostic criteria for Friedreich ataxia (FRDA) have been published.
FRDA
Progressive ataxia
Dysarthria
Decreased/loss of position sense and/or vibration sense in the lower limbs
Pyramidal involvement resulting in weakness of the legs, extensor plantar responses
Muscle weakness
Scoliosis
Pes cavus
Glucose intolerance
Diabetes mellitus
The diagnosis of Friedreich ataxia
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
The two classes of
Approximately 96% of individuals with FRDA have biallelic
Approximately 4% of individuals are compound heterozygotes for an
Molecular genetic testing approaches can include
Testing is targeted for the expanded
If an apparently heterozygous
For an introduction to multigene panels click
Note: The intronic pathogenic repeat expansion in
Molecular Genetic Testing Used in Friedreich Ataxia
See
See
Sequence-based multigene panels and exome sequencing cannot reliably detect pathogenic repeat expansions in this gene. However, pathogenic repeat expansions may be more reliably detected using customized tools and long-read sequencing.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• Progressive ataxia
• Dysarthria
• Decreased/loss of position sense and/or vibration sense in the lower limbs
• Pyramidal involvement resulting in weakness of the legs, extensor plantar responses
• Progressive ataxia
• Dysarthria
• Decreased/loss of position sense and/or vibration sense in the lower limbs
• Pyramidal involvement resulting in weakness of the legs, extensor plantar responses
•
• Muscle weakness
• Scoliosis
• Pes cavus
• Muscle weakness
• Scoliosis
• Pes cavus
•
•
• Glucose intolerance
• Diabetes mellitus
• Glucose intolerance
• Diabetes mellitus
•
• Progressive ataxia
• Dysarthria
• Decreased/loss of position sense and/or vibration sense in the lower limbs
• Pyramidal involvement resulting in weakness of the legs, extensor plantar responses
• Muscle weakness
• Scoliosis
• Pes cavus
• Glucose intolerance
• Diabetes mellitus
•
• Testing is targeted for the expanded
• If an apparently heterozygous
• Testing is targeted for the expanded
• If an apparently heterozygous
• For an introduction to multigene panels click
• Note: The intronic pathogenic repeat expansion in
• Testing is targeted for the expanded
• If an apparently heterozygous
## Suggestive Findings
FRDA
Progressive ataxia
Dysarthria
Decreased/loss of position sense and/or vibration sense in the lower limbs
Pyramidal involvement resulting in weakness of the legs, extensor plantar responses
Muscle weakness
Scoliosis
Pes cavus
Glucose intolerance
Diabetes mellitus
• Progressive ataxia
• Dysarthria
• Decreased/loss of position sense and/or vibration sense in the lower limbs
• Pyramidal involvement resulting in weakness of the legs, extensor plantar responses
• Progressive ataxia
• Dysarthria
• Decreased/loss of position sense and/or vibration sense in the lower limbs
• Pyramidal involvement resulting in weakness of the legs, extensor plantar responses
•
• Muscle weakness
• Scoliosis
• Pes cavus
• Muscle weakness
• Scoliosis
• Pes cavus
•
•
• Glucose intolerance
• Diabetes mellitus
• Glucose intolerance
• Diabetes mellitus
•
• Progressive ataxia
• Dysarthria
• Decreased/loss of position sense and/or vibration sense in the lower limbs
• Pyramidal involvement resulting in weakness of the legs, extensor plantar responses
• Muscle weakness
• Scoliosis
• Pes cavus
• Glucose intolerance
• Diabetes mellitus
## Establishing the Diagnosis
The diagnosis of Friedreich ataxia
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
The two classes of
Approximately 96% of individuals with FRDA have biallelic
Approximately 4% of individuals are compound heterozygotes for an
Molecular genetic testing approaches can include
Testing is targeted for the expanded
If an apparently heterozygous
For an introduction to multigene panels click
Note: The intronic pathogenic repeat expansion in
Molecular Genetic Testing Used in Friedreich Ataxia
See
See
Sequence-based multigene panels and exome sequencing cannot reliably detect pathogenic repeat expansions in this gene. However, pathogenic repeat expansions may be more reliably detected using customized tools and long-read sequencing.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
•
• Testing is targeted for the expanded
• If an apparently heterozygous
• Testing is targeted for the expanded
• If an apparently heterozygous
• For an introduction to multigene panels click
• Note: The intronic pathogenic repeat expansion in
• Testing is targeted for the expanded
• If an apparently heterozygous
## Repeat Expansions
Approximately 96% of individuals with FRDA have biallelic
Approximately 4% of individuals are compound heterozygotes for an
Molecular genetic testing approaches can include
Testing is targeted for the expanded
If an apparently heterozygous
For an introduction to multigene panels click
Note: The intronic pathogenic repeat expansion in
Molecular Genetic Testing Used in Friedreich Ataxia
See
See
Sequence-based multigene panels and exome sequencing cannot reliably detect pathogenic repeat expansions in this gene. However, pathogenic repeat expansions may be more reliably detected using customized tools and long-read sequencing.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
•
• Testing is targeted for the expanded
• If an apparently heterozygous
• Testing is targeted for the expanded
• If an apparently heterozygous
• For an introduction to multigene panels click
• Note: The intronic pathogenic repeat expansion in
• Testing is targeted for the expanded
• If an apparently heterozygous
## Clinical Characteristics
Friedreich ataxia (FRDA) is characterized by progressive ataxia with onset from early childhood to early adulthood with mean age at onset from 10 to 15 years (range: age two years to the eighth decade) [
Among individuals with FRDA, about 75% have "typical Friedreich ataxia" and about 25% of individuals with biallelic
Within five years of onset of manifestations, most individuals exhibit "scanning" dysarthria, lower-extremity weakness, and diminished or absent joint position and vibration sense distally. These neurologic manifestations result from progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, dorsal spinocerebellar tracts of the spinal cord, and cerebellum. Ankle and knee jerks are generally absent, and plantar responses are usually upgoing.
Mild dysphonia characterized by hoarseness (combined roughness and breathiness), increased strain, and altered pitch variability is also seen [
Muscle weakness, often present, is most prominent early in the disease course in the hip extensors and abductors. As disease advances, distal limb muscle weakness and wasting become evident. Although pes cavus is common (55%), it generally causes little problem.
Restless leg syndrome, an uncontrollable urge to move the legs usually because of an uncomfortable sensation
Likewise, spasticity may result in contractures and significant morbidity, particularly in individuals who are non-ambulatory [
Optic nerve atrophy, often asymptomatic, occurs in approximately 25% of individuals.
Echocardiographic evaluation may reveal left ventricular hypertrophy that is more commonly asymmetric than concentric [
When more subtle cardiac involvement is sought by methods such as tissue Doppler echocardiography, an even larger percentage of individuals have detectable abnormalities [
Later in the disease course, the cardiomyopathy may become dilated with reduction in left ventricular wall thickness [
Although supraventricular ectopy is observed with disease duration, associated diminished cardiac function or cardiac hypertrophy are uncommon [
Arrhythmias (especially atrial fibrillation) and congestive heart failure, which are prevalent in later stages of the disease, are the most common cause of death [
Impaired glucose tolerance is seen in up to an additional 49% of individuals with FRDA [
Individuals who are not diabetic demonstrate high insulin responsiveness to oral glucose testing and low insulin sensitivity [
Diabetes is an independent predictor of reduced survival in FRDA [
Motor planning is markedly impaired [
The intelligence profile of individuals with FRDA is characterized by concrete thinking, poor capacity in concept formation and visuospatial reasoning, and reduced speed of information processing [
In a meta-analysis of 18 studies reporting neuropsychological test results, individuals with FRDA exhibited reduced performance in cognitive domains including attention, executive functions, language, memory, and visuospatial functions [
Reduced N-acetylaspartate in the cerebellum has been demonstrated by
Volume loss in the dentate nucleus region, brain stem, and superior and inferior cerebellar penduncles appear to be early features in FRDA [
In a large study,
Survival into the sixth and seventh decades has been documented.
LOFA onset is defined as onset between age 26 and 39 years. VLOFA onset is defined as onset at age 40 years and older [
It typically takes five years to make a diagnosis in LOFA, compared to the three years described for typical FRDA [
In 44 individuals with LOFA and 30 individuals with VLOFA, milder clinical findings than those in typical FRDA included dysarthria, absent tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, loss of proprioception, cerebellar atrophy, scoliosis, cardiomyopathy, and functional disability.
When compared to individuals with onset between ages zero and seven years, eight to 14 years, and 15 to 24 years, difficulties with upright stability progress much more slowly in individuals with onset after age 24 years [
When compared to typical FRDA, secondary skeletal involvement (e.g., scoliosis and pes cavus) is less frequent in LOFA [
Tendon reflexes may be retained for more than ten years after disease onset. Some individuals with FARR have brisk tendon reflexes that can be accompanied by clonus. Other typical manifestations are later age of onset and lower incidence of secondary skeletal involvement and cardiomyopathy.
Chorea and pure sensory ataxia [
Apparently isolated cardiomyopathy, with ataxia becoming evident later [
Visual deficit with episodic blindness, optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia [
Despite some general genotype-phenotype correlations by class of
In the following discussion the definitions of the length of pathogenic expanded GAA repeats are the following:
GAA1 allele lengths of <300 triplets are generally associated with very late-onset FRDA (VLOFA) (i.e., onset after age 40 years) [
GAA1 allele lengths of <500 triplets are generally associated with late-onset FRDA (LOFA) (i.e., onset after age 25 years) [
Shorter GAA1 allele lengths inversely correlate with disease progression. For instance, time to loss of independent ambulation is about 8 years when GAA1 allele length is >780 triplets in contrast with about 14 years when GAA1 allele length is <520 triplets [
GAA1 allele lengths are a significant determinant and predictor of the rate of neurologic progression, as determined in several large longitudinal cohorts using validated rating scales [
GAA1 allele lengths also correlate inversely with disease duration and age of death [
In the full-penetrance range of GAA repeats (i.e., 66-1,300 repeats), some alleles are interrupted by G and/or A nucleotides that disrupt the otherwise pure tract of tandem GAA repeats. These alleles are typically short (equivalent to 100-300 GAA repeats) and associated with LOFA/VLOFA.
It is nevertheless clear that a sufficient length of tandem pure GAA repeats is required for pathogenicity, since an expanded allele with ~65 tandem repeats of the GAAGGA hexanucleotide (equivalent to ~130 GAA triplets) is non-pathogenic [
Individuals with somatically unstable borderline alleles (44-65 GAA repeats) often have LOFA/VLOFA, mild and gradually progressive disease, and normal reflexes/hyperreflexia [
The remaining variability in individuals with FRDA may be caused by genetic background (e.g., Acadian individuals, the presence of the p.Cys282Tyr variant in
About 4% of individuals who have FRDA are compound heterozygotes for one expanded GAA repeat and an
Non-repeat
The p.Gly130Val missense variant (see
Penetrance is complete in individuals with either biallelic FXN pathogenic GAA repeat sizes or compound heterozygosity for a pathogenic GAA repeat and an
Because the GAA repeat size at the lower end of the pathogenic (full-penetrance) range has not been clearly defined, it is possible that reduced penetrance is associated with borderline alleles (44-65 repeats) and expanded alleles comprising fewer than 100 GAA repeats. Individuals who are compound heterozygous for a borderline allele and a full-penetrance allele (range 66-1,300 repeats) may develop LOFA or VLOFA.
FRDA is typically caused by inheritance of an expanded GAA repeat allele from both parents. Indeed, the prevalence of FRDA is maintained in susceptible populations by the approximate 1% frequency of asymptomatic heterozygous carriers for an expanded GAA repeat allele. Although documented, expansion from premutation to fully penetrant alleles is very rare.
Moreover, intergenerational transmission of expanded alleles can result in changes in repeat length. Pathogenic GAA repeats tend to contract through paternal transmission, and contract or expand with equal frequency via maternal transmission. However, these changes are generally small in magnitude and have minimal phenotypic consequences.
Anticipation (i.e., the tendency in certain genetic disorders for individuals in successive generations to present at an earlier age and/or with more severe manifestations) is not observed in FRDA because FRDA is an autosomal recessive disorder and typically affects only one generation.
The prevalence of FRDA is 0.50:100,000 based on clinical and molecular diagnosis and 1.79:100,000 based on clinical diagnosis alone in countries with predominant European ancestry [
FRDA is the most common early-onset inherited ataxia in Europe, the Middle East, South Asia (Indian subcontinent), and North Africa.
FRDA has not been documented in Southeast Asians, in sub-Saharan Africans, or among Native Americans. A lower-than-average prevalence of FRDA is noted in Mexico.
• Chorea and pure sensory ataxia [
• Apparently isolated cardiomyopathy, with ataxia becoming evident later [
• Visual deficit with episodic blindness, optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia [
• GAA1 allele lengths of <300 triplets are generally associated with very late-onset FRDA (VLOFA) (i.e., onset after age 40 years) [
• GAA1 allele lengths of <500 triplets are generally associated with late-onset FRDA (LOFA) (i.e., onset after age 25 years) [
• Shorter GAA1 allele lengths inversely correlate with disease progression. For instance, time to loss of independent ambulation is about 8 years when GAA1 allele length is >780 triplets in contrast with about 14 years when GAA1 allele length is <520 triplets [
• GAA1 allele lengths are a significant determinant and predictor of the rate of neurologic progression, as determined in several large longitudinal cohorts using validated rating scales [
• GAA1 allele lengths also correlate inversely with disease duration and age of death [
## Clinical Description
Friedreich ataxia (FRDA) is characterized by progressive ataxia with onset from early childhood to early adulthood with mean age at onset from 10 to 15 years (range: age two years to the eighth decade) [
Among individuals with FRDA, about 75% have "typical Friedreich ataxia" and about 25% of individuals with biallelic
Within five years of onset of manifestations, most individuals exhibit "scanning" dysarthria, lower-extremity weakness, and diminished or absent joint position and vibration sense distally. These neurologic manifestations result from progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, dorsal spinocerebellar tracts of the spinal cord, and cerebellum. Ankle and knee jerks are generally absent, and plantar responses are usually upgoing.
Mild dysphonia characterized by hoarseness (combined roughness and breathiness), increased strain, and altered pitch variability is also seen [
Muscle weakness, often present, is most prominent early in the disease course in the hip extensors and abductors. As disease advances, distal limb muscle weakness and wasting become evident. Although pes cavus is common (55%), it generally causes little problem.
Restless leg syndrome, an uncontrollable urge to move the legs usually because of an uncomfortable sensation
Likewise, spasticity may result in contractures and significant morbidity, particularly in individuals who are non-ambulatory [
Optic nerve atrophy, often asymptomatic, occurs in approximately 25% of individuals.
Echocardiographic evaluation may reveal left ventricular hypertrophy that is more commonly asymmetric than concentric [
When more subtle cardiac involvement is sought by methods such as tissue Doppler echocardiography, an even larger percentage of individuals have detectable abnormalities [
Later in the disease course, the cardiomyopathy may become dilated with reduction in left ventricular wall thickness [
Although supraventricular ectopy is observed with disease duration, associated diminished cardiac function or cardiac hypertrophy are uncommon [
Arrhythmias (especially atrial fibrillation) and congestive heart failure, which are prevalent in later stages of the disease, are the most common cause of death [
Impaired glucose tolerance is seen in up to an additional 49% of individuals with FRDA [
Individuals who are not diabetic demonstrate high insulin responsiveness to oral glucose testing and low insulin sensitivity [
Diabetes is an independent predictor of reduced survival in FRDA [
Motor planning is markedly impaired [
The intelligence profile of individuals with FRDA is characterized by concrete thinking, poor capacity in concept formation and visuospatial reasoning, and reduced speed of information processing [
In a meta-analysis of 18 studies reporting neuropsychological test results, individuals with FRDA exhibited reduced performance in cognitive domains including attention, executive functions, language, memory, and visuospatial functions [
Reduced N-acetylaspartate in the cerebellum has been demonstrated by
Volume loss in the dentate nucleus region, brain stem, and superior and inferior cerebellar penduncles appear to be early features in FRDA [
In a large study,
Survival into the sixth and seventh decades has been documented.
LOFA onset is defined as onset between age 26 and 39 years. VLOFA onset is defined as onset at age 40 years and older [
It typically takes five years to make a diagnosis in LOFA, compared to the three years described for typical FRDA [
In 44 individuals with LOFA and 30 individuals with VLOFA, milder clinical findings than those in typical FRDA included dysarthria, absent tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, loss of proprioception, cerebellar atrophy, scoliosis, cardiomyopathy, and functional disability.
When compared to individuals with onset between ages zero and seven years, eight to 14 years, and 15 to 24 years, difficulties with upright stability progress much more slowly in individuals with onset after age 24 years [
When compared to typical FRDA, secondary skeletal involvement (e.g., scoliosis and pes cavus) is less frequent in LOFA [
Tendon reflexes may be retained for more than ten years after disease onset. Some individuals with FARR have brisk tendon reflexes that can be accompanied by clonus. Other typical manifestations are later age of onset and lower incidence of secondary skeletal involvement and cardiomyopathy.
Chorea and pure sensory ataxia [
Apparently isolated cardiomyopathy, with ataxia becoming evident later [
Visual deficit with episodic blindness, optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia [
• Chorea and pure sensory ataxia [
• Apparently isolated cardiomyopathy, with ataxia becoming evident later [
• Visual deficit with episodic blindness, optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia [
## Typical Friedreich Ataxia
Within five years of onset of manifestations, most individuals exhibit "scanning" dysarthria, lower-extremity weakness, and diminished or absent joint position and vibration sense distally. These neurologic manifestations result from progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, dorsal spinocerebellar tracts of the spinal cord, and cerebellum. Ankle and knee jerks are generally absent, and plantar responses are usually upgoing.
Mild dysphonia characterized by hoarseness (combined roughness and breathiness), increased strain, and altered pitch variability is also seen [
Muscle weakness, often present, is most prominent early in the disease course in the hip extensors and abductors. As disease advances, distal limb muscle weakness and wasting become evident. Although pes cavus is common (55%), it generally causes little problem.
Restless leg syndrome, an uncontrollable urge to move the legs usually because of an uncomfortable sensation
Likewise, spasticity may result in contractures and significant morbidity, particularly in individuals who are non-ambulatory [
Optic nerve atrophy, often asymptomatic, occurs in approximately 25% of individuals.
Echocardiographic evaluation may reveal left ventricular hypertrophy that is more commonly asymmetric than concentric [
When more subtle cardiac involvement is sought by methods such as tissue Doppler echocardiography, an even larger percentage of individuals have detectable abnormalities [
Later in the disease course, the cardiomyopathy may become dilated with reduction in left ventricular wall thickness [
Although supraventricular ectopy is observed with disease duration, associated diminished cardiac function or cardiac hypertrophy are uncommon [
Arrhythmias (especially atrial fibrillation) and congestive heart failure, which are prevalent in later stages of the disease, are the most common cause of death [
Impaired glucose tolerance is seen in up to an additional 49% of individuals with FRDA [
Individuals who are not diabetic demonstrate high insulin responsiveness to oral glucose testing and low insulin sensitivity [
Diabetes is an independent predictor of reduced survival in FRDA [
Motor planning is markedly impaired [
The intelligence profile of individuals with FRDA is characterized by concrete thinking, poor capacity in concept formation and visuospatial reasoning, and reduced speed of information processing [
In a meta-analysis of 18 studies reporting neuropsychological test results, individuals with FRDA exhibited reduced performance in cognitive domains including attention, executive functions, language, memory, and visuospatial functions [
Reduced N-acetylaspartate in the cerebellum has been demonstrated by
Volume loss in the dentate nucleus region, brain stem, and superior and inferior cerebellar penduncles appear to be early features in FRDA [
In a large study,
Survival into the sixth and seventh decades has been documented.
## Atypical Friedreich Ataxia
LOFA onset is defined as onset between age 26 and 39 years. VLOFA onset is defined as onset at age 40 years and older [
It typically takes five years to make a diagnosis in LOFA, compared to the three years described for typical FRDA [
In 44 individuals with LOFA and 30 individuals with VLOFA, milder clinical findings than those in typical FRDA included dysarthria, absent tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, loss of proprioception, cerebellar atrophy, scoliosis, cardiomyopathy, and functional disability.
When compared to individuals with onset between ages zero and seven years, eight to 14 years, and 15 to 24 years, difficulties with upright stability progress much more slowly in individuals with onset after age 24 years [
When compared to typical FRDA, secondary skeletal involvement (e.g., scoliosis and pes cavus) is less frequent in LOFA [
Tendon reflexes may be retained for more than ten years after disease onset. Some individuals with FARR have brisk tendon reflexes that can be accompanied by clonus. Other typical manifestations are later age of onset and lower incidence of secondary skeletal involvement and cardiomyopathy.
Chorea and pure sensory ataxia [
Apparently isolated cardiomyopathy, with ataxia becoming evident later [
Visual deficit with episodic blindness, optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia [
• Chorea and pure sensory ataxia [
• Apparently isolated cardiomyopathy, with ataxia becoming evident later [
• Visual deficit with episodic blindness, optic atrophy, spastic paraparesis, and sensory neuropathy without ataxia [
## Genotype-Phenotype Correlations
Despite some general genotype-phenotype correlations by class of
In the following discussion the definitions of the length of pathogenic expanded GAA repeats are the following:
GAA1 allele lengths of <300 triplets are generally associated with very late-onset FRDA (VLOFA) (i.e., onset after age 40 years) [
GAA1 allele lengths of <500 triplets are generally associated with late-onset FRDA (LOFA) (i.e., onset after age 25 years) [
Shorter GAA1 allele lengths inversely correlate with disease progression. For instance, time to loss of independent ambulation is about 8 years when GAA1 allele length is >780 triplets in contrast with about 14 years when GAA1 allele length is <520 triplets [
GAA1 allele lengths are a significant determinant and predictor of the rate of neurologic progression, as determined in several large longitudinal cohorts using validated rating scales [
GAA1 allele lengths also correlate inversely with disease duration and age of death [
In the full-penetrance range of GAA repeats (i.e., 66-1,300 repeats), some alleles are interrupted by G and/or A nucleotides that disrupt the otherwise pure tract of tandem GAA repeats. These alleles are typically short (equivalent to 100-300 GAA repeats) and associated with LOFA/VLOFA.
It is nevertheless clear that a sufficient length of tandem pure GAA repeats is required for pathogenicity, since an expanded allele with ~65 tandem repeats of the GAAGGA hexanucleotide (equivalent to ~130 GAA triplets) is non-pathogenic [
Individuals with somatically unstable borderline alleles (44-65 GAA repeats) often have LOFA/VLOFA, mild and gradually progressive disease, and normal reflexes/hyperreflexia [
The remaining variability in individuals with FRDA may be caused by genetic background (e.g., Acadian individuals, the presence of the p.Cys282Tyr variant in
About 4% of individuals who have FRDA are compound heterozygotes for one expanded GAA repeat and an
Non-repeat
The p.Gly130Val missense variant (see
• GAA1 allele lengths of <300 triplets are generally associated with very late-onset FRDA (VLOFA) (i.e., onset after age 40 years) [
• GAA1 allele lengths of <500 triplets are generally associated with late-onset FRDA (LOFA) (i.e., onset after age 25 years) [
• Shorter GAA1 allele lengths inversely correlate with disease progression. For instance, time to loss of independent ambulation is about 8 years when GAA1 allele length is >780 triplets in contrast with about 14 years when GAA1 allele length is <520 triplets [
• GAA1 allele lengths are a significant determinant and predictor of the rate of neurologic progression, as determined in several large longitudinal cohorts using validated rating scales [
• GAA1 allele lengths also correlate inversely with disease duration and age of death [
## Biallelic Pathogenic Expanded GAA Repeats
In the following discussion the definitions of the length of pathogenic expanded GAA repeats are the following:
GAA1 allele lengths of <300 triplets are generally associated with very late-onset FRDA (VLOFA) (i.e., onset after age 40 years) [
GAA1 allele lengths of <500 triplets are generally associated with late-onset FRDA (LOFA) (i.e., onset after age 25 years) [
Shorter GAA1 allele lengths inversely correlate with disease progression. For instance, time to loss of independent ambulation is about 8 years when GAA1 allele length is >780 triplets in contrast with about 14 years when GAA1 allele length is <520 triplets [
GAA1 allele lengths are a significant determinant and predictor of the rate of neurologic progression, as determined in several large longitudinal cohorts using validated rating scales [
GAA1 allele lengths also correlate inversely with disease duration and age of death [
• GAA1 allele lengths of <300 triplets are generally associated with very late-onset FRDA (VLOFA) (i.e., onset after age 40 years) [
• GAA1 allele lengths of <500 triplets are generally associated with late-onset FRDA (LOFA) (i.e., onset after age 25 years) [
• Shorter GAA1 allele lengths inversely correlate with disease progression. For instance, time to loss of independent ambulation is about 8 years when GAA1 allele length is >780 triplets in contrast with about 14 years when GAA1 allele length is <520 triplets [
• GAA1 allele lengths are a significant determinant and predictor of the rate of neurologic progression, as determined in several large longitudinal cohorts using validated rating scales [
• GAA1 allele lengths also correlate inversely with disease duration and age of death [
## Interrupted GAA Repeats
In the full-penetrance range of GAA repeats (i.e., 66-1,300 repeats), some alleles are interrupted by G and/or A nucleotides that disrupt the otherwise pure tract of tandem GAA repeats. These alleles are typically short (equivalent to 100-300 GAA repeats) and associated with LOFA/VLOFA.
It is nevertheless clear that a sufficient length of tandem pure GAA repeats is required for pathogenicity, since an expanded allele with ~65 tandem repeats of the GAAGGA hexanucleotide (equivalent to ~130 GAA triplets) is non-pathogenic [
## Compound Heterozygotes for a Full-Penetrance GAA Expansion and a Borderline "Mutable" Allele
Individuals with somatically unstable borderline alleles (44-65 GAA repeats) often have LOFA/VLOFA, mild and gradually progressive disease, and normal reflexes/hyperreflexia [
The remaining variability in individuals with FRDA may be caused by genetic background (e.g., Acadian individuals, the presence of the p.Cys282Tyr variant in
## Compound Heterozygotes for an Expanded GAA Repeat and an
About 4% of individuals who have FRDA are compound heterozygotes for one expanded GAA repeat and an
Non-repeat
The p.Gly130Val missense variant (see
## Penetrance
Penetrance is complete in individuals with either biallelic FXN pathogenic GAA repeat sizes or compound heterozygosity for a pathogenic GAA repeat and an
Because the GAA repeat size at the lower end of the pathogenic (full-penetrance) range has not been clearly defined, it is possible that reduced penetrance is associated with borderline alleles (44-65 repeats) and expanded alleles comprising fewer than 100 GAA repeats. Individuals who are compound heterozygous for a borderline allele and a full-penetrance allele (range 66-1,300 repeats) may develop LOFA or VLOFA.
FRDA is typically caused by inheritance of an expanded GAA repeat allele from both parents. Indeed, the prevalence of FRDA is maintained in susceptible populations by the approximate 1% frequency of asymptomatic heterozygous carriers for an expanded GAA repeat allele. Although documented, expansion from premutation to fully penetrant alleles is very rare.
Moreover, intergenerational transmission of expanded alleles can result in changes in repeat length. Pathogenic GAA repeats tend to contract through paternal transmission, and contract or expand with equal frequency via maternal transmission. However, these changes are generally small in magnitude and have minimal phenotypic consequences.
Anticipation (i.e., the tendency in certain genetic disorders for individuals in successive generations to present at an earlier age and/or with more severe manifestations) is not observed in FRDA because FRDA is an autosomal recessive disorder and typically affects only one generation.
## Germline Instability
FRDA is typically caused by inheritance of an expanded GAA repeat allele from both parents. Indeed, the prevalence of FRDA is maintained in susceptible populations by the approximate 1% frequency of asymptomatic heterozygous carriers for an expanded GAA repeat allele. Although documented, expansion from premutation to fully penetrant alleles is very rare.
Moreover, intergenerational transmission of expanded alleles can result in changes in repeat length. Pathogenic GAA repeats tend to contract through paternal transmission, and contract or expand with equal frequency via maternal transmission. However, these changes are generally small in magnitude and have minimal phenotypic consequences.
Anticipation (i.e., the tendency in certain genetic disorders for individuals in successive generations to present at an earlier age and/or with more severe manifestations) is not observed in FRDA because FRDA is an autosomal recessive disorder and typically affects only one generation.
## Prevalence
The prevalence of FRDA is 0.50:100,000 based on clinical and molecular diagnosis and 1.79:100,000 based on clinical diagnosis alone in countries with predominant European ancestry [
FRDA is the most common early-onset inherited ataxia in Europe, the Middle East, South Asia (Indian subcontinent), and North Africa.
FRDA has not been documented in Southeast Asians, in sub-Saharan Africans, or among Native Americans. A lower-than-average prevalence of FRDA is noted in Mexico.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Friedreich Ataxia
AD = autosomal dominant; AFP = alpha-fetoprotein; AR = autosomal recessive; CNS = central nervous system; FRDA = Friedreich ataxia; MT = mitochondrial; MOI = mode of inheritance; mtDNA = mitochondrial DNA; XL = X-linked
## Management
Guidelines have been published to assist with management of Friedreich ataxia (FRDA) [
To establish the extent of disease and needs in an individual diagnosed with FRDA, the evaluations summarized in
Friedreich Ataxia: Recommended Evaluations Following Initial Diagnosis
Assess need for balance exercises, gait training to maintain mobility, & exercises to help prevent falls & maintain function.
Consider adaptive devices to maintain/improve independence in mobility (e.g., orthotics, canes, walkers, motorized chairs).
Speech-language therapy;
Alternative means of communication.
Consider video fluoroscopic swallowing study to assess risk of aspiration.
Refer to nutritionist & OT if risk of aspiration is ↑.
Assess for nystagmus, saccades & smooth pursuit, & vertical & horizontal gaze limitation.
Evaluate for optic atrophy.
Consider referral for corrective measures incl prisms &/or surgery.
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; FRDA = Friedreich ataxia; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for FRDA.
Omaveloxolone is approved in the United States and Europe for individuals age 16 years and older. It has been shown to slow progression of FRDA. Omaveloxolone is generally well tolerated. The main side effects noted are alteration in liver function that is generally of short duration and increase in serum lipids that sometimes requires therapy.
Friedreich Ataxia: Targeted Treatment of Manifestations
Nrf2 = nuclear factor erythroid 2-related factor 2
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields, such as neurologists, ophthalmologists, orthoptists, physical therapists, occupational therapists, cardiologists, endocrinologists, speech-language therapists, and psychologists (see
Friedreich Ataxia: Treatment of Manifestations
PT to maintain mobility & function
Self-directed exercise as prescribed by PT; completion of exercise program 3 or more days per week
OT to optimize ADL
Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs)
Inpatient rehab w/PT/OT may improve ataxia & functional abilities, which has been shown to improve physical function as measured by the Functional Independence Measure.
OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats)
Avoid excessive alcohol intake.
Non-pharmacologic treatment
Pharmacologic treatment
PT & stretching exercises, standing frames & splints
Consider drugs such as baclofen & botulinum toxin for treatment of severe spasticity. Intrathecal baclofen can be beneficial when oral administration is unsuccessful or side effects are excessive.
Active treatment is recommended to prevent permanent contractures & need for surgery.
Intensive behavioral therapy can improve speech.
Consider alternative means of communication as needed (e.g., writing pads & digital devices).
Treatment options incl antiarrhythmic agents, anti-cardiac failure medication, anticoagulants, &/or pacemaker/implantable cardioverter defibrillator.
Cardiac transplantation can be considered, particularly when cardiac disease is severe in those w/mild neurologic manifestations.
Treat vitamin D deficiency.
Bisphosphonate therapy for proven osteoporosis
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Friedreich Ataxia: Recommended Surveillance
Neurology eval to assess progression & need for pharmacotherapy
Monitor ataxia progression w/standardized scale (SARA).
In those w/known cardiomyopathy: per treating cardiologist
If EKG & echocardiogram performed at time of initial diagnosis are normal, repeat annually
Per treating endocrinologist
Annual fasting blood glucose & hemoglobin A1c w/oral glucose tolerance test if impaired glucose/hemoglobin A1c.
Annual assessment for sleep apnea by history of screening scale (e.g., Epworth Sleepiness Scale)
Sleep study to evaluate for obstructive sleep apnea if concerns on clinical history or screening scale
ADL= activities of daily living; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
Avoid the following:
Use and misuse of illegal and controlled drugs, as they may affect neuronal well-being and, thus, exacerbate disease manifestations
Circumstances that increase the risk of falling (e.g., rough surfaces)
Medications that are toxic or potentially toxic to persons with FRDA. See the Charcot-Marie-Tooth Association
Alcohol, which can exacerbate ataxia, should be consumed in moderation.
At-risk minor and adult sibs of an individual with FRDA should be offered echocardiography surveillance to determine if treatable cardiac manifestations of presymptomatic disease are present.
See
A study of 65 pregnancies in 31 women with FRDA found no increase in the rate of spontaneous miscarriage, preeclampsia, prematurity, or cesarean section delivery [
Women with reduced cardiac ejection fraction are advised to seek counseling about potential morbidity and mortality during pregnancy [
Close cardiac monitoring and regular testing for diabetes mellitus during pregnancy is recommended in any woman with FRDA [
If cesarean section is required, it is recommended that it be done under epidural or spinal anesthesia rather than general anesthesia if possible [
A pipeline of therapies under investigation can be found at
Friedreich Ataxia: Therapies Under Investigation
AAV = adeno-associated virus; FRDA = Friedreich ataxia
Search
• Assess need for balance exercises, gait training to maintain mobility, & exercises to help prevent falls & maintain function.
• Consider adaptive devices to maintain/improve independence in mobility (e.g., orthotics, canes, walkers, motorized chairs).
• Speech-language therapy;
• Alternative means of communication.
• Consider video fluoroscopic swallowing study to assess risk of aspiration.
• Refer to nutritionist & OT if risk of aspiration is ↑.
• Assess for nystagmus, saccades & smooth pursuit, & vertical & horizontal gaze limitation.
• Evaluate for optic atrophy.
• Consider referral for corrective measures incl prisms &/or surgery.
• Community or
• Social work involvement for parental support
• Home nursing referral
• PT to maintain mobility & function
• Self-directed exercise as prescribed by PT; completion of exercise program 3 or more days per week
• OT to optimize ADL
• Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs)
• Inpatient rehab w/PT/OT may improve ataxia & functional abilities, which has been shown to improve physical function as measured by the Functional Independence Measure.
• OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats)
• Avoid excessive alcohol intake.
• Non-pharmacologic treatment
• Pharmacologic treatment
• PT & stretching exercises, standing frames & splints
• Consider drugs such as baclofen & botulinum toxin for treatment of severe spasticity. Intrathecal baclofen can be beneficial when oral administration is unsuccessful or side effects are excessive.
• Active treatment is recommended to prevent permanent contractures & need for surgery.
• Intensive behavioral therapy can improve speech.
• Consider alternative means of communication as needed (e.g., writing pads & digital devices).
• Treatment options incl antiarrhythmic agents, anti-cardiac failure medication, anticoagulants, &/or pacemaker/implantable cardioverter defibrillator.
• Cardiac transplantation can be considered, particularly when cardiac disease is severe in those w/mild neurologic manifestations.
• Treat vitamin D deficiency.
• Bisphosphonate therapy for proven osteoporosis
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Neurology eval to assess progression & need for pharmacotherapy
• Monitor ataxia progression w/standardized scale (SARA).
• In those w/known cardiomyopathy: per treating cardiologist
• If EKG & echocardiogram performed at time of initial diagnosis are normal, repeat annually
• Per treating endocrinologist
• Annual fasting blood glucose & hemoglobin A1c w/oral glucose tolerance test if impaired glucose/hemoglobin A1c.
• Annual assessment for sleep apnea by history of screening scale (e.g., Epworth Sleepiness Scale)
• Sleep study to evaluate for obstructive sleep apnea if concerns on clinical history or screening scale
• Use and misuse of illegal and controlled drugs, as they may affect neuronal well-being and, thus, exacerbate disease manifestations
• Circumstances that increase the risk of falling (e.g., rough surfaces)
• Medications that are toxic or potentially toxic to persons with FRDA. See the Charcot-Marie-Tooth Association
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with FRDA, the evaluations summarized in
Friedreich Ataxia: Recommended Evaluations Following Initial Diagnosis
Assess need for balance exercises, gait training to maintain mobility, & exercises to help prevent falls & maintain function.
Consider adaptive devices to maintain/improve independence in mobility (e.g., orthotics, canes, walkers, motorized chairs).
Speech-language therapy;
Alternative means of communication.
Consider video fluoroscopic swallowing study to assess risk of aspiration.
Refer to nutritionist & OT if risk of aspiration is ↑.
Assess for nystagmus, saccades & smooth pursuit, & vertical & horizontal gaze limitation.
Evaluate for optic atrophy.
Consider referral for corrective measures incl prisms &/or surgery.
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; FRDA = Friedreich ataxia; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Assess need for balance exercises, gait training to maintain mobility, & exercises to help prevent falls & maintain function.
• Consider adaptive devices to maintain/improve independence in mobility (e.g., orthotics, canes, walkers, motorized chairs).
• Speech-language therapy;
• Alternative means of communication.
• Consider video fluoroscopic swallowing study to assess risk of aspiration.
• Refer to nutritionist & OT if risk of aspiration is ↑.
• Assess for nystagmus, saccades & smooth pursuit, & vertical & horizontal gaze limitation.
• Evaluate for optic atrophy.
• Consider referral for corrective measures incl prisms &/or surgery.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for FRDA.
Omaveloxolone is approved in the United States and Europe for individuals age 16 years and older. It has been shown to slow progression of FRDA. Omaveloxolone is generally well tolerated. The main side effects noted are alteration in liver function that is generally of short duration and increase in serum lipids that sometimes requires therapy.
Friedreich Ataxia: Targeted Treatment of Manifestations
Nrf2 = nuclear factor erythroid 2-related factor 2
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields, such as neurologists, ophthalmologists, orthoptists, physical therapists, occupational therapists, cardiologists, endocrinologists, speech-language therapists, and psychologists (see
Friedreich Ataxia: Treatment of Manifestations
PT to maintain mobility & function
Self-directed exercise as prescribed by PT; completion of exercise program 3 or more days per week
OT to optimize ADL
Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs)
Inpatient rehab w/PT/OT may improve ataxia & functional abilities, which has been shown to improve physical function as measured by the Functional Independence Measure.
OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats)
Avoid excessive alcohol intake.
Non-pharmacologic treatment
Pharmacologic treatment
PT & stretching exercises, standing frames & splints
Consider drugs such as baclofen & botulinum toxin for treatment of severe spasticity. Intrathecal baclofen can be beneficial when oral administration is unsuccessful or side effects are excessive.
Active treatment is recommended to prevent permanent contractures & need for surgery.
Intensive behavioral therapy can improve speech.
Consider alternative means of communication as needed (e.g., writing pads & digital devices).
Treatment options incl antiarrhythmic agents, anti-cardiac failure medication, anticoagulants, &/or pacemaker/implantable cardioverter defibrillator.
Cardiac transplantation can be considered, particularly when cardiac disease is severe in those w/mild neurologic manifestations.
Treat vitamin D deficiency.
Bisphosphonate therapy for proven osteoporosis
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
• PT to maintain mobility & function
• Self-directed exercise as prescribed by PT; completion of exercise program 3 or more days per week
• OT to optimize ADL
• Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs)
• Inpatient rehab w/PT/OT may improve ataxia & functional abilities, which has been shown to improve physical function as measured by the Functional Independence Measure.
• OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats)
• Avoid excessive alcohol intake.
• Non-pharmacologic treatment
• Pharmacologic treatment
• PT & stretching exercises, standing frames & splints
• Consider drugs such as baclofen & botulinum toxin for treatment of severe spasticity. Intrathecal baclofen can be beneficial when oral administration is unsuccessful or side effects are excessive.
• Active treatment is recommended to prevent permanent contractures & need for surgery.
• Intensive behavioral therapy can improve speech.
• Consider alternative means of communication as needed (e.g., writing pads & digital devices).
• Treatment options incl antiarrhythmic agents, anti-cardiac failure medication, anticoagulants, &/or pacemaker/implantable cardioverter defibrillator.
• Cardiac transplantation can be considered, particularly when cardiac disease is severe in those w/mild neurologic manifestations.
• Treat vitamin D deficiency.
• Bisphosphonate therapy for proven osteoporosis
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
## Targeted Therapy
Omaveloxolone is approved in the United States and Europe for individuals age 16 years and older. It has been shown to slow progression of FRDA. Omaveloxolone is generally well tolerated. The main side effects noted are alteration in liver function that is generally of short duration and increase in serum lipids that sometimes requires therapy.
Friedreich Ataxia: Targeted Treatment of Manifestations
Nrf2 = nuclear factor erythroid 2-related factor 2
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields, such as neurologists, ophthalmologists, orthoptists, physical therapists, occupational therapists, cardiologists, endocrinologists, speech-language therapists, and psychologists (see
Friedreich Ataxia: Treatment of Manifestations
PT to maintain mobility & function
Self-directed exercise as prescribed by PT; completion of exercise program 3 or more days per week
OT to optimize ADL
Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs)
Inpatient rehab w/PT/OT may improve ataxia & functional abilities, which has been shown to improve physical function as measured by the Functional Independence Measure.
OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats)
Avoid excessive alcohol intake.
Non-pharmacologic treatment
Pharmacologic treatment
PT & stretching exercises, standing frames & splints
Consider drugs such as baclofen & botulinum toxin for treatment of severe spasticity. Intrathecal baclofen can be beneficial when oral administration is unsuccessful or side effects are excessive.
Active treatment is recommended to prevent permanent contractures & need for surgery.
Intensive behavioral therapy can improve speech.
Consider alternative means of communication as needed (e.g., writing pads & digital devices).
Treatment options incl antiarrhythmic agents, anti-cardiac failure medication, anticoagulants, &/or pacemaker/implantable cardioverter defibrillator.
Cardiac transplantation can be considered, particularly when cardiac disease is severe in those w/mild neurologic manifestations.
Treat vitamin D deficiency.
Bisphosphonate therapy for proven osteoporosis
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
• PT to maintain mobility & function
• Self-directed exercise as prescribed by PT; completion of exercise program 3 or more days per week
• OT to optimize ADL
• Adaptive devices to maintain/improve mobility (e.g., orthotics, canes, walking sticks, walkers, wheelchairs)
• Inpatient rehab w/PT/OT may improve ataxia & functional abilities, which has been shown to improve physical function as measured by the Functional Independence Measure.
• OT & home adaptations to ensure safe environment & prevent falls (e.g., grab bars, raised toilet seats)
• Avoid excessive alcohol intake.
• Non-pharmacologic treatment
• Pharmacologic treatment
• PT & stretching exercises, standing frames & splints
• Consider drugs such as baclofen & botulinum toxin for treatment of severe spasticity. Intrathecal baclofen can be beneficial when oral administration is unsuccessful or side effects are excessive.
• Active treatment is recommended to prevent permanent contractures & need for surgery.
• Intensive behavioral therapy can improve speech.
• Consider alternative means of communication as needed (e.g., writing pads & digital devices).
• Treatment options incl antiarrhythmic agents, anti-cardiac failure medication, anticoagulants, &/or pacemaker/implantable cardioverter defibrillator.
• Cardiac transplantation can be considered, particularly when cardiac disease is severe in those w/mild neurologic manifestations.
• Treat vitamin D deficiency.
• Bisphosphonate therapy for proven osteoporosis
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Friedreich Ataxia: Recommended Surveillance
Neurology eval to assess progression & need for pharmacotherapy
Monitor ataxia progression w/standardized scale (SARA).
In those w/known cardiomyopathy: per treating cardiologist
If EKG & echocardiogram performed at time of initial diagnosis are normal, repeat annually
Per treating endocrinologist
Annual fasting blood glucose & hemoglobin A1c w/oral glucose tolerance test if impaired glucose/hemoglobin A1c.
Annual assessment for sleep apnea by history of screening scale (e.g., Epworth Sleepiness Scale)
Sleep study to evaluate for obstructive sleep apnea if concerns on clinical history or screening scale
ADL= activities of daily living; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
• Neurology eval to assess progression & need for pharmacotherapy
• Monitor ataxia progression w/standardized scale (SARA).
• In those w/known cardiomyopathy: per treating cardiologist
• If EKG & echocardiogram performed at time of initial diagnosis are normal, repeat annually
• Per treating endocrinologist
• Annual fasting blood glucose & hemoglobin A1c w/oral glucose tolerance test if impaired glucose/hemoglobin A1c.
• Annual assessment for sleep apnea by history of screening scale (e.g., Epworth Sleepiness Scale)
• Sleep study to evaluate for obstructive sleep apnea if concerns on clinical history or screening scale
## Agents/Circumstances to Avoid
Avoid the following:
Use and misuse of illegal and controlled drugs, as they may affect neuronal well-being and, thus, exacerbate disease manifestations
Circumstances that increase the risk of falling (e.g., rough surfaces)
Medications that are toxic or potentially toxic to persons with FRDA. See the Charcot-Marie-Tooth Association
Alcohol, which can exacerbate ataxia, should be consumed in moderation.
• Use and misuse of illegal and controlled drugs, as they may affect neuronal well-being and, thus, exacerbate disease manifestations
• Circumstances that increase the risk of falling (e.g., rough surfaces)
• Medications that are toxic or potentially toxic to persons with FRDA. See the Charcot-Marie-Tooth Association
## Evaluation of Relatives at Risk
At-risk minor and adult sibs of an individual with FRDA should be offered echocardiography surveillance to determine if treatable cardiac manifestations of presymptomatic disease are present.
See
## Pregnancy Management
A study of 65 pregnancies in 31 women with FRDA found no increase in the rate of spontaneous miscarriage, preeclampsia, prematurity, or cesarean section delivery [
Women with reduced cardiac ejection fraction are advised to seek counseling about potential morbidity and mortality during pregnancy [
Close cardiac monitoring and regular testing for diabetes mellitus during pregnancy is recommended in any woman with FRDA [
If cesarean section is required, it is recommended that it be done under epidural or spinal anesthesia rather than general anesthesia if possible [
## Therapies Under Investigation
A pipeline of therapies under investigation can be found at
Friedreich Ataxia: Therapies Under Investigation
AAV = adeno-associated virus; FRDA = Friedreich ataxia
Search
## Genetic Counseling
Friedreich ataxia (FRDA) is inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for an FRDA-related genetic alteration (i.e., a pathogenic [full-penetrance]
* Mutable normal GAA repeat expansions are rare. Although the exact prevalence is unknown, mutable normal GAA repeat expansions are far less commonly identified in carriers than pathogenic GAA repeat expansions. Consequently, expansion of mutable normal alleles as a means of transmitting FRDA is very unusual.
Molecular genetic testing is recommended for the parents of the proband to evaluate the genetic status of the parents and inform recurrence risk assessment.
Individuals who are heterozygous (carriers) for one FRDA-related genetic alteration are asymptomatic and are not at risk of developing the disorder.
If both parents are heterozygous for an
Sibs who inherit biallelic
Sibs who inherit one FRDA-related genetic alteration (i.e., carriers) are asymptomatic and are not at risk of developing the disorder.
If one parent is known to be heterozygous for a pathogenic full-penetrance GAA repeat expansion (or an intragenic
Because of the wide range in age of onset that can occur within sibships and intergenerational instability of the GAA repeat expansion (sibs can have markedly different
All offspring will inherit an FRDA-related genetic alteration from the affected parent. The risk to offspring of being affected with FRDA depends on the genetic status of the proband's reproductive partner (see
Is not a carrier of an FRDA-related genetic alteration, offspring will be obligate heterozygotes (carriers) for an FRDA-related genetic alteration;
Is a carrier of an
Is a carrier for an intermediate (mutable normal) GAA repeat expansion, the risk to each offspring of developing FRDA is less than 50%.
Carrier testing for at-risk relatives requires prior identification of the FRDA-related genetic alterations in the family.
See Management,
Predictive molecular genetic testing for at-risk sibs is possible once a molecular diagnosis of FRDA has been established (i.e., once biallelic
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
In a family with an established diagnosis of FRDA, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with FRDA (see
Once the FRDA-related genetic alterations have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for an FRDA-related genetic alteration (i.e., a pathogenic [full-penetrance]
• * Mutable normal GAA repeat expansions are rare. Although the exact prevalence is unknown, mutable normal GAA repeat expansions are far less commonly identified in carriers than pathogenic GAA repeat expansions. Consequently, expansion of mutable normal alleles as a means of transmitting FRDA is very unusual.
• Molecular genetic testing is recommended for the parents of the proband to evaluate the genetic status of the parents and inform recurrence risk assessment.
• Individuals who are heterozygous (carriers) for one FRDA-related genetic alteration are asymptomatic and are not at risk of developing the disorder.
• If both parents are heterozygous for an
• Sibs who inherit biallelic
• Sibs who inherit one FRDA-related genetic alteration (i.e., carriers) are asymptomatic and are not at risk of developing the disorder.
• Sibs who inherit biallelic
• Sibs who inherit one FRDA-related genetic alteration (i.e., carriers) are asymptomatic and are not at risk of developing the disorder.
• If one parent is known to be heterozygous for a pathogenic full-penetrance GAA repeat expansion (or an intragenic
• Because of the wide range in age of onset that can occur within sibships and intergenerational instability of the GAA repeat expansion (sibs can have markedly different
• Sibs who inherit biallelic
• Sibs who inherit one FRDA-related genetic alteration (i.e., carriers) are asymptomatic and are not at risk of developing the disorder.
• All offspring will inherit an FRDA-related genetic alteration from the affected parent. The risk to offspring of being affected with FRDA depends on the genetic status of the proband's reproductive partner (see
• Is not a carrier of an FRDA-related genetic alteration, offspring will be obligate heterozygotes (carriers) for an FRDA-related genetic alteration;
• Is a carrier of an
• Is a carrier for an intermediate (mutable normal) GAA repeat expansion, the risk to each offspring of developing FRDA is less than 50%.
• Is not a carrier of an FRDA-related genetic alteration, offspring will be obligate heterozygotes (carriers) for an FRDA-related genetic alteration;
• Is a carrier of an
• Is a carrier for an intermediate (mutable normal) GAA repeat expansion, the risk to each offspring of developing FRDA is less than 50%.
• Is not a carrier of an FRDA-related genetic alteration, offspring will be obligate heterozygotes (carriers) for an FRDA-related genetic alteration;
• Is a carrier of an
• Is a carrier for an intermediate (mutable normal) GAA repeat expansion, the risk to each offspring of developing FRDA is less than 50%.
• Predictive molecular genetic testing for at-risk sibs is possible once a molecular diagnosis of FRDA has been established (i.e., once biallelic
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with FRDA (see
## Mode of Inheritance
Friedreich ataxia (FRDA) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for an FRDA-related genetic alteration (i.e., a pathogenic [full-penetrance]
* Mutable normal GAA repeat expansions are rare. Although the exact prevalence is unknown, mutable normal GAA repeat expansions are far less commonly identified in carriers than pathogenic GAA repeat expansions. Consequently, expansion of mutable normal alleles as a means of transmitting FRDA is very unusual.
Molecular genetic testing is recommended for the parents of the proband to evaluate the genetic status of the parents and inform recurrence risk assessment.
Individuals who are heterozygous (carriers) for one FRDA-related genetic alteration are asymptomatic and are not at risk of developing the disorder.
If both parents are heterozygous for an
Sibs who inherit biallelic
Sibs who inherit one FRDA-related genetic alteration (i.e., carriers) are asymptomatic and are not at risk of developing the disorder.
If one parent is known to be heterozygous for a pathogenic full-penetrance GAA repeat expansion (or an intragenic
Because of the wide range in age of onset that can occur within sibships and intergenerational instability of the GAA repeat expansion (sibs can have markedly different
All offspring will inherit an FRDA-related genetic alteration from the affected parent. The risk to offspring of being affected with FRDA depends on the genetic status of the proband's reproductive partner (see
Is not a carrier of an FRDA-related genetic alteration, offspring will be obligate heterozygotes (carriers) for an FRDA-related genetic alteration;
Is a carrier of an
Is a carrier for an intermediate (mutable normal) GAA repeat expansion, the risk to each offspring of developing FRDA is less than 50%.
• The parents of an affected individual are presumed to be heterozygous for an FRDA-related genetic alteration (i.e., a pathogenic [full-penetrance]
• * Mutable normal GAA repeat expansions are rare. Although the exact prevalence is unknown, mutable normal GAA repeat expansions are far less commonly identified in carriers than pathogenic GAA repeat expansions. Consequently, expansion of mutable normal alleles as a means of transmitting FRDA is very unusual.
• Molecular genetic testing is recommended for the parents of the proband to evaluate the genetic status of the parents and inform recurrence risk assessment.
• Individuals who are heterozygous (carriers) for one FRDA-related genetic alteration are asymptomatic and are not at risk of developing the disorder.
• If both parents are heterozygous for an
• Sibs who inherit biallelic
• Sibs who inherit one FRDA-related genetic alteration (i.e., carriers) are asymptomatic and are not at risk of developing the disorder.
• Sibs who inherit biallelic
• Sibs who inherit one FRDA-related genetic alteration (i.e., carriers) are asymptomatic and are not at risk of developing the disorder.
• If one parent is known to be heterozygous for a pathogenic full-penetrance GAA repeat expansion (or an intragenic
• Because of the wide range in age of onset that can occur within sibships and intergenerational instability of the GAA repeat expansion (sibs can have markedly different
• Sibs who inherit biallelic
• Sibs who inherit one FRDA-related genetic alteration (i.e., carriers) are asymptomatic and are not at risk of developing the disorder.
• All offspring will inherit an FRDA-related genetic alteration from the affected parent. The risk to offspring of being affected with FRDA depends on the genetic status of the proband's reproductive partner (see
• Is not a carrier of an FRDA-related genetic alteration, offspring will be obligate heterozygotes (carriers) for an FRDA-related genetic alteration;
• Is a carrier of an
• Is a carrier for an intermediate (mutable normal) GAA repeat expansion, the risk to each offspring of developing FRDA is less than 50%.
• Is not a carrier of an FRDA-related genetic alteration, offspring will be obligate heterozygotes (carriers) for an FRDA-related genetic alteration;
• Is a carrier of an
• Is a carrier for an intermediate (mutable normal) GAA repeat expansion, the risk to each offspring of developing FRDA is less than 50%.
• Is not a carrier of an FRDA-related genetic alteration, offspring will be obligate heterozygotes (carriers) for an FRDA-related genetic alteration;
• Is a carrier of an
• Is a carrier for an intermediate (mutable normal) GAA repeat expansion, the risk to each offspring of developing FRDA is less than 50%.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the FRDA-related genetic alterations in the family.
## Related Genetic Counseling Issues
See Management,
Predictive molecular genetic testing for at-risk sibs is possible once a molecular diagnosis of FRDA has been established (i.e., once biallelic
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
In a family with an established diagnosis of FRDA, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with FRDA (see
• Predictive molecular genetic testing for at-risk sibs is possible once a molecular diagnosis of FRDA has been established (i.e., once biallelic
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with FRDA (see
## Prenatal Testing and Preimplantation Genetic Testing
Once the FRDA-related genetic alterations have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Friedreich's Ataxia Research Alliance
Friedreich Ataxia Research Association
Australia
United Kingdom
United Kingdom
Spain
Sanford Research
European Friedreich’s Ataxia Consortium for Translational Studies
Friedreich's Ataxia Research Alliance
•
• Friedreich's Ataxia Research Alliance
•
•
• Friedreich Ataxia Research Association
• Australia
•
•
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
•
•
• Spain
•
•
• Sanford Research
•
•
• European Friedreich’s Ataxia Consortium for Translational Studies
•
•
• Friedreich's Ataxia Research Alliance
•
## Molecular Genetics
Friedreich Ataxia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Friedreich Ataxia (
Friedreich ataxia (FRDA) is caused by deficiency of the nuclear-encoded mitochondrial protein frataxin, encoded by
The tissues primarily affected in FRDA are known to express high levels of frataxin. Deficiency of
The three types of inactivating
The pathogenic expanded GAA repeat (fully penetrant alleles; see
Epigenetic silencing via repressive chromatin formation in the sequence flanking the expanded GAA repeat that interferes with both transcriptional initiation and elongation [
Formation of one or more abnormal DNA and/or DNA/RNA structures that interferes with transcriptional elongation [
In about 96% of individuals with FRDA, the expanded GAA repeat is biallelic; in about 4%, one allele is the expanded GAA repeat and the second allele is one of the other classes of pathogenic variants. Of note, the single report of biallelic
Long-range PCR (LR-PCR)
Repeat-primed PCR (RP-PCR)
Long-read sequencing
Variants listed in the table have been provided by the authors.
Although the exact frequency of mutable normal alleles has not been formally determined, they likely account for fewer than 1% of
The shortest repeat length associated with disease (i.e., the exact demarcation between normal and full-penetrance alleles) has not been clearly determined (see
An affected individual with an allele of 56 GAA repeats has been reported by
• Epigenetic silencing via repressive chromatin formation in the sequence flanking the expanded GAA repeat that interferes with both transcriptional initiation and elongation [
• Formation of one or more abnormal DNA and/or DNA/RNA structures that interferes with transcriptional elongation [
• Long-range PCR (LR-PCR)
• Repeat-primed PCR (RP-PCR)
• Long-read sequencing
## Molecular Pathogenesis
Friedreich ataxia (FRDA) is caused by deficiency of the nuclear-encoded mitochondrial protein frataxin, encoded by
The tissues primarily affected in FRDA are known to express high levels of frataxin. Deficiency of
The three types of inactivating
The pathogenic expanded GAA repeat (fully penetrant alleles; see
Epigenetic silencing via repressive chromatin formation in the sequence flanking the expanded GAA repeat that interferes with both transcriptional initiation and elongation [
Formation of one or more abnormal DNA and/or DNA/RNA structures that interferes with transcriptional elongation [
In about 96% of individuals with FRDA, the expanded GAA repeat is biallelic; in about 4%, one allele is the expanded GAA repeat and the second allele is one of the other classes of pathogenic variants. Of note, the single report of biallelic
Long-range PCR (LR-PCR)
Repeat-primed PCR (RP-PCR)
Long-read sequencing
Variants listed in the table have been provided by the authors.
Although the exact frequency of mutable normal alleles has not been formally determined, they likely account for fewer than 1% of
The shortest repeat length associated with disease (i.e., the exact demarcation between normal and full-penetrance alleles) has not been clearly determined (see
An affected individual with an allele of 56 GAA repeats has been reported by
• Epigenetic silencing via repressive chromatin formation in the sequence flanking the expanded GAA repeat that interferes with both transcriptional initiation and elongation [
• Formation of one or more abnormal DNA and/or DNA/RNA structures that interferes with transcriptional elongation [
• Long-range PCR (LR-PCR)
• Repeat-primed PCR (RP-PCR)
• Long-read sequencing
## Chapter Notes
Tetsuo Ashizawa, MD; University of Texas Medical Branch (1998-2009)Sanjay I Bidichandani, MBBS, PhD (1998-present)Martin Delatycki, MBBS, FRACP, PhD (2006-present)Antoine Duquette, MD, MSc, FRCP(C) (2024-present)Marek Napierala, PhD, DSc (2024-present)Pragna I Patel, PhD; Baylor College of Medicine (1998-2002)
26 June 2025 (bp) Revision: classes of repeat size clarified (see
10 April 2025 (md) Revision:
31 October 2024 (bp) Comprehensive update posted live
1 June 2017 (ma) Comprehensive update posted live
24 July 2014 (me) Comprehensive update posted live
2 February 2012 (me) Comprehensive update posted live
25 June 2009 (me) Comprehensive update posted live
25 August 2006 (me) Comprehensive update posted live
22 June 2004 (me) Comprehensive update posted live
3 April 2002 (me) Comprehensive update posted live
18 December 1998 (pb) Review posted live
20 September 1998 (sb) Original submission
• 26 June 2025 (bp) Revision: classes of repeat size clarified (see
• 10 April 2025 (md) Revision:
• 31 October 2024 (bp) Comprehensive update posted live
• 1 June 2017 (ma) Comprehensive update posted live
• 24 July 2014 (me) Comprehensive update posted live
• 2 February 2012 (me) Comprehensive update posted live
• 25 June 2009 (me) Comprehensive update posted live
• 25 August 2006 (me) Comprehensive update posted live
• 22 June 2004 (me) Comprehensive update posted live
• 3 April 2002 (me) Comprehensive update posted live
• 18 December 1998 (pb) Review posted live
• 20 September 1998 (sb) Original submission
## Author History
Tetsuo Ashizawa, MD; University of Texas Medical Branch (1998-2009)Sanjay I Bidichandani, MBBS, PhD (1998-present)Martin Delatycki, MBBS, FRACP, PhD (2006-present)Antoine Duquette, MD, MSc, FRCP(C) (2024-present)Marek Napierala, PhD, DSc (2024-present)Pragna I Patel, PhD; Baylor College of Medicine (1998-2002)
## Revision History
26 June 2025 (bp) Revision: classes of repeat size clarified (see
10 April 2025 (md) Revision:
31 October 2024 (bp) Comprehensive update posted live
1 June 2017 (ma) Comprehensive update posted live
24 July 2014 (me) Comprehensive update posted live
2 February 2012 (me) Comprehensive update posted live
25 June 2009 (me) Comprehensive update posted live
25 August 2006 (me) Comprehensive update posted live
22 June 2004 (me) Comprehensive update posted live
3 April 2002 (me) Comprehensive update posted live
18 December 1998 (pb) Review posted live
20 September 1998 (sb) Original submission
• 26 June 2025 (bp) Revision: classes of repeat size clarified (see
• 10 April 2025 (md) Revision:
• 31 October 2024 (bp) Comprehensive update posted live
• 1 June 2017 (ma) Comprehensive update posted live
• 24 July 2014 (me) Comprehensive update posted live
• 2 February 2012 (me) Comprehensive update posted live
• 25 June 2009 (me) Comprehensive update posted live
• 25 August 2006 (me) Comprehensive update posted live
• 22 June 2004 (me) Comprehensive update posted live
• 3 April 2002 (me) Comprehensive update posted live
• 18 December 1998 (pb) Review posted live
• 20 September 1998 (sb) Original submission
## Key Sections in This
## References
Corben LA, Collins V, Milne S, Farmer J, Musheno A, Lynch D, Subramony S, Pandolfo M, Schulz JB, Lin K, Delatycki MB; Clinical Management Guidelines Writing Group. Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 2022;17:415. [
Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB, et al. Consensus clinical management guidelines for Friedreich ataxia. Available
Friedreich's Ataxia Research Alliance. Consensus Clinical Management Guidelines for Friedreich's Ataxia. Available
• Corben LA, Collins V, Milne S, Farmer J, Musheno A, Lynch D, Subramony S, Pandolfo M, Schulz JB, Lin K, Delatycki MB; Clinical Management Guidelines Writing Group. Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 2022;17:415. [
• Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB, et al. Consensus clinical management guidelines for Friedreich ataxia. Available
• Friedreich's Ataxia Research Alliance. Consensus Clinical Management Guidelines for Friedreich's Ataxia. Available
## Published Guidelines / Consensus Statements
Corben LA, Collins V, Milne S, Farmer J, Musheno A, Lynch D, Subramony S, Pandolfo M, Schulz JB, Lin K, Delatycki MB; Clinical Management Guidelines Writing Group. Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 2022;17:415. [
Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB, et al. Consensus clinical management guidelines for Friedreich ataxia. Available
Friedreich's Ataxia Research Alliance. Consensus Clinical Management Guidelines for Friedreich's Ataxia. Available
• Corben LA, Collins V, Milne S, Farmer J, Musheno A, Lynch D, Subramony S, Pandolfo M, Schulz JB, Lin K, Delatycki MB; Clinical Management Guidelines Writing Group. Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 2022;17:415. [
• Corben LA, Lynch D, Pandolfo M, Schulz JB, Delatycki MB, et al. Consensus clinical management guidelines for Friedreich ataxia. Available
• Friedreich's Ataxia Research Alliance. Consensus Clinical Management Guidelines for Friedreich's Ataxia. Available
## Literature Cited
|
[] |
18/12/1998
|
31/10/2024
|
26/6/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
fructose1-6-def
|
fructose1-6-def
|
[
"FBP1 Deficiency",
"FBPase Deficiency",
"Fructose 1,6 Diphosphatase Deficiency",
"FBP1 Deficiency",
"FBPase Deficiency",
"Fructose 1,6 Diphosphatase Deficiency",
"Fructose-1,6-bisphosphatase 1",
"FBP1",
"Fructose-1,6-Bisphosphatase Deficiency"
] |
Fructose-1,6-Bisphosphatase Deficiency
|
Sunita Bijarnia-Mahay, Sameer Bhatia, Veronica Arora
|
Summary Fructose-1,6-bisphosphatase (FBP1) deficiency is characterized by episodic acute crises of lactic acidosis and ketotic hypoglycemia, manifesting as hyperventilation, apneic spells, seizures, and/or coma. Acute crises are most common in early childhood; nearly half of affected children have hypoglycemia in the neonatal period (especially the first 4 days) resulting from deficient glycogen stores. Factors known to trigger episodes include fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose. In untreated individuals, symptoms worsen progressively as continued catabolism leads to multiorgan failure (especially liver, brain, and later heart). Morbidity and mortality are high. Sepsis, blindness, and Reye syndrome-like presentation have been reported. In between acute episodes, children are asymptomatic. While the majority of affected children have normal growth and psychomotor development, a few have intellectual disability, presumably due to early and prolonged hypoglycemia. The diagnosis of FBP1 deficiency is established in a proband with suggestive clinical and metabolic findings by identification of EITHER biallelic The mainstay of routine daily management is prevention of hypoglycemia by avoiding fasting (including use of uncooked cornstarch overnight), consuming frequent meals, and appropriate management of acute intercurrent illnesses. FBP1 deficiency is inherited in an autosomal recessive manner. When both parents are known to be heterozygous for an
|
## Diagnosis
Formal diagnostic criteria for fructose-1,6-bisphosphatase (FBP1) deficiency have not been established.
FBP1 deficiency
Episodes of acute crisis may manifest as hyperventilation, apneic spells, seizures, and/or coma, most commonly in neonates and infants. The course of illness is precipitous and may be lethal, especially in neonates and infants.
Other features can include episodic irritability, tachycardia, hypotonia, and hyperhidrosis.
Hepatomegaly is common.
Inter-crisis periods are uneventful with normal development and growth.
Hypoglycemia (plasma glucose <40mg/dL in neonates; <60 mg/dL in older infants, children, and adults; reference range 70-120 mg/dL)
High anion-gap metabolic acidosis
Lactic acidemia (plasma lactate >2.5 mmol/L; reference range: 0.5-2.2 mmol/L) with possible elevated lactate:pyruvate ratio and hyperalaninemia.
Ketosis (individuals with low ketones have been reported)
Elevated glycerol 3-phosphate is an important biomarker for this disorder on urine organic acid analysis. Glycerol 3-phosphate is more specific as glycerol is also elevated in glycerol kinase deficiency (see
Pseudo-hypertriglyceridemia. Although plasma triglycerides are commonly increased, it is not the triglycerides but the glycerol levels that are high (often referred to as "pseudo-hypertriglyceridemia"). The commonly available biochemical assays for plasma triglycerides cannot differentiate glycerol from triglycerides, and hence overestimate the triglyceride levels due to the high concentration of glycerol in plasma [
Hyperuricemia (plasma uric acid >5.0 mg/dL; reference range 2.0-5.0 mmol/L
Increased free fatty acids (in some cases)
The diagnosis of fructose-1,6-bisphosphatase 1 deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When the clinical and metabolic findings suggest the diagnosis of fructose-1,6-bisphosphatase deficiency, molecular genetic testing approaches can include
Note: Pathogenic variants reported frequently in individuals of certain ancestries are noted in
For an introduction to multigene panels click
Molecular Genetic Testing Used in Fructose-1,6-Bisphosphatase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
While enzymatic activity in leukocytes and liver is very specific, testing is not widely available [
• Episodes of acute crisis may manifest as hyperventilation, apneic spells, seizures, and/or coma, most commonly in neonates and infants. The course of illness is precipitous and may be lethal, especially in neonates and infants.
• Other features can include episodic irritability, tachycardia, hypotonia, and hyperhidrosis.
• Hepatomegaly is common.
• Inter-crisis periods are uneventful with normal development and growth.
• Hypoglycemia (plasma glucose <40mg/dL in neonates; <60 mg/dL in older infants, children, and adults; reference range 70-120 mg/dL)
• High anion-gap metabolic acidosis
• Lactic acidemia (plasma lactate >2.5 mmol/L; reference range: 0.5-2.2 mmol/L) with possible elevated lactate:pyruvate ratio and hyperalaninemia.
• Ketosis (individuals with low ketones have been reported)
• Lactic acidemia (plasma lactate >2.5 mmol/L; reference range: 0.5-2.2 mmol/L) with possible elevated lactate:pyruvate ratio and hyperalaninemia.
• Ketosis (individuals with low ketones have been reported)
• Elevated glycerol 3-phosphate is an important biomarker for this disorder on urine organic acid analysis. Glycerol 3-phosphate is more specific as glycerol is also elevated in glycerol kinase deficiency (see
• Pseudo-hypertriglyceridemia. Although plasma triglycerides are commonly increased, it is not the triglycerides but the glycerol levels that are high (often referred to as "pseudo-hypertriglyceridemia"). The commonly available biochemical assays for plasma triglycerides cannot differentiate glycerol from triglycerides, and hence overestimate the triglyceride levels due to the high concentration of glycerol in plasma [
• Hyperuricemia (plasma uric acid >5.0 mg/dL; reference range 2.0-5.0 mmol/L
• Increased free fatty acids (in some cases)
• Lactic acidemia (plasma lactate >2.5 mmol/L; reference range: 0.5-2.2 mmol/L) with possible elevated lactate:pyruvate ratio and hyperalaninemia.
• Ketosis (individuals with low ketones have been reported)
• Note: Pathogenic variants reported frequently in individuals of certain ancestries are noted in
• For an introduction to multigene panels click
## Suggestive Findings
FBP1 deficiency
Episodes of acute crisis may manifest as hyperventilation, apneic spells, seizures, and/or coma, most commonly in neonates and infants. The course of illness is precipitous and may be lethal, especially in neonates and infants.
Other features can include episodic irritability, tachycardia, hypotonia, and hyperhidrosis.
Hepatomegaly is common.
Inter-crisis periods are uneventful with normal development and growth.
Hypoglycemia (plasma glucose <40mg/dL in neonates; <60 mg/dL in older infants, children, and adults; reference range 70-120 mg/dL)
High anion-gap metabolic acidosis
Lactic acidemia (plasma lactate >2.5 mmol/L; reference range: 0.5-2.2 mmol/L) with possible elevated lactate:pyruvate ratio and hyperalaninemia.
Ketosis (individuals with low ketones have been reported)
Elevated glycerol 3-phosphate is an important biomarker for this disorder on urine organic acid analysis. Glycerol 3-phosphate is more specific as glycerol is also elevated in glycerol kinase deficiency (see
Pseudo-hypertriglyceridemia. Although plasma triglycerides are commonly increased, it is not the triglycerides but the glycerol levels that are high (often referred to as "pseudo-hypertriglyceridemia"). The commonly available biochemical assays for plasma triglycerides cannot differentiate glycerol from triglycerides, and hence overestimate the triglyceride levels due to the high concentration of glycerol in plasma [
Hyperuricemia (plasma uric acid >5.0 mg/dL; reference range 2.0-5.0 mmol/L
Increased free fatty acids (in some cases)
• Episodes of acute crisis may manifest as hyperventilation, apneic spells, seizures, and/or coma, most commonly in neonates and infants. The course of illness is precipitous and may be lethal, especially in neonates and infants.
• Other features can include episodic irritability, tachycardia, hypotonia, and hyperhidrosis.
• Hepatomegaly is common.
• Inter-crisis periods are uneventful with normal development and growth.
• Hypoglycemia (plasma glucose <40mg/dL in neonates; <60 mg/dL in older infants, children, and adults; reference range 70-120 mg/dL)
• High anion-gap metabolic acidosis
• Lactic acidemia (plasma lactate >2.5 mmol/L; reference range: 0.5-2.2 mmol/L) with possible elevated lactate:pyruvate ratio and hyperalaninemia.
• Ketosis (individuals with low ketones have been reported)
• Lactic acidemia (plasma lactate >2.5 mmol/L; reference range: 0.5-2.2 mmol/L) with possible elevated lactate:pyruvate ratio and hyperalaninemia.
• Ketosis (individuals with low ketones have been reported)
• Elevated glycerol 3-phosphate is an important biomarker for this disorder on urine organic acid analysis. Glycerol 3-phosphate is more specific as glycerol is also elevated in glycerol kinase deficiency (see
• Pseudo-hypertriglyceridemia. Although plasma triglycerides are commonly increased, it is not the triglycerides but the glycerol levels that are high (often referred to as "pseudo-hypertriglyceridemia"). The commonly available biochemical assays for plasma triglycerides cannot differentiate glycerol from triglycerides, and hence overestimate the triglyceride levels due to the high concentration of glycerol in plasma [
• Hyperuricemia (plasma uric acid >5.0 mg/dL; reference range 2.0-5.0 mmol/L
• Increased free fatty acids (in some cases)
• Lactic acidemia (plasma lactate >2.5 mmol/L; reference range: 0.5-2.2 mmol/L) with possible elevated lactate:pyruvate ratio and hyperalaninemia.
• Ketosis (individuals with low ketones have been reported)
## Establishing the Diagnosis
The diagnosis of fructose-1,6-bisphosphatase 1 deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
When the clinical and metabolic findings suggest the diagnosis of fructose-1,6-bisphosphatase deficiency, molecular genetic testing approaches can include
Note: Pathogenic variants reported frequently in individuals of certain ancestries are noted in
For an introduction to multigene panels click
Molecular Genetic Testing Used in Fructose-1,6-Bisphosphatase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
While enzymatic activity in leukocytes and liver is very specific, testing is not widely available [
• Note: Pathogenic variants reported frequently in individuals of certain ancestries are noted in
• For an introduction to multigene panels click
## Molecular Genetic Testing
When the clinical and metabolic findings suggest the diagnosis of fructose-1,6-bisphosphatase deficiency, molecular genetic testing approaches can include
Note: Pathogenic variants reported frequently in individuals of certain ancestries are noted in
For an introduction to multigene panels click
Molecular Genetic Testing Used in Fructose-1,6-Bisphosphatase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Note: Pathogenic variants reported frequently in individuals of certain ancestries are noted in
• For an introduction to multigene panels click
## Analysis of Fructose-1,6-Bisphosphatase (FBP1 or FBPase) Activity
While enzymatic activity in leukocytes and liver is very specific, testing is not widely available [
## Clinical Characteristics
The manifestations of fructose-1,6-bisphosphatase (FBP1) deficiency are generally episodic due to lactic acidosis and ketotic hypoglycemia, which are often triggered by fasting or febrile infections. The episodes of acute crisis are most frequent in early life – neonatal period, infancy, and early childhood – and subsequently decrease in frequency. In FBP1 deficiency, several metabolic derangements can occur with or without hypoglycemia.
Classically, FBP1 deficiency manifests in the first year of life. Nearly half of affected infants present within the first four days of life with an acute crisis. Neonatal presentation results from hypoglycemia due to deficient glycogen stores [
Acute crises are characterized by episodes of hyperventilation, apneic spells, seizures, and/or coma, often with hepatomegaly. Muscular hypotonia may also be present. This may be associated with transient liver dysfunction (transaminitis), which does not require specific treatment [
Factors known to trigger episodes include fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose. Episodes tend to be recurrent. Often four to five episodes occur before the correct diagnosis is established [
In between crises, children are asymptomatic and the majority experience normal growth and psychomotor development [
In untreated individuals, symptoms worsen progressively as continued catabolism leads to multiorgan failure (especially liver, brain, and later heart). Morbidity and mortality are high. Sepsis, blindness, and Reye syndrome-like presentation have been reported [
No clinically relevant genotype-phenotype correlations have been identified.
Fructose-1,6-bisphosphatase deficiency is rare. Approximately 150 affected individuals have been reported to date.
An estimated prevalence of fructose-1,6-bisphosphatase deficiency is 1:350,000 in the Dutch population [
## Clinical Description
The manifestations of fructose-1,6-bisphosphatase (FBP1) deficiency are generally episodic due to lactic acidosis and ketotic hypoglycemia, which are often triggered by fasting or febrile infections. The episodes of acute crisis are most frequent in early life – neonatal period, infancy, and early childhood – and subsequently decrease in frequency. In FBP1 deficiency, several metabolic derangements can occur with or without hypoglycemia.
Classically, FBP1 deficiency manifests in the first year of life. Nearly half of affected infants present within the first four days of life with an acute crisis. Neonatal presentation results from hypoglycemia due to deficient glycogen stores [
Acute crises are characterized by episodes of hyperventilation, apneic spells, seizures, and/or coma, often with hepatomegaly. Muscular hypotonia may also be present. This may be associated with transient liver dysfunction (transaminitis), which does not require specific treatment [
Factors known to trigger episodes include fever, fasting, decreased oral intake, vomiting, infections, and ingestion of large amounts of fructose. Episodes tend to be recurrent. Often four to five episodes occur before the correct diagnosis is established [
In between crises, children are asymptomatic and the majority experience normal growth and psychomotor development [
In untreated individuals, symptoms worsen progressively as continued catabolism leads to multiorgan failure (especially liver, brain, and later heart). Morbidity and mortality are high. Sepsis, blindness, and Reye syndrome-like presentation have been reported [
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified.
## Nomenclature
## Prevalence
Fructose-1,6-bisphosphatase deficiency is rare. Approximately 150 affected individuals have been reported to date.
An estimated prevalence of fructose-1,6-bisphosphatase deficiency is 1:350,000 in the Dutch population [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Information on mitochondrial respiratory chain and Krebs cycle disorders and fatty acid oxidation defects follows
Disorders (and Associated Genes) of Interest in the Differential Diagnosis of Fructose-1,6-Bisphosphatase Deficiency
When weaned onto sucrose- or fructose-containing foods, infants can manifest nausea, bloating, vomiting, sweating, abdominal pain, & growth restriction.
Chronic liver & kidney disease occur in untreated children.
Overall, HFI has a more chronic course than FBP1D.
Children w/HFI have strong aversion to sweets & often have renal tubular dysfunction, (not seen in FBP1D).
Children w/FBP1D do not have GI symptoms or FTT w/chronic fructose ingestion.
Accumulation of glycogen & fat in liver & kidneys, resulting in hepatomegaly & renomegaly
Untreated infants present at age 3-4 mos w/hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia, &/or hypoglycemic seizures.
Short stature, birth defects (incl cleft palate, bifid uvula), & dilated cardiomyopathy may be present in PGM1-CDG.
Transferrin isoforms are abnormal & aid in diagnosis of PGM1-CDG.
Typically hypoketotic hypoglycemia
↑ acylcarnitine in MS/MS
BKD = beta-ketothiolase deficiency; CDG = congenital disorder of glycosylation; FBP1D = FBP1 deficiency; FTT = failure to thrive; HFI = hereditary fructose intolerance; ID = intellectual disability; MS/MS = tandem mass spectrometry; PCD = pyruvate carboxylase deficiency
Disorders included in this table are inherited in an autosomal recessive manner with the exception of mitochondrial respiratory chain and Krebs cycle disorders, which may be inherited in an autosomal recessive manner, an autosomal dominant manner, or by maternal inheritance.
Hereditary fructose intolerance is due to deficiency of enzyme aldolase B, which facilitates the breakdown of fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde.
GSDI is due to the deficiency of enzyme glucose-6-phosphatase.
Pyruvate carboxylase enzyme aids in the irreversible carboxylation of pyruvate to oxaloacetate.
Biochemical Parameters of Disorders in the Differential Diagnosis of Fructose-1,6-Bisphosphatase Deficiency
• When weaned onto sucrose- or fructose-containing foods, infants can manifest nausea, bloating, vomiting, sweating, abdominal pain, & growth restriction.
• Chronic liver & kidney disease occur in untreated children.
• Overall, HFI has a more chronic course than FBP1D.
• Children w/HFI have strong aversion to sweets & often have renal tubular dysfunction, (not seen in FBP1D).
• Children w/FBP1D do not have GI symptoms or FTT w/chronic fructose ingestion.
• Accumulation of glycogen & fat in liver & kidneys, resulting in hepatomegaly & renomegaly
• Untreated infants present at age 3-4 mos w/hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia, &/or hypoglycemic seizures.
• Short stature, birth defects (incl cleft palate, bifid uvula), & dilated cardiomyopathy may be present in PGM1-CDG.
• Transferrin isoforms are abnormal & aid in diagnosis of PGM1-CDG.
• Typically hypoketotic hypoglycemia
• ↑ acylcarnitine in MS/MS
## Management
To establish the extent of disease and needs in a child diagnosed with fructose-1,6-bisphosphatase (FBP1) deficiency who is not in acute crisis, the evaluations summarized in
Note that the management of possible multisystem complications resulting from early and prolonged hypoglycemia are not discussed in this
Recommended Evaluations Following Initial Diagnosis of Fructose-1,6-Bisphosphatase Deficiency for a Child Not in Acute Crisis
Consider obtaining baseline blood gas, lactate, ketones, CK.
Assess growth parameters (height, weight, head circumference).
Assess diet & nutritional status.
Abdominal ultrasound to assess for hepatomegaly
Baseline liver function tests
Baseline serum lipid panel
Baseline serum uric acid
Use of community or online resources such as Parent to Parent;
Need for social work involvement for parental support.
Elevation of CK has been noted in at least one individual in acute crisis [
See pseudo-hypertriglyceridemia in
An international survey of 126 affected individuals from 36 centers revealed widely varying practices of fructose/sucrose restriction; the authors concluded that internationally accepted guidelines for management and surveillance were needed [
Intervention (oral glucose or IV dextrose) should take place early in an acute crisis while the blood glucose is normal due to the possibility of delayed hypoglycemia, which only occurs relatively late in the course of acute metabolic decompensation.
The family must be given the contact information for an expert metabolic center and a clear emergency outpatient treatment plan during illness (
Laboratory evaluations during acute illnesses should include pH and blood gases, glucose (laboratory and bedside strip test), urea and electrolytes, complete blood count, lactate, blood culture, and urine ketones.
The child should receive emergency treatment if the child is vomiting, complaining of stomach pain, or not wanting to eat or drink, irrespective of associated symptoms (e.g., fever, cough, cold).
Emergency Outpatient Treatment in Individuals with Fructose-1,6-Bisphosphatase Deficiency
Restriction of fructose, sucrose, glycerol, & sorbitol
↑ frequency of carbohydrate feedings
Intake of glucose polymers
Trial of outpatient treatment at home requires good communication between family & providers.
Frequent reassessment of affected person
Acute In-Patient Treatment in Individuals with Fructose-1,6-Bisphosphatase Deficiency
IV glucose bolus (2 mL/kg of 10% dextrose) followed by continuous infusion of glucose at high rates (10% dextrose infusion)
Transition to oral/enteral feeds as clinically tolerated
IV glucose bolus as above
If pH remains <7.1 or worsens, administer NaHCO
Restrict fructose, glycerol, sucrose, & sorbitol.
Acidosis usually corrects quickly w/out NaHCO
No consensus exists re restriction of dietary fructose & sucrose.
IV = intravenous; NaHCO
The main principles of routine daily management are the following:
Prevention of hypoglycemia (by avoiding fasting and consuming frequent meals). Slowly absorbed carbohydrates such as uncooked cornstarch (1-2 g/kg) mixed in milk or water at bedtime may be introduced to children after age six to 12 months who have nocturnal hypoglycemia [
Appropriate management of acute intercurrent illnesses, which can exacerbate the need for glucose
Restriction of food items or medicines that contain fructose, sucrose, glycerol, and/or sorbitol
Also advised are routine immunizations, including annual influenza vaccine, to reduce the risk of infections that can precipitate hypoglycemia.
No formal guidelines for long-term surveillance for individuals with FBP1 deficiency exist.
Recommended Long-Term Surveillance for Individuals with Fructose-1,6-Bisphosphatase Deficiency
Avoid ingestion of food items or medicines that contain fructose, sucrose, glycerol, and/or sorbitol, especially during acute crises in infancy or early childhood.
Although small amounts of fructose (≤2 g/kg/day) are well tolerated by individuals with FBP1 deficiency, single ingestion of high doses of fructose (>1g/kg) is harmful, especially in younger children.
The fructose tolerance testing ("fructose challenge") to diagnose FBP1 deficiency can be hazardous and should not be performed.
It is appropriate to clarify the status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of measures to prevent acute crises (frequent feedings and avoidance of fasting) and prompt treatment of infections / febrile illnesses. Evaluations should include targeted molecular genetic testing if the
For newborns who may be at risk for FBP1 deficiency, it is important to avoid fasting, to feed regularly, and to monitor for hypoglycemia and acidosis while awaiting results of biochemical and/or molecular genetic testing. Monitoring for hypoglycemia can include use of bedside glucometers and clinical monitoring for lethargy, poor intake, vomiting, hypothermia, and/or tachypnea. A low threshold for starting an intravenous infusion of 5%-10% dextrose may help prevent triggering of an acute crisis, especially in newborns who have low birth weight, are preterm, or have a diabetic mother.
See
Although successful pregnancies have been reported in women with FBP1 deficiency [
Counseling that emphasizes the importance of frequent eating in preventing hypoglycemia and the use of blood glucose monitoring for early detection of hypoglycemia
Consider referral to a high-risk obstetric center and consultation with a metabolic physician.
Close home glucose monitoring for early detection of hypoglycemia
Maintenance of glycemic control by taking uncooked cornstarch at night as needed [
In the third trimester when the physiologic requirements of energy are highest, increase in dietary intake and glucose monitoring as needed
Search
• Consider obtaining baseline blood gas, lactate, ketones, CK.
• Assess growth parameters (height, weight, head circumference).
• Assess diet & nutritional status.
• Abdominal ultrasound to assess for hepatomegaly
• Baseline liver function tests
• Baseline serum lipid panel
• Baseline serum uric acid
• Use of community or online resources such as Parent to Parent;
• Need for social work involvement for parental support.
• Restriction of fructose, sucrose, glycerol, & sorbitol
• ↑ frequency of carbohydrate feedings
• Intake of glucose polymers
• Trial of outpatient treatment at home requires good communication between family & providers.
• Frequent reassessment of affected person
• IV glucose bolus (2 mL/kg of 10% dextrose) followed by continuous infusion of glucose at high rates (10% dextrose infusion)
• Transition to oral/enteral feeds as clinically tolerated
• IV glucose bolus as above
• If pH remains <7.1 or worsens, administer NaHCO
• Restrict fructose, glycerol, sucrose, & sorbitol.
• Acidosis usually corrects quickly w/out NaHCO
• No consensus exists re restriction of dietary fructose & sucrose.
• Prevention of hypoglycemia (by avoiding fasting and consuming frequent meals). Slowly absorbed carbohydrates such as uncooked cornstarch (1-2 g/kg) mixed in milk or water at bedtime may be introduced to children after age six to 12 months who have nocturnal hypoglycemia [
• Appropriate management of acute intercurrent illnesses, which can exacerbate the need for glucose
• Restriction of food items or medicines that contain fructose, sucrose, glycerol, and/or sorbitol
•
• Counseling that emphasizes the importance of frequent eating in preventing hypoglycemia and the use of blood glucose monitoring for early detection of hypoglycemia
• Consider referral to a high-risk obstetric center and consultation with a metabolic physician.
• Counseling that emphasizes the importance of frequent eating in preventing hypoglycemia and the use of blood glucose monitoring for early detection of hypoglycemia
• Consider referral to a high-risk obstetric center and consultation with a metabolic physician.
•
• Close home glucose monitoring for early detection of hypoglycemia
• Maintenance of glycemic control by taking uncooked cornstarch at night as needed [
• In the third trimester when the physiologic requirements of energy are highest, increase in dietary intake and glucose monitoring as needed
• Close home glucose monitoring for early detection of hypoglycemia
• Maintenance of glycemic control by taking uncooked cornstarch at night as needed [
• In the third trimester when the physiologic requirements of energy are highest, increase in dietary intake and glucose monitoring as needed
• Counseling that emphasizes the importance of frequent eating in preventing hypoglycemia and the use of blood glucose monitoring for early detection of hypoglycemia
• Consider referral to a high-risk obstetric center and consultation with a metabolic physician.
• Close home glucose monitoring for early detection of hypoglycemia
• Maintenance of glycemic control by taking uncooked cornstarch at night as needed [
• In the third trimester when the physiologic requirements of energy are highest, increase in dietary intake and glucose monitoring as needed
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in a child diagnosed with fructose-1,6-bisphosphatase (FBP1) deficiency who is not in acute crisis, the evaluations summarized in
Note that the management of possible multisystem complications resulting from early and prolonged hypoglycemia are not discussed in this
Recommended Evaluations Following Initial Diagnosis of Fructose-1,6-Bisphosphatase Deficiency for a Child Not in Acute Crisis
Consider obtaining baseline blood gas, lactate, ketones, CK.
Assess growth parameters (height, weight, head circumference).
Assess diet & nutritional status.
Abdominal ultrasound to assess for hepatomegaly
Baseline liver function tests
Baseline serum lipid panel
Baseline serum uric acid
Use of community or online resources such as Parent to Parent;
Need for social work involvement for parental support.
Elevation of CK has been noted in at least one individual in acute crisis [
See pseudo-hypertriglyceridemia in
• Consider obtaining baseline blood gas, lactate, ketones, CK.
• Assess growth parameters (height, weight, head circumference).
• Assess diet & nutritional status.
• Abdominal ultrasound to assess for hepatomegaly
• Baseline liver function tests
• Baseline serum lipid panel
• Baseline serum uric acid
• Use of community or online resources such as Parent to Parent;
• Need for social work involvement for parental support.
## Treatment of Manifestations
An international survey of 126 affected individuals from 36 centers revealed widely varying practices of fructose/sucrose restriction; the authors concluded that internationally accepted guidelines for management and surveillance were needed [
Intervention (oral glucose or IV dextrose) should take place early in an acute crisis while the blood glucose is normal due to the possibility of delayed hypoglycemia, which only occurs relatively late in the course of acute metabolic decompensation.
The family must be given the contact information for an expert metabolic center and a clear emergency outpatient treatment plan during illness (
Laboratory evaluations during acute illnesses should include pH and blood gases, glucose (laboratory and bedside strip test), urea and electrolytes, complete blood count, lactate, blood culture, and urine ketones.
The child should receive emergency treatment if the child is vomiting, complaining of stomach pain, or not wanting to eat or drink, irrespective of associated symptoms (e.g., fever, cough, cold).
Emergency Outpatient Treatment in Individuals with Fructose-1,6-Bisphosphatase Deficiency
Restriction of fructose, sucrose, glycerol, & sorbitol
↑ frequency of carbohydrate feedings
Intake of glucose polymers
Trial of outpatient treatment at home requires good communication between family & providers.
Frequent reassessment of affected person
Acute In-Patient Treatment in Individuals with Fructose-1,6-Bisphosphatase Deficiency
IV glucose bolus (2 mL/kg of 10% dextrose) followed by continuous infusion of glucose at high rates (10% dextrose infusion)
Transition to oral/enteral feeds as clinically tolerated
IV glucose bolus as above
If pH remains <7.1 or worsens, administer NaHCO
Restrict fructose, glycerol, sucrose, & sorbitol.
Acidosis usually corrects quickly w/out NaHCO
No consensus exists re restriction of dietary fructose & sucrose.
IV = intravenous; NaHCO
• Restriction of fructose, sucrose, glycerol, & sorbitol
• ↑ frequency of carbohydrate feedings
• Intake of glucose polymers
• Trial of outpatient treatment at home requires good communication between family & providers.
• Frequent reassessment of affected person
• IV glucose bolus (2 mL/kg of 10% dextrose) followed by continuous infusion of glucose at high rates (10% dextrose infusion)
• Transition to oral/enteral feeds as clinically tolerated
• IV glucose bolus as above
• If pH remains <7.1 or worsens, administer NaHCO
• Restrict fructose, glycerol, sucrose, & sorbitol.
• Acidosis usually corrects quickly w/out NaHCO
• No consensus exists re restriction of dietary fructose & sucrose.
## Prevention of Primary Manifestations
The main principles of routine daily management are the following:
Prevention of hypoglycemia (by avoiding fasting and consuming frequent meals). Slowly absorbed carbohydrates such as uncooked cornstarch (1-2 g/kg) mixed in milk or water at bedtime may be introduced to children after age six to 12 months who have nocturnal hypoglycemia [
Appropriate management of acute intercurrent illnesses, which can exacerbate the need for glucose
Restriction of food items or medicines that contain fructose, sucrose, glycerol, and/or sorbitol
Also advised are routine immunizations, including annual influenza vaccine, to reduce the risk of infections that can precipitate hypoglycemia.
• Prevention of hypoglycemia (by avoiding fasting and consuming frequent meals). Slowly absorbed carbohydrates such as uncooked cornstarch (1-2 g/kg) mixed in milk or water at bedtime may be introduced to children after age six to 12 months who have nocturnal hypoglycemia [
• Appropriate management of acute intercurrent illnesses, which can exacerbate the need for glucose
• Restriction of food items or medicines that contain fructose, sucrose, glycerol, and/or sorbitol
## Surveillance
No formal guidelines for long-term surveillance for individuals with FBP1 deficiency exist.
Recommended Long-Term Surveillance for Individuals with Fructose-1,6-Bisphosphatase Deficiency
## Agents/Circumstances to Avoid
Avoid ingestion of food items or medicines that contain fructose, sucrose, glycerol, and/or sorbitol, especially during acute crises in infancy or early childhood.
Although small amounts of fructose (≤2 g/kg/day) are well tolerated by individuals with FBP1 deficiency, single ingestion of high doses of fructose (>1g/kg) is harmful, especially in younger children.
The fructose tolerance testing ("fructose challenge") to diagnose FBP1 deficiency can be hazardous and should not be performed.
## Evaluation of Relatives at Risk
It is appropriate to clarify the status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of measures to prevent acute crises (frequent feedings and avoidance of fasting) and prompt treatment of infections / febrile illnesses. Evaluations should include targeted molecular genetic testing if the
For newborns who may be at risk for FBP1 deficiency, it is important to avoid fasting, to feed regularly, and to monitor for hypoglycemia and acidosis while awaiting results of biochemical and/or molecular genetic testing. Monitoring for hypoglycemia can include use of bedside glucometers and clinical monitoring for lethargy, poor intake, vomiting, hypothermia, and/or tachypnea. A low threshold for starting an intravenous infusion of 5%-10% dextrose may help prevent triggering of an acute crisis, especially in newborns who have low birth weight, are preterm, or have a diabetic mother.
See
## Pregnancy Management
Although successful pregnancies have been reported in women with FBP1 deficiency [
Counseling that emphasizes the importance of frequent eating in preventing hypoglycemia and the use of blood glucose monitoring for early detection of hypoglycemia
Consider referral to a high-risk obstetric center and consultation with a metabolic physician.
Close home glucose monitoring for early detection of hypoglycemia
Maintenance of glycemic control by taking uncooked cornstarch at night as needed [
In the third trimester when the physiologic requirements of energy are highest, increase in dietary intake and glucose monitoring as needed
•
• Counseling that emphasizes the importance of frequent eating in preventing hypoglycemia and the use of blood glucose monitoring for early detection of hypoglycemia
• Consider referral to a high-risk obstetric center and consultation with a metabolic physician.
• Counseling that emphasizes the importance of frequent eating in preventing hypoglycemia and the use of blood glucose monitoring for early detection of hypoglycemia
• Consider referral to a high-risk obstetric center and consultation with a metabolic physician.
•
• Close home glucose monitoring for early detection of hypoglycemia
• Maintenance of glycemic control by taking uncooked cornstarch at night as needed [
• In the third trimester when the physiologic requirements of energy are highest, increase in dietary intake and glucose monitoring as needed
• Close home glucose monitoring for early detection of hypoglycemia
• Maintenance of glycemic control by taking uncooked cornstarch at night as needed [
• In the third trimester when the physiologic requirements of energy are highest, increase in dietary intake and glucose monitoring as needed
• Counseling that emphasizes the importance of frequent eating in preventing hypoglycemia and the use of blood glucose monitoring for early detection of hypoglycemia
• Consider referral to a high-risk obstetric center and consultation with a metabolic physician.
• Close home glucose monitoring for early detection of hypoglycemia
• Maintenance of glycemic control by taking uncooked cornstarch at night as needed [
• In the third trimester when the physiologic requirements of energy are highest, increase in dietary intake and glucose monitoring as needed
## Therapies Under Investigation
Search
## Genetic Counseling
Fructose-1,6-bisphosphatase (FBP1) deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Note: Biochemical enzyme-based testing is not reliable for carrier detection.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Note: Biochemical testing is not a reliable method for prenatal diagnosis as FBP1 enzyme activity has been reported to be low in human placenta [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Fructose-1,6-bisphosphatase (FBP1) deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Note: Biochemical enzyme-based testing is not reliable for carrier detection.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Biochemical testing is not a reliable method for prenatal diagnosis as FBP1 enzyme activity has been reported to be low in human placenta [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
• United Kingdom
•
## Molecular Genetics
Fructose-1,6-Bisphosphatase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Fructose-1,6-Bisphosphatase Deficiency (
Fructose-1,6-bisphosphatase 1 (FBPase, or FBP1) is a key enzyme of the gluconeogenic pathway. Its deficiency impairs glucose production from all gluconeogenic precursors, including dietary fructose. As a result, euglycemia in persons with FBP1 deficiency depends on glycogen stores in the liver. During glycemic stress (including catabolic states such as infections and fasting), glycogen stores are depleted and the gluconeogenic substrates pyruvate, alanine, and glycerol accumulate (
Deficient conversion of glucose-1-phosphate to glucose also activates the pentose phosphate pathway, causing both the production of ribose-5-phosphate and the synthesis of purines and pyrimidines. The subsequent breakdown of purines and pyrimidines results in hyperuricemia.
(The six
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Fructose-1,6-bisphosphatase 1 (FBPase, or FBP1) is a key enzyme of the gluconeogenic pathway. Its deficiency impairs glucose production from all gluconeogenic precursors, including dietary fructose. As a result, euglycemia in persons with FBP1 deficiency depends on glycogen stores in the liver. During glycemic stress (including catabolic states such as infections and fasting), glycogen stores are depleted and the gluconeogenic substrates pyruvate, alanine, and glycerol accumulate (
Deficient conversion of glucose-1-phosphate to glucose also activates the pentose phosphate pathway, causing both the production of ribose-5-phosphate and the synthesis of purines and pyrimidines. The subsequent breakdown of purines and pyrimidines results in hyperuricemia.
(The six
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
The authors would like to acknowledge our senior colleagues, Dr Ishwar Chander Verma, Dr Ratna D Puri, and Dr Renu Saxena, for rendering support in writing this article. Significant contributions from other colleagues, Dr Pratibha Bhai, Dr Deepti Gupta, Dr Ranjana Mishra, Dr Vibha Jain, and Dr Jyotsna Verma, are also gratefully acknowledged.
5 December 2019 (bp) Review posted live
20 May 2019 (sbm) Original submission
• 5 December 2019 (bp) Review posted live
• 20 May 2019 (sbm) Original submission
## Acknowledgments
The authors would like to acknowledge our senior colleagues, Dr Ishwar Chander Verma, Dr Ratna D Puri, and Dr Renu Saxena, for rendering support in writing this article. Significant contributions from other colleagues, Dr Pratibha Bhai, Dr Deepti Gupta, Dr Ranjana Mishra, Dr Vibha Jain, and Dr Jyotsna Verma, are also gratefully acknowledged.
## Revision History
5 December 2019 (bp) Review posted live
20 May 2019 (sbm) Original submission
• 5 December 2019 (bp) Review posted live
• 20 May 2019 (sbm) Original submission
## References
## Literature Cited
Pathophysiology of FBP1 deficiency
|
[] |
5/12/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
fryns
|
fryns
|
[
"GPI ethanolamine phosphate transferase 1",
"PIGN",
"Fryns Syndrome"
] |
Fryns Syndrome
|
Anne Slavotinek
|
Summary Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia, eventration, hypoplasia, or agenesis); characteristic facial appearance (coarse facies, wide-set eyes, a wide and depressed nasal bridge with a broad nasal tip, long philtrum, low-set and anomalous ears, tented vermilion of the upper lip, wide mouth, and a small jaw); short distal phalanges of the fingers and toes (the nails may also be small); pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts, and/or malformations involving the brain, cardiovascular system, gastrointestinal system, and/or genitalia). Survival beyond the neonatal period is rare. Data on postnatal growth and psychomotor development are limited; however, severe developmental delay and intellectual disability are common. The clinical diagnosis of Fryns syndrome can be established in a proband based on six proposed criteria (diaphragmatic defect, characteristic facial appearance, distal digital hypoplasia, pulmonary hypoplasia, at least one characteristic associated anomaly, and a family history consistent with autosomal recessive inheritance). The molecular diagnosis can be established in a proband with suggestive findings and biallelic pathogenic variants in Assess for new onset of seizures. Monitor developmental progress and educational needs. Follow up with ophthalmology, cardiology, gastroenterology, nephrology, urology, and craniofacial specialists as needed. Fryns syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the
|
## Diagnosis
Diagnostic criteria for Fryns syndrome were reformulated by
Note: Controversies regarding diagnostic criteria include the extent to which phenotypic deviation from the original case reports of Fryns syndrome is tolerable. For example, cases with atypical limb manifestations such as ectrodactyly, radial ray aplasia, limb shortening, and multiple pterygia have been labeled as Fryns syndrome by some authors, but not by others.
Diagnosis of Fryns syndrome
Polyhydramnios
Cloudy corneas and/or microphthalmia
Orofacial clefting
Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
Cardiovascular malformation
Renal dysplasia / renal cortical cysts
Gastrointestinal malformation
Genital malformation
The clinical diagnosis of Fryns syndrome can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by multiple congenital anomalies,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fryns Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.07-kb deletion with breakpoints in exon 5 and intron 7 (See
Genetic heterogeneity for Fryns syndrome remains highly probable, as some individuals with a clinical diagnosis of Fryns syndrome have not had
• Polyhydramnios
• Cloudy corneas and/or microphthalmia
• Orofacial clefting
• Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
• Cardiovascular malformation
• Renal dysplasia / renal cortical cysts
• Gastrointestinal malformation
• Genital malformation
• Polyhydramnios
• Cloudy corneas and/or microphthalmia
• Orofacial clefting
• Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
• Cardiovascular malformation
• Renal dysplasia / renal cortical cysts
• Gastrointestinal malformation
• Genital malformation
• Polyhydramnios
• Cloudy corneas and/or microphthalmia
• Orofacial clefting
• Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
• Cardiovascular malformation
• Renal dysplasia / renal cortical cysts
• Gastrointestinal malformation
• Genital malformation
## Suggestive Findings
Diagnosis of Fryns syndrome
Polyhydramnios
Cloudy corneas and/or microphthalmia
Orofacial clefting
Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
Cardiovascular malformation
Renal dysplasia / renal cortical cysts
Gastrointestinal malformation
Genital malformation
• Polyhydramnios
• Cloudy corneas and/or microphthalmia
• Orofacial clefting
• Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
• Cardiovascular malformation
• Renal dysplasia / renal cortical cysts
• Gastrointestinal malformation
• Genital malformation
• Polyhydramnios
• Cloudy corneas and/or microphthalmia
• Orofacial clefting
• Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
• Cardiovascular malformation
• Renal dysplasia / renal cortical cysts
• Gastrointestinal malformation
• Genital malformation
• Polyhydramnios
• Cloudy corneas and/or microphthalmia
• Orofacial clefting
• Brain malformations including hydrocephalus, abnormalities of the corpus callosum, and Dandy-Walker malformation
• Cardiovascular malformation
• Renal dysplasia / renal cortical cysts
• Gastrointestinal malformation
• Genital malformation
## Establishing the Diagnosis
The clinical diagnosis of Fryns syndrome can be
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by multiple congenital anomalies,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fryns Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.07-kb deletion with breakpoints in exon 5 and intron 7 (See
Genetic heterogeneity for Fryns syndrome remains highly probable, as some individuals with a clinical diagnosis of Fryns syndrome have not had
## Option 1
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by multiple congenital anomalies,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fryns Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.07-kb deletion with breakpoints in exon 5 and intron 7 (See
Genetic heterogeneity for Fryns syndrome remains highly probable, as some individuals with a clinical diagnosis of Fryns syndrome have not had
## Clinical Characteristics
The term "Fryns syndrome" was first used to describe the clinical findings in two stillborn female sibs, each with a coarse facial appearance, cloudy corneas, a cleft of the soft palate, a small thorax with hypoplastic nipples, proximal insertion of the thumbs, hypoplasia of the terminal phalanges and nails, lung hypoplasia, and congenital diaphragmatic hernia (CDH) with bilateral agenesis of the posterolateral diaphragms [
Recently, biallelic variants in
The following description of the phenotypic features associated with this condition is based on reports of individuals with a clinical diagnosis of Fryns syndrome and those with a molecular diagnosis of Fryns syndrome caused by biallelic pathogenic variants in
Fryns Syndrome: Frequency of Select Features
No clinically relevant genotype-phenotype correlations for
Fryns syndrome was present in seven of 100,000 live births in a French population [
Fryns syndrome may be the most common autosomal recessive disorder associated with congenital diaphragmatic hernia (CDH). The incidence of Fryns syndrome has been estimated in large cohorts of individuals with CDH.
In one study, 23 (1.3%) of 1,833 persons with CDH observed over a six-year period were diagnosed with Fryns syndrome [
Earlier studies estimated the incidence of Fryns syndrome at 4%-10% of persons with CDH.
Some individuals with
• In one study, 23 (1.3%) of 1,833 persons with CDH observed over a six-year period were diagnosed with Fryns syndrome [
• Earlier studies estimated the incidence of Fryns syndrome at 4%-10% of persons with CDH.
## Clinical Description
The term "Fryns syndrome" was first used to describe the clinical findings in two stillborn female sibs, each with a coarse facial appearance, cloudy corneas, a cleft of the soft palate, a small thorax with hypoplastic nipples, proximal insertion of the thumbs, hypoplasia of the terminal phalanges and nails, lung hypoplasia, and congenital diaphragmatic hernia (CDH) with bilateral agenesis of the posterolateral diaphragms [
Recently, biallelic variants in
The following description of the phenotypic features associated with this condition is based on reports of individuals with a clinical diagnosis of Fryns syndrome and those with a molecular diagnosis of Fryns syndrome caused by biallelic pathogenic variants in
Fryns Syndrome: Frequency of Select Features
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations for
## Prevalence
Fryns syndrome was present in seven of 100,000 live births in a French population [
Fryns syndrome may be the most common autosomal recessive disorder associated with congenital diaphragmatic hernia (CDH). The incidence of Fryns syndrome has been estimated in large cohorts of individuals with CDH.
In one study, 23 (1.3%) of 1,833 persons with CDH observed over a six-year period were diagnosed with Fryns syndrome [
Earlier studies estimated the incidence of Fryns syndrome at 4%-10% of persons with CDH.
Some individuals with
• In one study, 23 (1.3%) of 1,833 persons with CDH observed over a six-year period were diagnosed with Fryns syndrome [
• Earlier studies estimated the incidence of Fryns syndrome at 4%-10% of persons with CDH.
## Genetically Related (Allelic) Disorders
Biallelic pathogenic variants in
Almost all known MCAHS1-related
## Differential Diagnosis
Disorders associated with complex congenital diaphragmatic hernia (CDH) may resemble Fryns syndrome, but are distinguishable from Fryns syndrome by their recognizable patterns of anomalies and an absence of characteristic nail or digital hypoplasia. See
Monogenic Disorders Associated with Complex Congenital Diaphragmatic Hernia of Interest in the Differential Diagnosis of Fryns Syndrome
Overgrowth (pre- & postnatal), macrocephaly, dysmorphic features (coarse facies, macrostomia, wide-set eyes, palatal abnormalities), polydactyly, syndactyly, CHD & mild-to-severe ID ± structural brain anomalies
Overgrowth, skeletal anomalies, & tumors distinguish SGBS1 from Fryns syndrome.
Micro-/anophthalmia, pulmonary agenesis or hypoplasia, CHD, genitourinary anomalies
Matthew-Wood syndrome is not assoc w/small nails or small digits.
AD = autosomal dominant; AR = autosomal recessive; CDH = congenital diaphragmatic hernia; CHD = congenital heart defect; ID = intellectual disability; MOI = mode of inheritance; PDAC =
SGBS1 is caused by a pathogenic variant in
Individuals with SGBS are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, and hepatocellular carcinoma.
CDH occurring in CdLS is typically associated with pathogenic variants in
Frasier syndrome, Denys-Drash syndrome, and Meacham syndrome were originally described as distinct disorders on the basis of clinical findings but are now understood to represent a continuum of features caused by a
Chromosome Anomalies Associated With Congenital Diaphragmatic Hernia and Additional Major Malformations/Dysmorphology
Coarse w/wide-set eyes, prominent cheeks, & eversion of vermilion of lower lip
Considered similar to Fryns syndrome
Sparse hair,
Hypotonia, seizures, & ID common
Short distal phalanges of fingers & toes, small nails, cloudy corneas, CHD, & internal malformations may be seen but are typically less frequent in PKS than in Fryns syndrome.
CHD, skeletal anomalies, hypocalcemia
CDH is present in 0.8% of persons w/22q11 deletion.
AD = autosomal dominant; AR = autosomal recessive; CDH = congenital diaphragmatic hernia; CHD = congenital heart defect; ID = intellectual disability; MODY = maturity-onset diabetes of the young
In some persons, only chromosome analysis and/or the inheritance pattern can distinguish between PKS and Fryns syndrome [
Sparse hair is characteristic of PKS, in contrast to Fryns syndrome, in which the sisters originally described by Fryns had low hairlines and hypertrichosis.
• Overgrowth (pre- & postnatal), macrocephaly, dysmorphic features (coarse facies, macrostomia, wide-set eyes, palatal abnormalities), polydactyly, syndactyly, CHD & mild-to-severe ID ± structural brain anomalies
• Overgrowth, skeletal anomalies, & tumors distinguish SGBS1 from Fryns syndrome.
• Micro-/anophthalmia, pulmonary agenesis or hypoplasia, CHD, genitourinary anomalies
• Matthew-Wood syndrome is not assoc w/small nails or small digits.
• Coarse w/wide-set eyes, prominent cheeks, & eversion of vermilion of lower lip
• Considered similar to Fryns syndrome
• Sparse hair,
• Hypotonia, seizures, & ID common
• Short distal phalanges of fingers & toes, small nails, cloudy corneas, CHD, & internal malformations may be seen but are typically less frequent in PKS than in Fryns syndrome.
• CHD, skeletal anomalies, hypocalcemia
• CDH is present in 0.8% of persons w/22q11 deletion.
## Management
No clinical practice guidelines for Fryns syndrome have been published.
To establish the extent of disease and needs in an individual with Fryns syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fryns Syndrome
Cranial US exam to evaluate for structural brain malformations
Neurologic eval & EEG if seizures are suspected
Brain MRI exam
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
CDH = congenital diaphragmatic hernia; MOI = mode of inheritance; US = ultrasound
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment of Manifestations in Individuals with Fryns Syndrome
CDH = congenital diaphragmatic hernia
Recommended Surveillance for Individuals with Fryns Syndrome
CDH = congenital diaphragmatic hernia
See
Pregnancies are managed according to the malformations that have been diagnosed. One literature review concluded that fetoscopic endoluminal tracheal occlusion used as a prenatal interventional strategy can increase survival in cases with severe CDH [
Many different treatments are currently being evaluated for the management of congenital diaphragmatic hernia.
Search
• Cranial US exam to evaluate for structural brain malformations
• Neurologic eval & EEG if seizures are suspected
• Brain MRI exam
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual with Fryns syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fryns Syndrome
Cranial US exam to evaluate for structural brain malformations
Neurologic eval & EEG if seizures are suspected
Brain MRI exam
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
CDH = congenital diaphragmatic hernia; MOI = mode of inheritance; US = ultrasound
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Cranial US exam to evaluate for structural brain malformations
• Neurologic eval & EEG if seizures are suspected
• Brain MRI exam
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Fryns Syndrome
CDH = congenital diaphragmatic hernia
## Surveillance
Recommended Surveillance for Individuals with Fryns Syndrome
CDH = congenital diaphragmatic hernia
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Pregnancies are managed according to the malformations that have been diagnosed. One literature review concluded that fetoscopic endoluminal tracheal occlusion used as a prenatal interventional strategy can increase survival in cases with severe CDH [
## Therapies Under Investigation
Many different treatments are currently being evaluated for the management of congenital diaphragmatic hernia.
Search
## Genetic Counseling
Fryns syndrome caused by pathogenic variants in
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Fryns syndrome-causing pathogenic variant based on family history).
If biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Assuming that both parent are heterozygous for a Fryns syndrome-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives is possible if biallelic
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had a child with Fryns syndrome and young adults who are at risk of being carriers.
If the reproductive partner of an individual known to be heterozygous for a
Thus, a detailed sonographic examination of the fetus with echocardiography and measurement of growth parameters and amniotic fluid levels is recommended. Fetal MRI can be considered to confirm the presence of a diaphragmatic defect and to search for other anomalies. However, it is possible that Fryns syndrome will be missed during pregnancy without a prior index case [
A routine prenatal ultrasound examination may identify a diaphragmatic hernia and/or other malformations raising the possibility of Fryns syndrome in a fetus not known to be at increased risk. In such situations, chromosome analysis, including karyotype (for evaluation for mosaicism for isochromosome 12p or tetrasomy 12p associated with Pallister-Killian syndrome) and CMA (for other chromosome abnormalities) (see
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Fryns syndrome-causing pathogenic variant based on family history).
• If biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Assuming that both parent are heterozygous for a Fryns syndrome-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had a child with Fryns syndrome and young adults who are at risk of being carriers.
• If the reproductive partner of an individual known to be heterozygous for a
## Mode of Inheritance
Fryns syndrome caused by pathogenic variants in
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Fryns syndrome-causing pathogenic variant based on family history).
If biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Assuming that both parent are heterozygous for a Fryns syndrome-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Fryns syndrome-causing pathogenic variant based on family history).
• If biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Assuming that both parent are heterozygous for a Fryns syndrome-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives is possible if biallelic
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had a child with Fryns syndrome and young adults who are at risk of being carriers.
If the reproductive partner of an individual known to be heterozygous for a
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to couples who have had a child with Fryns syndrome and young adults who are at risk of being carriers.
• If the reproductive partner of an individual known to be heterozygous for a
## Prenatal Testing and Preimplantation Genetic Testing
Thus, a detailed sonographic examination of the fetus with echocardiography and measurement of growth parameters and amniotic fluid levels is recommended. Fetal MRI can be considered to confirm the presence of a diaphragmatic defect and to search for other anomalies. However, it is possible that Fryns syndrome will be missed during pregnancy without a prior index case [
A routine prenatal ultrasound examination may identify a diaphragmatic hernia and/or other malformations raising the possibility of Fryns syndrome in a fetus not known to be at increased risk. In such situations, chromosome analysis, including karyotype (for evaluation for mosaicism for isochromosome 12p or tetrasomy 12p associated with Pallister-Killian syndrome) and CMA (for other chromosome abnormalities) (see
## A Priori High-Risk Pregnancy – Sib with Fryns Syndrome
Thus, a detailed sonographic examination of the fetus with echocardiography and measurement of growth parameters and amniotic fluid levels is recommended. Fetal MRI can be considered to confirm the presence of a diaphragmatic defect and to search for other anomalies. However, it is possible that Fryns syndrome will be missed during pregnancy without a prior index case [
## A Priori High-Risk Pregnancy – Sib with Possible Fryns Syndrome
## A Priori Low-Risk Pregnancy – No Family History of Fryns Syndrome
A routine prenatal ultrasound examination may identify a diaphragmatic hernia and/or other malformations raising the possibility of Fryns syndrome in a fetus not known to be at increased risk. In such situations, chromosome analysis, including karyotype (for evaluation for mosaicism for isochromosome 12p or tetrasomy 12p associated with Pallister-Killian syndrome) and CMA (for other chromosome abnormalities) (see
## Resources
•
•
•
•
•
•
•
## Molecular Genetics
Fryns Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Fryns Syndrome (
PIGN is one of a family of proteins responsible for the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors proteins to the outer leaflet of the lipid bilayer of the cell membrane, enabling diverse cellular functions including signal transduction, cell adhesion, and antigen presentation [
Notable
Variants listed in the table have been provided by the author.
c.[1966C>T]; [c.1674+1G>C]; designation for two variants on two alleles
5.07-kb deletion with breakpoints in exon 5 and intron 7; precise breakpoints unknown (GRCh37/hg19). Using other reference sequences, the designations are
Splicing of deleted allele cannot be predicted; it is predicted to span at least 90 amino acid residues [
## Molecular Pathogenesis
PIGN is one of a family of proteins responsible for the biosynthesis of glycosylphosphatidylinositol (GPI), which anchors proteins to the outer leaflet of the lipid bilayer of the cell membrane, enabling diverse cellular functions including signal transduction, cell adhesion, and antigen presentation [
Notable
Variants listed in the table have been provided by the author.
c.[1966C>T]; [c.1674+1G>C]; designation for two variants on two alleles
5.07-kb deletion with breakpoints in exon 5 and intron 7; precise breakpoints unknown (GRCh37/hg19). Using other reference sequences, the designations are
Splicing of deleted allele cannot be predicted; it is predicted to span at least 90 amino acid residues [
## Chapter Notes
17 September 2020 (sw) Comprehensive update posted live
29 January 2015 (me) Comprehensive update posted live
1 June 2010 (me) Comprehensive update posted live
18 April 2007 (me) Review posted live
8 January 2007 (ams) Original submission
• 17 September 2020 (sw) Comprehensive update posted live
• 29 January 2015 (me) Comprehensive update posted live
• 1 June 2010 (me) Comprehensive update posted live
• 18 April 2007 (me) Review posted live
• 8 January 2007 (ams) Original submission
## Revision History
17 September 2020 (sw) Comprehensive update posted live
29 January 2015 (me) Comprehensive update posted live
1 June 2010 (me) Comprehensive update posted live
18 April 2007 (me) Review posted live
8 January 2007 (ams) Original submission
• 17 September 2020 (sw) Comprehensive update posted live
• 29 January 2015 (me) Comprehensive update posted live
• 1 June 2010 (me) Comprehensive update posted live
• 18 April 2007 (me) Review posted live
• 8 January 2007 (ams) Original submission
## References
## Literature Cited
|
[] |
18/4/2007
|
17/9/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
fsh
|
fsh
|
[
"FSHD",
"FSH Muscular Dystrophy",
"FSH Muscular Dystrophy",
"FSHD",
"FSHD1",
"FSHD2",
"DNA (cytosine-5)-methyltransferase 3B",
"Double homeobox protein 4",
"Ligand-dependent nuclear receptor-interacting factor 1",
"Structural maintenance of chromosomes flexible hinge domain-containing protein 1",
"DNMT3B",
"DUX4L1",
"LRIF1",
"SMCHD1",
"Facioscapulohumeral Muscular Dystrophy"
] |
Facioscapulohumeral Muscular Dystrophy
|
Matthew K Preston, Leo H Wang
|
Summary Facioscapulohumeral muscular dystrophy (FSHD) typically presents with weakness of the facial muscles, the stabilizers of the scapula, and/or the dorsiflexors of the foot. Severity is highly variable. Weakness can be slowly progressive and approximately 20% of affected individuals eventually require a wheelchair. Life expectancy is not shortened. The diagnosis of FSHD1 is established in a proband with characteristic clinical features and a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype. The diagnosis of FSHD2 is established in a proband with characteristic clinical features and hypomethylation of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype. Hypomethylation of the D4Z4 repeat array can be the result of a heterozygous pathogenic variant in
|
## Diagnosis
Evidence-based guidelines for diagnosis of facioscapulohumeral muscular dystrophy (FSHD) are available [
FSHD
Weakness that predominantly involves the facial, scapular stabilizer, and/or foot dorsiflexor muscles without associated ocular or bulbar muscle weakness. Weakness is often asymmetric.
Progression of weakness after pregnancy [
Prior diagnosis with inflammatory myopathy that is refractory to immunosuppression
The diagnosis of FSHD
A heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD1; ~95% of FSHD)
Hypomethylation of a shortened (but not to the extent of FSHD1) D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD2; ~5% of FSHD), as a result of one of the following:
A heterozygous
A heterozygous
A homozygous nonsense variant in
Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (affected individuals in 1 family) [
Note: (1) Affected individuals from India, Japan, and South Korea have lower penetrance in allele sizes 8-10 than affected individuals from Europe [
Note: (1) Penetrance of allele sizes is dependent on multiple factors (see
Molecular genetic testing approaches can include
Note: Targeted testing can be done by Southern blotting after pulsed field gel electrophoresis, OGM, molecular combing (MC), and long-read nanopore sequencing [
Examples of chromosome 4q35 permissive (known as 4A or A) and non-permissive (known as 4B or B) haplotypes:
Permissive: 4A161, 4A159, 4A168, 4A166H
Non-permissive: 4A166, 4B
Note: The presence of a typical FSHD clinical profile without a contracted repeat but with at least one allele with a permissive haplotype raises the possibility of FSHD2.
In individuals who do not have a contracted D4Z4 repeat array identified and have at least one repeat array with a permissive chromosome 4 haplotype, D4Z4 methylation analysis should be done next. D4Z4 hypomethylation suggests the presence of a heterozygous pathogenic variant in
Sequence analysis of
Molecular Genetic Testing Used in Facioscapulohumeral Muscular Dystrophy
See
See
The ability of the test method used to detect a variant that is present in the indicated gene/locus
Molecular genetic testing to determine the length or number of repeat units of the D4Z4 locus has typically relied on Southern blot analysis, typically with a probe (e.g., p13E-11) immediately proximal to D4Z4. Standard DNA diagnostic testing (defined here as linear gel electrophoresis and Southern blot analysis) uses the restriction enzyme EcoRI, which recognizes the D4Z4 locus on chromosomes 4 and 10. Pulsed-field gel electrophoresis and Southern blot analysis requires EcoRI/HindIII double digestion for a better resolution of DNA fragments between 20 and 50 kb. An EcoRI/BlnI double digestion further fragments the chromosome 10 array, allowing one to distinguish D4Z4 arrays located on chromosome 4 from the similar benign arrays on chromosome 10. Molecular combing, which has a higher resolution than Southern blotting [
Detection of the pathogenic contraction of the D4Z4 locus by Southern blot analysis requires high-quality DNA; a false negative test result can be caused by poor-quality DNA that was sheared into small fragments.
In approximately 3% of the European families with FSHD1, the D4Z4 contraction on chromosome 4q35 is not visible using the standard genetic test because a deletion encompasses the region of the molecular diagnostic probe p13E-11. These individuals require additional testing to visualize the contracted D4Z4 repeat and resolve the size of the repeat [
A combination of Southern blotting and molecular combing detected complex rearrangements of 4q35 with duplication of D4Z4 array [
4A161 is the most common permissive haplotype, but others are reported (4A159, 4A168, 4A166H) [
D4Z4 methylation values below the threshold of 25% are indicative of FSHD. However, the CpG methylation at the D4Z4 repeat array is also determined by the size of the D4Z4 arrays on chromosomes 4 and 10. Contracted D4Z4 arrays on chromosomes 4 and 10 have a significantly lower level of methylation than normal-sized arrays. D4Z4 methylation levels should always be evaluated with respect to the repeat size. A Southern blot-based method has been developed that measures the total D4Z4 methylation at chromosomes 4 and 10 by using methylation-sensitive restriction enzyme (FseI) in the promoter region of
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Fifty-one families of 60 with FSHD2 were found to have an
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications.
Deletions including
• Weakness that predominantly involves the facial, scapular stabilizer, and/or foot dorsiflexor muscles without associated ocular or bulbar muscle weakness. Weakness is often asymmetric.
• Progression of weakness after pregnancy [
• Prior diagnosis with inflammatory myopathy that is refractory to immunosuppression
• A heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD1; ~95% of FSHD)
• Hypomethylation of a shortened (but not to the extent of FSHD1) D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD2; ~5% of FSHD), as a result of one of the following:
• A heterozygous
• A heterozygous
• A homozygous nonsense variant in
• Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (affected individuals in 1 family) [
• A heterozygous
• A heterozygous
• A homozygous nonsense variant in
• Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (affected individuals in 1 family) [
• A heterozygous
• A heterozygous
• A homozygous nonsense variant in
• Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (affected individuals in 1 family) [
• Note: (1) Affected individuals from India, Japan, and South Korea have lower penetrance in allele sizes 8-10 than affected individuals from Europe [
• Permissive: 4A161, 4A159, 4A168, 4A166H
• Non-permissive: 4A166, 4B
## Suggestive Findings
FSHD
Weakness that predominantly involves the facial, scapular stabilizer, and/or foot dorsiflexor muscles without associated ocular or bulbar muscle weakness. Weakness is often asymmetric.
Progression of weakness after pregnancy [
Prior diagnosis with inflammatory myopathy that is refractory to immunosuppression
• Weakness that predominantly involves the facial, scapular stabilizer, and/or foot dorsiflexor muscles without associated ocular or bulbar muscle weakness. Weakness is often asymmetric.
• Progression of weakness after pregnancy [
• Prior diagnosis with inflammatory myopathy that is refractory to immunosuppression
## Supportive Findings
## Establishing the Diagnosis
The diagnosis of FSHD
A heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD1; ~95% of FSHD)
Hypomethylation of a shortened (but not to the extent of FSHD1) D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD2; ~5% of FSHD), as a result of one of the following:
A heterozygous
A heterozygous
A homozygous nonsense variant in
Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (affected individuals in 1 family) [
Note: (1) Affected individuals from India, Japan, and South Korea have lower penetrance in allele sizes 8-10 than affected individuals from Europe [
Note: (1) Penetrance of allele sizes is dependent on multiple factors (see
Molecular genetic testing approaches can include
Note: Targeted testing can be done by Southern blotting after pulsed field gel electrophoresis, OGM, molecular combing (MC), and long-read nanopore sequencing [
Examples of chromosome 4q35 permissive (known as 4A or A) and non-permissive (known as 4B or B) haplotypes:
Permissive: 4A161, 4A159, 4A168, 4A166H
Non-permissive: 4A166, 4B
Note: The presence of a typical FSHD clinical profile without a contracted repeat but with at least one allele with a permissive haplotype raises the possibility of FSHD2.
In individuals who do not have a contracted D4Z4 repeat array identified and have at least one repeat array with a permissive chromosome 4 haplotype, D4Z4 methylation analysis should be done next. D4Z4 hypomethylation suggests the presence of a heterozygous pathogenic variant in
Sequence analysis of
Molecular Genetic Testing Used in Facioscapulohumeral Muscular Dystrophy
See
See
The ability of the test method used to detect a variant that is present in the indicated gene/locus
Molecular genetic testing to determine the length or number of repeat units of the D4Z4 locus has typically relied on Southern blot analysis, typically with a probe (e.g., p13E-11) immediately proximal to D4Z4. Standard DNA diagnostic testing (defined here as linear gel electrophoresis and Southern blot analysis) uses the restriction enzyme EcoRI, which recognizes the D4Z4 locus on chromosomes 4 and 10. Pulsed-field gel electrophoresis and Southern blot analysis requires EcoRI/HindIII double digestion for a better resolution of DNA fragments between 20 and 50 kb. An EcoRI/BlnI double digestion further fragments the chromosome 10 array, allowing one to distinguish D4Z4 arrays located on chromosome 4 from the similar benign arrays on chromosome 10. Molecular combing, which has a higher resolution than Southern blotting [
Detection of the pathogenic contraction of the D4Z4 locus by Southern blot analysis requires high-quality DNA; a false negative test result can be caused by poor-quality DNA that was sheared into small fragments.
In approximately 3% of the European families with FSHD1, the D4Z4 contraction on chromosome 4q35 is not visible using the standard genetic test because a deletion encompasses the region of the molecular diagnostic probe p13E-11. These individuals require additional testing to visualize the contracted D4Z4 repeat and resolve the size of the repeat [
A combination of Southern blotting and molecular combing detected complex rearrangements of 4q35 with duplication of D4Z4 array [
4A161 is the most common permissive haplotype, but others are reported (4A159, 4A168, 4A166H) [
D4Z4 methylation values below the threshold of 25% are indicative of FSHD. However, the CpG methylation at the D4Z4 repeat array is also determined by the size of the D4Z4 arrays on chromosomes 4 and 10. Contracted D4Z4 arrays on chromosomes 4 and 10 have a significantly lower level of methylation than normal-sized arrays. D4Z4 methylation levels should always be evaluated with respect to the repeat size. A Southern blot-based method has been developed that measures the total D4Z4 methylation at chromosomes 4 and 10 by using methylation-sensitive restriction enzyme (FseI) in the promoter region of
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Fifty-one families of 60 with FSHD2 were found to have an
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications.
Deletions including
• A heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD1; ~95% of FSHD)
• Hypomethylation of a shortened (but not to the extent of FSHD1) D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype (FSHD2; ~5% of FSHD), as a result of one of the following:
• A heterozygous
• A heterozygous
• A homozygous nonsense variant in
• Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (affected individuals in 1 family) [
• A heterozygous
• A heterozygous
• A homozygous nonsense variant in
• Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (affected individuals in 1 family) [
• A heterozygous
• A heterozygous
• A homozygous nonsense variant in
• Unknown cause of hypomethylation of D4Z4 repeat array at 4q35 (affected individuals in 1 family) [
• Note: (1) Affected individuals from India, Japan, and South Korea have lower penetrance in allele sizes 8-10 than affected individuals from Europe [
• Permissive: 4A161, 4A159, 4A168, 4A166H
• Non-permissive: 4A166, 4B
## Targeted Analysis and Haplotype Analysis
Note: Targeted testing can be done by Southern blotting after pulsed field gel electrophoresis, OGM, molecular combing (MC), and long-read nanopore sequencing [
Examples of chromosome 4q35 permissive (known as 4A or A) and non-permissive (known as 4B or B) haplotypes:
Permissive: 4A161, 4A159, 4A168, 4A166H
Non-permissive: 4A166, 4B
Note: The presence of a typical FSHD clinical profile without a contracted repeat but with at least one allele with a permissive haplotype raises the possibility of FSHD2.
• Permissive: 4A161, 4A159, 4A168, 4A166H
• Non-permissive: 4A166, 4B
## DNA Methylation Studies
In individuals who do not have a contracted D4Z4 repeat array identified and have at least one repeat array with a permissive chromosome 4 haplotype, D4Z4 methylation analysis should be done next. D4Z4 hypomethylation suggests the presence of a heterozygous pathogenic variant in
## Concurrent Gene Testing
Sequence analysis of
Molecular Genetic Testing Used in Facioscapulohumeral Muscular Dystrophy
See
See
The ability of the test method used to detect a variant that is present in the indicated gene/locus
Molecular genetic testing to determine the length or number of repeat units of the D4Z4 locus has typically relied on Southern blot analysis, typically with a probe (e.g., p13E-11) immediately proximal to D4Z4. Standard DNA diagnostic testing (defined here as linear gel electrophoresis and Southern blot analysis) uses the restriction enzyme EcoRI, which recognizes the D4Z4 locus on chromosomes 4 and 10. Pulsed-field gel electrophoresis and Southern blot analysis requires EcoRI/HindIII double digestion for a better resolution of DNA fragments between 20 and 50 kb. An EcoRI/BlnI double digestion further fragments the chromosome 10 array, allowing one to distinguish D4Z4 arrays located on chromosome 4 from the similar benign arrays on chromosome 10. Molecular combing, which has a higher resolution than Southern blotting [
Detection of the pathogenic contraction of the D4Z4 locus by Southern blot analysis requires high-quality DNA; a false negative test result can be caused by poor-quality DNA that was sheared into small fragments.
In approximately 3% of the European families with FSHD1, the D4Z4 contraction on chromosome 4q35 is not visible using the standard genetic test because a deletion encompasses the region of the molecular diagnostic probe p13E-11. These individuals require additional testing to visualize the contracted D4Z4 repeat and resolve the size of the repeat [
A combination of Southern blotting and molecular combing detected complex rearrangements of 4q35 with duplication of D4Z4 array [
4A161 is the most common permissive haplotype, but others are reported (4A159, 4A168, 4A166H) [
D4Z4 methylation values below the threshold of 25% are indicative of FSHD. However, the CpG methylation at the D4Z4 repeat array is also determined by the size of the D4Z4 arrays on chromosomes 4 and 10. Contracted D4Z4 arrays on chromosomes 4 and 10 have a significantly lower level of methylation than normal-sized arrays. D4Z4 methylation levels should always be evaluated with respect to the repeat size. A Southern blot-based method has been developed that measures the total D4Z4 methylation at chromosomes 4 and 10 by using methylation-sensitive restriction enzyme (FseI) in the promoter region of
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Fifty-one families of 60 with FSHD2 were found to have an
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications.
Deletions including
## Clinical Characteristics
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive muscle weakness involving the face, shoulder girdle, upper arm, lower leg (peroneal muscles), and hip girdle in later stages [
Scapular winging is the most common initial finding; preferential weakness of the lower trapezius muscle results in characteristic upward movement of the scapula when attempting to flex or abduct the arms. The shoulders tend to slope forward with straight clavicles and pectoral muscle atrophy.
Affected individuals show facial weakness, with symptoms more pronounced in the lower facial muscles than the upper. Some affected individuals recall having facial weakness before the onset of shoulder weakness. Earliest signs are often difficulty whistling or sleeping with eyes partially open in childhood. Individuals with FSHD are often unable to purse their lips, turn up the corners of their mouth when smiling, or bury their eyelashes when attempting to close their eyelids tightly. Extraocular, eyelid, and bulbar muscles are spared.
The deltoids remain minimally affected until late in the disease; however, the biceps and triceps are selectively involved, resulting in atrophy of the upper arm and sparing of the forearm muscles. The latter results in the appearance of "Popeye arms." In more severely affected individuals, distal upper extremity weakness typically involves the wrist and finger extensors.
Abdominal muscle weakness results in protuberance of the abdomen and exaggerated lumbar lordosis. The lower abdominal muscles are selectively involved, resulting in Beevor sign (upward displacement of the umbilicus upon flexion of the neck in a supine position).
The legs are variably involved, with peroneal muscle weakness with or without weakness of the hip girdle muscles, resulting in foot drop.
Sensation is preserved; reflexes are often diminished when the reflex involves weak muscles.
Respiratory dysfunction prevalence is unclear, with up to 50% of those tested in a cohort having abnormal results, though the majority of individuals have not had testing. Individuals with respiratory weakness have a restrictive pattern on pulmonary function testing with reduced forced vital capacity. Respiratory weakness is typically mild or subclinical [
Chronic pain is a common symptom in FSHD, seen in 82% of individuals, with a negative impact on quality of life. Chronic pain can occur regardless of duration of disease or age [
Retinal arterial tortuosity may be prevalent in individuals with FSHD; however, these retinal vascular changes seem subclinical and are not symptomatic (i.e., do not cause visual changes) [
Approximately 15% of individuals with FSHD have an abnormal audiogram. An abnormal audiogram was identified in up to 32% of individuals with a large pathogenic contraction of D4Z4 (D4Z4 fragments <20 kb) [
Cardiac conduction abnormalities can be seen in 5%-13% of individuals and are typically atrial arrhythmias that are mild or asymptomatic [
Scapulohumeral dystrophy onset with facial sparing
Early-onset disease (age <10 years) is associated with earlier median age of lower extremity involvement and more severe disease overall.
Allele size explains roughly 10% of variability in phenotype [
A study of Italy's National Registry concluded that 76% of early-onset (age <10 years) disease was a result of
Penetrance is increased with smaller D4Z4 repeat arrays; however, significant variation exists. In one study, penetrance of FSHD varied by age and sex; it was 83% by age 30 years, but significantly greater for males (95%) than for females (69%) [
Anticipation is not reported in FSHD and repeat size remains stable throughout generations [
The term "Landouzy-Dejerine muscular dystrophy," used in the past for a syndrome similar or identical to FSHD, is no longer in use.
Persons with FSHD are sometimes included under the descriptive terms "scapulo-humeral" or "scapulo-peroneal" syndromes.
The estimated prevalence of FSHD is between four and ten in 100,000.
• Chronic pain is a common symptom in FSHD, seen in 82% of individuals, with a negative impact on quality of life. Chronic pain can occur regardless of duration of disease or age [
• Retinal arterial tortuosity may be prevalent in individuals with FSHD; however, these retinal vascular changes seem subclinical and are not symptomatic (i.e., do not cause visual changes) [
• Approximately 15% of individuals with FSHD have an abnormal audiogram. An abnormal audiogram was identified in up to 32% of individuals with a large pathogenic contraction of D4Z4 (D4Z4 fragments <20 kb) [
• Cardiac conduction abnormalities can be seen in 5%-13% of individuals and are typically atrial arrhythmias that are mild or asymptomatic [
• Scapulohumeral dystrophy onset with facial sparing
• Early-onset disease (age <10 years) is associated with earlier median age of lower extremity involvement and more severe disease overall.
## Clinical Description
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive muscle weakness involving the face, shoulder girdle, upper arm, lower leg (peroneal muscles), and hip girdle in later stages [
Scapular winging is the most common initial finding; preferential weakness of the lower trapezius muscle results in characteristic upward movement of the scapula when attempting to flex or abduct the arms. The shoulders tend to slope forward with straight clavicles and pectoral muscle atrophy.
Affected individuals show facial weakness, with symptoms more pronounced in the lower facial muscles than the upper. Some affected individuals recall having facial weakness before the onset of shoulder weakness. Earliest signs are often difficulty whistling or sleeping with eyes partially open in childhood. Individuals with FSHD are often unable to purse their lips, turn up the corners of their mouth when smiling, or bury their eyelashes when attempting to close their eyelids tightly. Extraocular, eyelid, and bulbar muscles are spared.
The deltoids remain minimally affected until late in the disease; however, the biceps and triceps are selectively involved, resulting in atrophy of the upper arm and sparing of the forearm muscles. The latter results in the appearance of "Popeye arms." In more severely affected individuals, distal upper extremity weakness typically involves the wrist and finger extensors.
Abdominal muscle weakness results in protuberance of the abdomen and exaggerated lumbar lordosis. The lower abdominal muscles are selectively involved, resulting in Beevor sign (upward displacement of the umbilicus upon flexion of the neck in a supine position).
The legs are variably involved, with peroneal muscle weakness with or without weakness of the hip girdle muscles, resulting in foot drop.
Sensation is preserved; reflexes are often diminished when the reflex involves weak muscles.
Respiratory dysfunction prevalence is unclear, with up to 50% of those tested in a cohort having abnormal results, though the majority of individuals have not had testing. Individuals with respiratory weakness have a restrictive pattern on pulmonary function testing with reduced forced vital capacity. Respiratory weakness is typically mild or subclinical [
Chronic pain is a common symptom in FSHD, seen in 82% of individuals, with a negative impact on quality of life. Chronic pain can occur regardless of duration of disease or age [
Retinal arterial tortuosity may be prevalent in individuals with FSHD; however, these retinal vascular changes seem subclinical and are not symptomatic (i.e., do not cause visual changes) [
Approximately 15% of individuals with FSHD have an abnormal audiogram. An abnormal audiogram was identified in up to 32% of individuals with a large pathogenic contraction of D4Z4 (D4Z4 fragments <20 kb) [
Cardiac conduction abnormalities can be seen in 5%-13% of individuals and are typically atrial arrhythmias that are mild or asymptomatic [
Scapulohumeral dystrophy onset with facial sparing
Early-onset disease (age <10 years) is associated with earlier median age of lower extremity involvement and more severe disease overall.
• Chronic pain is a common symptom in FSHD, seen in 82% of individuals, with a negative impact on quality of life. Chronic pain can occur regardless of duration of disease or age [
• Retinal arterial tortuosity may be prevalent in individuals with FSHD; however, these retinal vascular changes seem subclinical and are not symptomatic (i.e., do not cause visual changes) [
• Approximately 15% of individuals with FSHD have an abnormal audiogram. An abnormal audiogram was identified in up to 32% of individuals with a large pathogenic contraction of D4Z4 (D4Z4 fragments <20 kb) [
• Cardiac conduction abnormalities can be seen in 5%-13% of individuals and are typically atrial arrhythmias that are mild or asymptomatic [
• Scapulohumeral dystrophy onset with facial sparing
• Early-onset disease (age <10 years) is associated with earlier median age of lower extremity involvement and more severe disease overall.
## Genotype-Phenotype Correlations
Allele size explains roughly 10% of variability in phenotype [
A study of Italy's National Registry concluded that 76% of early-onset (age <10 years) disease was a result of
## Penetrance
Penetrance is increased with smaller D4Z4 repeat arrays; however, significant variation exists. In one study, penetrance of FSHD varied by age and sex; it was 83% by age 30 years, but significantly greater for males (95%) than for females (69%) [
## Anticipation
Anticipation is not reported in FSHD and repeat size remains stable throughout generations [
## Nomenclature
The term "Landouzy-Dejerine muscular dystrophy," used in the past for a syndrome similar or identical to FSHD, is no longer in use.
Persons with FSHD are sometimes included under the descriptive terms "scapulo-humeral" or "scapulo-peroneal" syndromes.
## Prevalence
The estimated prevalence of FSHD is between four and ten in 100,000.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
No phenotypes other than those discussed in this
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
## Differential Diagnosis
Genetic disorders that are similar clinically to facioscapulohumeral muscular dystrophy (FSHD) are listed in
Genetic Disorders of Interest in the Differential Diagnosis of Facioscapulohumeral Muscular Dystrophy
AD = autosomal dominant; AR = autosomal recessive; FSHD = facioscapulohumeral muscular dystrophy; MOI = mode of inheritance; MT = mitochondrial; XL = X-linked
## Management
Clinical practice guidelines for facioscapulohumeral muscular dystrophy (FSHD) have been published [
To establish the extent of disease and needs in an individual diagnosed with FSHD, the evaluations summarized in
Facioscapulohumeral Muscular Dystrophy: Recommended Evaluations Following Initial Diagnosis
Eval for hypoventilation
Screen for daytime somnolence, nonrestorative sleep
Baseline PFTs
Low threshold for pulmonary/sleep eval if abnormal PFTs or sleep symptoms
In persons w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb) or visual symptoms
For presence of retinal vasculopathy
In all affected infants & children
In adults w/symptomatic hearing loss
FSHD = facioscapulohumeral muscular dystrophy; MOI = mode of inheritance; OT = occupational therapy; PFT = pulmonary function test; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Standards of care and management of FSHD were agreed upon at the 171st ENMC International Workshop. A consensus on the following topics and the recommendations from that conference [
Facioscapulohumeral Muscular Dystrophy: Treatment of Manifestations
Establish appropriate exercise regimens (e.g., moderate weight training, aerobic training).
Identify assistive devices that may ↑ mobility & ↓ risk of falls at home.
PT
Pain medication
NSAIDs for acute pain
Antidepressants or anti-seizure medications for chronic pain
Integrative pain clinic referral
NSAID = nonsteroidal anti-inflammatory drug; OT = occupational therapy; PT = physical therapy
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Facioscapulohumeral Muscular Dystrophy: Recommended Surveillance
As needed for those w/FVC <60%, excessive daytime somnolence, or nonrestorative sleep
Before surgical procedures requiring anesthesia
Annually in those w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb)
In adults only if visual symptoms develop
At each visit in infants w/early-onset FSHD
Annually in children until starting school
In adults only if symptoms of hearing loss reported
FSHD = facioscapulohumeral muscular dystrophy; FVC = forced vital capacity; OT = occupational therapy; PCP = primary care physician; PFT = pulmonary function test; PT = physical therapy/therapist
See
Outcome of 105 pregnancies in 38 women with FSHD was generally favorable [
Genetic treatments such as siRNA treatment to silence
Search
• Eval for hypoventilation
• Screen for daytime somnolence, nonrestorative sleep
• Baseline PFTs
• Low threshold for pulmonary/sleep eval if abnormal PFTs or sleep symptoms
• In persons w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb) or visual symptoms
• For presence of retinal vasculopathy
• In all affected infants & children
• In adults w/symptomatic hearing loss
• Establish appropriate exercise regimens (e.g., moderate weight training, aerobic training).
• Identify assistive devices that may ↑ mobility & ↓ risk of falls at home.
• PT
• Pain medication
• NSAIDs for acute pain
• Antidepressants or anti-seizure medications for chronic pain
• Integrative pain clinic referral
• As needed for those w/FVC <60%, excessive daytime somnolence, or nonrestorative sleep
• Before surgical procedures requiring anesthesia
• Annually in those w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb)
• In adults only if visual symptoms develop
• At each visit in infants w/early-onset FSHD
• Annually in children until starting school
• In adults only if symptoms of hearing loss reported
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with FSHD, the evaluations summarized in
Facioscapulohumeral Muscular Dystrophy: Recommended Evaluations Following Initial Diagnosis
Eval for hypoventilation
Screen for daytime somnolence, nonrestorative sleep
Baseline PFTs
Low threshold for pulmonary/sleep eval if abnormal PFTs or sleep symptoms
In persons w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb) or visual symptoms
For presence of retinal vasculopathy
In all affected infants & children
In adults w/symptomatic hearing loss
FSHD = facioscapulohumeral muscular dystrophy; MOI = mode of inheritance; OT = occupational therapy; PFT = pulmonary function test; PT = physical therapy
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Eval for hypoventilation
• Screen for daytime somnolence, nonrestorative sleep
• Baseline PFTs
• Low threshold for pulmonary/sleep eval if abnormal PFTs or sleep symptoms
• In persons w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb) or visual symptoms
• For presence of retinal vasculopathy
• In all affected infants & children
• In adults w/symptomatic hearing loss
## Treatment of Manifestations
Standards of care and management of FSHD were agreed upon at the 171st ENMC International Workshop. A consensus on the following topics and the recommendations from that conference [
Facioscapulohumeral Muscular Dystrophy: Treatment of Manifestations
Establish appropriate exercise regimens (e.g., moderate weight training, aerobic training).
Identify assistive devices that may ↑ mobility & ↓ risk of falls at home.
PT
Pain medication
NSAIDs for acute pain
Antidepressants or anti-seizure medications for chronic pain
Integrative pain clinic referral
NSAID = nonsteroidal anti-inflammatory drug; OT = occupational therapy; PT = physical therapy
• Establish appropriate exercise regimens (e.g., moderate weight training, aerobic training).
• Identify assistive devices that may ↑ mobility & ↓ risk of falls at home.
• PT
• Pain medication
• NSAIDs for acute pain
• Antidepressants or anti-seizure medications for chronic pain
• Integrative pain clinic referral
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Facioscapulohumeral Muscular Dystrophy: Recommended Surveillance
As needed for those w/FVC <60%, excessive daytime somnolence, or nonrestorative sleep
Before surgical procedures requiring anesthesia
Annually in those w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb)
In adults only if visual symptoms develop
At each visit in infants w/early-onset FSHD
Annually in children until starting school
In adults only if symptoms of hearing loss reported
FSHD = facioscapulohumeral muscular dystrophy; FVC = forced vital capacity; OT = occupational therapy; PCP = primary care physician; PFT = pulmonary function test; PT = physical therapy/therapist
• As needed for those w/FVC <60%, excessive daytime somnolence, or nonrestorative sleep
• Before surgical procedures requiring anesthesia
• Annually in those w/large pathogenic contraction of D4Z4 (D4Z4 fragments of 10-20 kb)
• In adults only if visual symptoms develop
• At each visit in infants w/early-onset FSHD
• Annually in children until starting school
• In adults only if symptoms of hearing loss reported
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Outcome of 105 pregnancies in 38 women with FSHD was generally favorable [
## Therapies Under Investigation
Genetic treatments such as siRNA treatment to silence
Search
## Genetic Counseling
Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant disorder caused by a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype.
FSHD2 is caused by hypomethylation of a shortened (but not to the extent of FSHD1) D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype, as a result of one of the following:
A heterozygous
A heterozygous
A homozygous
An unknown cause.
Approximately 70%-90% of individuals diagnosed with FSHD1 have a parent with clinical findings of FSHD and one D4Z4 repeat array with a pathogenic contraction.
Approximately 10%-30% of probands with FSHD1 have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of a proband to evaluate their genetic status and inform recurrence risk assessment.
Note: An individual with FSHD1 may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
If a pathogenic contraction of the D4Z4 repeat array is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic contraction of the D4Z4 repeat array from an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [
The proband inherited the D4Z4 contraction from a parent with gonadal (or somatic and gonadal) mosaicism.* Gonadal mosaicism has been reported [
* If the parent is the individual in whom the pathogenic contraction first occurred, the parent may have somatic mosaicism for the contraction and may be mildly/minimally affected.
If a parent of the proband is affected and/or is known to have the pathogenic D4Z4 repeat array contraction, the risk to the sibs of inheriting the pathogenic D4Z4 repeat array contraction is 50%.
Clinical variability may be observed among family members with a pathogenic D4Z4 repeat array contraction [
Clinical manifestations in a sib who inherits a familial D4Z4 pathogenic repeat array contraction may be impacted by the age and sex of the sib and the size of the D4Z4 repeat array contraction (see
If a pathogenic D4Z4 repeat array contraction cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
If the parents have not been tested for the pathogenic D4Z4 repeat array contraction but are clinically unaffected, sibs of a proband are presumed to be at increased risk for FSHD1 because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
Each offspring of a proband who is heterozygous for a pathogenic contraction of the D4Z4 repeat array has a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction.
Each offspring of a proband who is mosaic for a pathogenic contraction of the D4Z4 repeat array has up to a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction. Offspring who inherit a D4Z4 repeat array contraction from a mosaic proband will be heterozygous for the contraction (i.e., the contraction will be constitutional rather than mosaic) and may be more severely affected than the proband [
Proband with a heterozygous pathogenic variant in
Both parents of an individual with FSHD2 may be heterozygous for an FSHD2-related genetic alteration (either a pathogenic variant in a chromatin modifier gene or a permissive chromosome 4 haplotype). A parent who is heterozygous for one FSHD2-related genetic alteration is asymptomatic and is not at risk of developing FSHD2.
Alternatively, one parent may have both FSHD2-related genetic alterations (a pathogenic variant in a chromatin modifier gene and a permissive chromosome 4 haplotype) (and may or may not be clinically affected) and the other parent may have no FSHD2-related genetic alterations.
In the one individual reported to date with FSHD2 involving homozygous nonsense variants in
Paternal inheritance was described in the one family reported to date in which the genetic etiology underlying hypomethylation of the D4Z4 repeat array was not identified [
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
Proband with a heterozygous pathogenic variant in
If each parent has one FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting FSHD2-related genetic alterations from both parents, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
If one parent is heterozygous for both FSHD2-related genetic alterations and the other parent does not have an FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting both FSHD2-related genetic alterations from one parent, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
Sibs who inherit a pathogenic variant in
Sibs who are heterozygous for one FSHD2-related genetic alteration are asymptomatic and are not at risk of developing FSHD2.
Sibs who inherit a pathogenic variant in a chromatin modifier gene and a D4Z4 repeat array of ≤10 repeat units on a permissive chromosome 4 haplotype are at risk of developing FSHD. They would have a genetic condition that is contributed by FSHD1 and FSHD2 and may be more severely affected.
Proband with homozygous nonsense variants in
Proband with hypomethylation of the D4Z4 repeat array of unknown cause: sibs are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.
Proband with a heterozygous pathogenic variant in
If the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
If the proband's reproductive partner has a permissive chromosome 4 haplotype, each child of the proband has a 37.5% chance of being affected, a 50% chance of inheriting either the permissive chromosome 4 haplotype from one or both parents OR a heterozygous pathogenic variant in
Proband with homozygous nonsense variants in
Proband with hypomethylation of the D4Z4 repeat array of unknown cause: offspring are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.
Predictive testing for at-risk relatives is possible once the FSHD-related genetic alterations been identified in an affected family member.
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
In a family with an established diagnosis of FSHD, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• A heterozygous
• A heterozygous
• A homozygous
• An unknown cause.
• Approximately 70%-90% of individuals diagnosed with FSHD1 have a parent with clinical findings of FSHD and one D4Z4 repeat array with a pathogenic contraction.
• Approximately 10%-30% of probands with FSHD1 have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of a proband to evaluate their genetic status and inform recurrence risk assessment.
• Note: An individual with FSHD1 may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
• If a pathogenic contraction of the D4Z4 repeat array is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic contraction of the D4Z4 repeat array from an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [
• The proband inherited the D4Z4 contraction from a parent with gonadal (or somatic and gonadal) mosaicism.* Gonadal mosaicism has been reported [
• * If the parent is the individual in whom the pathogenic contraction first occurred, the parent may have somatic mosaicism for the contraction and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic contraction of the D4Z4 repeat array from an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [
• The proband inherited the D4Z4 contraction from a parent with gonadal (or somatic and gonadal) mosaicism.* Gonadal mosaicism has been reported [
• * If the parent is the individual in whom the pathogenic contraction first occurred, the parent may have somatic mosaicism for the contraction and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic contraction of the D4Z4 repeat array from an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [
• The proband inherited the D4Z4 contraction from a parent with gonadal (or somatic and gonadal) mosaicism.* Gonadal mosaicism has been reported [
• * If the parent is the individual in whom the pathogenic contraction first occurred, the parent may have somatic mosaicism for the contraction and may be mildly/minimally affected.
• If a parent of the proband is affected and/or is known to have the pathogenic D4Z4 repeat array contraction, the risk to the sibs of inheriting the pathogenic D4Z4 repeat array contraction is 50%.
• Clinical variability may be observed among family members with a pathogenic D4Z4 repeat array contraction [
• Clinical manifestations in a sib who inherits a familial D4Z4 pathogenic repeat array contraction may be impacted by the age and sex of the sib and the size of the D4Z4 repeat array contraction (see
• Clinical variability may be observed among family members with a pathogenic D4Z4 repeat array contraction [
• Clinical manifestations in a sib who inherits a familial D4Z4 pathogenic repeat array contraction may be impacted by the age and sex of the sib and the size of the D4Z4 repeat array contraction (see
• If a pathogenic D4Z4 repeat array contraction cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
• If the parents have not been tested for the pathogenic D4Z4 repeat array contraction but are clinically unaffected, sibs of a proband are presumed to be at increased risk for FSHD1 because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
• Clinical variability may be observed among family members with a pathogenic D4Z4 repeat array contraction [
• Clinical manifestations in a sib who inherits a familial D4Z4 pathogenic repeat array contraction may be impacted by the age and sex of the sib and the size of the D4Z4 repeat array contraction (see
• Each offspring of a proband who is heterozygous for a pathogenic contraction of the D4Z4 repeat array has a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction.
• Each offspring of a proband who is mosaic for a pathogenic contraction of the D4Z4 repeat array has up to a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction. Offspring who inherit a D4Z4 repeat array contraction from a mosaic proband will be heterozygous for the contraction (i.e., the contraction will be constitutional rather than mosaic) and may be more severely affected than the proband [
• Proband with a heterozygous pathogenic variant in
• Both parents of an individual with FSHD2 may be heterozygous for an FSHD2-related genetic alteration (either a pathogenic variant in a chromatin modifier gene or a permissive chromosome 4 haplotype). A parent who is heterozygous for one FSHD2-related genetic alteration is asymptomatic and is not at risk of developing FSHD2.
• Alternatively, one parent may have both FSHD2-related genetic alterations (a pathogenic variant in a chromatin modifier gene and a permissive chromosome 4 haplotype) (and may or may not be clinically affected) and the other parent may have no FSHD2-related genetic alterations.
• Both parents of an individual with FSHD2 may be heterozygous for an FSHD2-related genetic alteration (either a pathogenic variant in a chromatin modifier gene or a permissive chromosome 4 haplotype). A parent who is heterozygous for one FSHD2-related genetic alteration is asymptomatic and is not at risk of developing FSHD2.
• Alternatively, one parent may have both FSHD2-related genetic alterations (a pathogenic variant in a chromatin modifier gene and a permissive chromosome 4 haplotype) (and may or may not be clinically affected) and the other parent may have no FSHD2-related genetic alterations.
• In the one individual reported to date with FSHD2 involving homozygous nonsense variants in
• Paternal inheritance was described in the one family reported to date in which the genetic etiology underlying hypomethylation of the D4Z4 repeat array was not identified [
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• Both parents of an individual with FSHD2 may be heterozygous for an FSHD2-related genetic alteration (either a pathogenic variant in a chromatin modifier gene or a permissive chromosome 4 haplotype). A parent who is heterozygous for one FSHD2-related genetic alteration is asymptomatic and is not at risk of developing FSHD2.
• Alternatively, one parent may have both FSHD2-related genetic alterations (a pathogenic variant in a chromatin modifier gene and a permissive chromosome 4 haplotype) (and may or may not be clinically affected) and the other parent may have no FSHD2-related genetic alterations.
• Proband with a heterozygous pathogenic variant in
• If each parent has one FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting FSHD2-related genetic alterations from both parents, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If one parent is heterozygous for both FSHD2-related genetic alterations and the other parent does not have an FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting both FSHD2-related genetic alterations from one parent, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• Sibs who inherit a pathogenic variant in
• Sibs who are heterozygous for one FSHD2-related genetic alteration are asymptomatic and are not at risk of developing FSHD2.
• Sibs who inherit a pathogenic variant in a chromatin modifier gene and a D4Z4 repeat array of ≤10 repeat units on a permissive chromosome 4 haplotype are at risk of developing FSHD. They would have a genetic condition that is contributed by FSHD1 and FSHD2 and may be more severely affected.
• If each parent has one FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting FSHD2-related genetic alterations from both parents, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If one parent is heterozygous for both FSHD2-related genetic alterations and the other parent does not have an FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting both FSHD2-related genetic alterations from one parent, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• Sibs who inherit a pathogenic variant in
• Sibs who are heterozygous for one FSHD2-related genetic alteration are asymptomatic and are not at risk of developing FSHD2.
• Sibs who inherit a pathogenic variant in a chromatin modifier gene and a D4Z4 repeat array of ≤10 repeat units on a permissive chromosome 4 haplotype are at risk of developing FSHD. They would have a genetic condition that is contributed by FSHD1 and FSHD2 and may be more severely affected.
• Proband with homozygous nonsense variants in
• Proband with hypomethylation of the D4Z4 repeat array of unknown cause: sibs are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.
• If each parent has one FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting FSHD2-related genetic alterations from both parents, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If one parent is heterozygous for both FSHD2-related genetic alterations and the other parent does not have an FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting both FSHD2-related genetic alterations from one parent, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• Sibs who inherit a pathogenic variant in
• Sibs who are heterozygous for one FSHD2-related genetic alteration are asymptomatic and are not at risk of developing FSHD2.
• Sibs who inherit a pathogenic variant in a chromatin modifier gene and a D4Z4 repeat array of ≤10 repeat units on a permissive chromosome 4 haplotype are at risk of developing FSHD. They would have a genetic condition that is contributed by FSHD1 and FSHD2 and may be more severely affected.
• Proband with a heterozygous pathogenic variant in
• If the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If the proband's reproductive partner has a permissive chromosome 4 haplotype, each child of the proband has a 37.5% chance of being affected, a 50% chance of inheriting either the permissive chromosome 4 haplotype from one or both parents OR a heterozygous pathogenic variant in
• If the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If the proband's reproductive partner has a permissive chromosome 4 haplotype, each child of the proband has a 37.5% chance of being affected, a 50% chance of inheriting either the permissive chromosome 4 haplotype from one or both parents OR a heterozygous pathogenic variant in
• Proband with homozygous nonsense variants in
• Proband with hypomethylation of the D4Z4 repeat array of unknown cause: offspring are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.
• If the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If the proband's reproductive partner has a permissive chromosome 4 haplotype, each child of the proband has a 37.5% chance of being affected, a 50% chance of inheriting either the permissive chromosome 4 haplotype from one or both parents OR a heterozygous pathogenic variant in
• Predictive testing for at-risk relatives is possible once the FSHD-related genetic alterations been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant disorder caused by a heterozygous pathogenic contraction of the D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype.
FSHD2 is caused by hypomethylation of a shortened (but not to the extent of FSHD1) D4Z4 repeat array in the subtelomeric region of chromosome 4q35 on a permissive chromosome 4 haplotype, as a result of one of the following:
A heterozygous
A heterozygous
A homozygous
An unknown cause.
• A heterozygous
• A heterozygous
• A homozygous
• An unknown cause.
## Autosomal Dominant Inheritance (FSHD1) – Risk to Family Members
Approximately 70%-90% of individuals diagnosed with FSHD1 have a parent with clinical findings of FSHD and one D4Z4 repeat array with a pathogenic contraction.
Approximately 10%-30% of probands with FSHD1 have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of a proband to evaluate their genetic status and inform recurrence risk assessment.
Note: An individual with FSHD1 may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
If a pathogenic contraction of the D4Z4 repeat array is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic contraction of the D4Z4 repeat array from an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [
The proband inherited the D4Z4 contraction from a parent with gonadal (or somatic and gonadal) mosaicism.* Gonadal mosaicism has been reported [
* If the parent is the individual in whom the pathogenic contraction first occurred, the parent may have somatic mosaicism for the contraction and may be mildly/minimally affected.
If a parent of the proband is affected and/or is known to have the pathogenic D4Z4 repeat array contraction, the risk to the sibs of inheriting the pathogenic D4Z4 repeat array contraction is 50%.
Clinical variability may be observed among family members with a pathogenic D4Z4 repeat array contraction [
Clinical manifestations in a sib who inherits a familial D4Z4 pathogenic repeat array contraction may be impacted by the age and sex of the sib and the size of the D4Z4 repeat array contraction (see
If a pathogenic D4Z4 repeat array contraction cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
If the parents have not been tested for the pathogenic D4Z4 repeat array contraction but are clinically unaffected, sibs of a proband are presumed to be at increased risk for FSHD1 because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
Each offspring of a proband who is heterozygous for a pathogenic contraction of the D4Z4 repeat array has a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction.
Each offspring of a proband who is mosaic for a pathogenic contraction of the D4Z4 repeat array has up to a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction. Offspring who inherit a D4Z4 repeat array contraction from a mosaic proband will be heterozygous for the contraction (i.e., the contraction will be constitutional rather than mosaic) and may be more severely affected than the proband [
• Approximately 70%-90% of individuals diagnosed with FSHD1 have a parent with clinical findings of FSHD and one D4Z4 repeat array with a pathogenic contraction.
• Approximately 10%-30% of probands with FSHD1 have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of a proband to evaluate their genetic status and inform recurrence risk assessment.
• Note: An individual with FSHD1 may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
• If a pathogenic contraction of the D4Z4 repeat array is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic contraction of the D4Z4 repeat array from an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [
• The proband inherited the D4Z4 contraction from a parent with gonadal (or somatic and gonadal) mosaicism.* Gonadal mosaicism has been reported [
• * If the parent is the individual in whom the pathogenic contraction first occurred, the parent may have somatic mosaicism for the contraction and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic contraction of the D4Z4 repeat array from an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [
• The proband inherited the D4Z4 contraction from a parent with gonadal (or somatic and gonadal) mosaicism.* Gonadal mosaicism has been reported [
• * If the parent is the individual in whom the pathogenic contraction first occurred, the parent may have somatic mosaicism for the contraction and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic contraction of the D4Z4 repeat array from an asymptomatic parent who has a deletion of the region subtelomeric to the D4Z4 locus where the probe hybridizes (and is therefore probe negative) [
• The proband inherited the D4Z4 contraction from a parent with gonadal (or somatic and gonadal) mosaicism.* Gonadal mosaicism has been reported [
• * If the parent is the individual in whom the pathogenic contraction first occurred, the parent may have somatic mosaicism for the contraction and may be mildly/minimally affected.
• If a parent of the proband is affected and/or is known to have the pathogenic D4Z4 repeat array contraction, the risk to the sibs of inheriting the pathogenic D4Z4 repeat array contraction is 50%.
• Clinical variability may be observed among family members with a pathogenic D4Z4 repeat array contraction [
• Clinical manifestations in a sib who inherits a familial D4Z4 pathogenic repeat array contraction may be impacted by the age and sex of the sib and the size of the D4Z4 repeat array contraction (see
• Clinical variability may be observed among family members with a pathogenic D4Z4 repeat array contraction [
• Clinical manifestations in a sib who inherits a familial D4Z4 pathogenic repeat array contraction may be impacted by the age and sex of the sib and the size of the D4Z4 repeat array contraction (see
• If a pathogenic D4Z4 repeat array contraction cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
• If the parents have not been tested for the pathogenic D4Z4 repeat array contraction but are clinically unaffected, sibs of a proband are presumed to be at increased risk for FSHD1 because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
• Clinical variability may be observed among family members with a pathogenic D4Z4 repeat array contraction [
• Clinical manifestations in a sib who inherits a familial D4Z4 pathogenic repeat array contraction may be impacted by the age and sex of the sib and the size of the D4Z4 repeat array contraction (see
• Each offspring of a proband who is heterozygous for a pathogenic contraction of the D4Z4 repeat array has a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction.
• Each offspring of a proband who is mosaic for a pathogenic contraction of the D4Z4 repeat array has up to a 50% chance of inheriting the pathogenic D4Z4 repeat array contraction. Offspring who inherit a D4Z4 repeat array contraction from a mosaic proband will be heterozygous for the contraction (i.e., the contraction will be constitutional rather than mosaic) and may be more severely affected than the proband [
## Complex Inheritance (FSHD2) – Risk to Family Members
Proband with a heterozygous pathogenic variant in
Both parents of an individual with FSHD2 may be heterozygous for an FSHD2-related genetic alteration (either a pathogenic variant in a chromatin modifier gene or a permissive chromosome 4 haplotype). A parent who is heterozygous for one FSHD2-related genetic alteration is asymptomatic and is not at risk of developing FSHD2.
Alternatively, one parent may have both FSHD2-related genetic alterations (a pathogenic variant in a chromatin modifier gene and a permissive chromosome 4 haplotype) (and may or may not be clinically affected) and the other parent may have no FSHD2-related genetic alterations.
In the one individual reported to date with FSHD2 involving homozygous nonsense variants in
Paternal inheritance was described in the one family reported to date in which the genetic etiology underlying hypomethylation of the D4Z4 repeat array was not identified [
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
Proband with a heterozygous pathogenic variant in
If each parent has one FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting FSHD2-related genetic alterations from both parents, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
If one parent is heterozygous for both FSHD2-related genetic alterations and the other parent does not have an FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting both FSHD2-related genetic alterations from one parent, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
Sibs who inherit a pathogenic variant in
Sibs who are heterozygous for one FSHD2-related genetic alteration are asymptomatic and are not at risk of developing FSHD2.
Sibs who inherit a pathogenic variant in a chromatin modifier gene and a D4Z4 repeat array of ≤10 repeat units on a permissive chromosome 4 haplotype are at risk of developing FSHD. They would have a genetic condition that is contributed by FSHD1 and FSHD2 and may be more severely affected.
Proband with homozygous nonsense variants in
Proband with hypomethylation of the D4Z4 repeat array of unknown cause: sibs are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.
Proband with a heterozygous pathogenic variant in
If the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
If the proband's reproductive partner has a permissive chromosome 4 haplotype, each child of the proband has a 37.5% chance of being affected, a 50% chance of inheriting either the permissive chromosome 4 haplotype from one or both parents OR a heterozygous pathogenic variant in
Proband with homozygous nonsense variants in
Proband with hypomethylation of the D4Z4 repeat array of unknown cause: offspring are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.
• Proband with a heterozygous pathogenic variant in
• Both parents of an individual with FSHD2 may be heterozygous for an FSHD2-related genetic alteration (either a pathogenic variant in a chromatin modifier gene or a permissive chromosome 4 haplotype). A parent who is heterozygous for one FSHD2-related genetic alteration is asymptomatic and is not at risk of developing FSHD2.
• Alternatively, one parent may have both FSHD2-related genetic alterations (a pathogenic variant in a chromatin modifier gene and a permissive chromosome 4 haplotype) (and may or may not be clinically affected) and the other parent may have no FSHD2-related genetic alterations.
• Both parents of an individual with FSHD2 may be heterozygous for an FSHD2-related genetic alteration (either a pathogenic variant in a chromatin modifier gene or a permissive chromosome 4 haplotype). A parent who is heterozygous for one FSHD2-related genetic alteration is asymptomatic and is not at risk of developing FSHD2.
• Alternatively, one parent may have both FSHD2-related genetic alterations (a pathogenic variant in a chromatin modifier gene and a permissive chromosome 4 haplotype) (and may or may not be clinically affected) and the other parent may have no FSHD2-related genetic alterations.
• In the one individual reported to date with FSHD2 involving homozygous nonsense variants in
• Paternal inheritance was described in the one family reported to date in which the genetic etiology underlying hypomethylation of the D4Z4 repeat array was not identified [
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• Both parents of an individual with FSHD2 may be heterozygous for an FSHD2-related genetic alteration (either a pathogenic variant in a chromatin modifier gene or a permissive chromosome 4 haplotype). A parent who is heterozygous for one FSHD2-related genetic alteration is asymptomatic and is not at risk of developing FSHD2.
• Alternatively, one parent may have both FSHD2-related genetic alterations (a pathogenic variant in a chromatin modifier gene and a permissive chromosome 4 haplotype) (and may or may not be clinically affected) and the other parent may have no FSHD2-related genetic alterations.
• Proband with a heterozygous pathogenic variant in
• If each parent has one FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting FSHD2-related genetic alterations from both parents, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If one parent is heterozygous for both FSHD2-related genetic alterations and the other parent does not have an FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting both FSHD2-related genetic alterations from one parent, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• Sibs who inherit a pathogenic variant in
• Sibs who are heterozygous for one FSHD2-related genetic alteration are asymptomatic and are not at risk of developing FSHD2.
• Sibs who inherit a pathogenic variant in a chromatin modifier gene and a D4Z4 repeat array of ≤10 repeat units on a permissive chromosome 4 haplotype are at risk of developing FSHD. They would have a genetic condition that is contributed by FSHD1 and FSHD2 and may be more severely affected.
• If each parent has one FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting FSHD2-related genetic alterations from both parents, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If one parent is heterozygous for both FSHD2-related genetic alterations and the other parent does not have an FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting both FSHD2-related genetic alterations from one parent, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• Sibs who inherit a pathogenic variant in
• Sibs who are heterozygous for one FSHD2-related genetic alteration are asymptomatic and are not at risk of developing FSHD2.
• Sibs who inherit a pathogenic variant in a chromatin modifier gene and a D4Z4 repeat array of ≤10 repeat units on a permissive chromosome 4 haplotype are at risk of developing FSHD. They would have a genetic condition that is contributed by FSHD1 and FSHD2 and may be more severely affected.
• Proband with homozygous nonsense variants in
• Proband with hypomethylation of the D4Z4 repeat array of unknown cause: sibs are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.
• If each parent has one FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting FSHD2-related genetic alterations from both parents, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If one parent is heterozygous for both FSHD2-related genetic alterations and the other parent does not have an FSHD2-related genetic alteration, each sib has at conception a 25% chance of inheriting both FSHD2-related genetic alterations from one parent, a 50% chance of inheriting one FSHD2-related genetic alteration, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• Sibs who inherit a pathogenic variant in
• Sibs who are heterozygous for one FSHD2-related genetic alteration are asymptomatic and are not at risk of developing FSHD2.
• Sibs who inherit a pathogenic variant in a chromatin modifier gene and a D4Z4 repeat array of ≤10 repeat units on a permissive chromosome 4 haplotype are at risk of developing FSHD. They would have a genetic condition that is contributed by FSHD1 and FSHD2 and may be more severely affected.
• Proband with a heterozygous pathogenic variant in
• If the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If the proband's reproductive partner has a permissive chromosome 4 haplotype, each child of the proband has a 37.5% chance of being affected, a 50% chance of inheriting either the permissive chromosome 4 haplotype from one or both parents OR a heterozygous pathogenic variant in
• If the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If the proband's reproductive partner has a permissive chromosome 4 haplotype, each child of the proband has a 37.5% chance of being affected, a 50% chance of inheriting either the permissive chromosome 4 haplotype from one or both parents OR a heterozygous pathogenic variant in
• Proband with homozygous nonsense variants in
• Proband with hypomethylation of the D4Z4 repeat array of unknown cause: offspring are presumed to be at risk of inheriting FSHD2-related genetic alterations and being affected with FSHD2.
• If the proband's reproductive partner is not affected and not heterozygous for an FSHD2-related genetic alteration, each child of the proband has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote, and a 25% chance of inheriting neither of the FSHD2-related genetic alterations.
• If the proband's reproductive partner has a permissive chromosome 4 haplotype, each child of the proband has a 37.5% chance of being affected, a 50% chance of inheriting either the permissive chromosome 4 haplotype from one or both parents OR a heterozygous pathogenic variant in
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once the FSHD-related genetic alterations been identified in an affected family member.
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
In a family with an established diagnosis of FSHD, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once the FSHD-related genetic alterations been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Australia
Japan
Canada
•
•
•
• Australia
•
•
•
•
•
•
• Japan
•
•
• Canada
•
•
•
## Molecular Genetics
Facioscapulohumeral Muscular Dystrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Facioscapulohumeral Muscular Dystrophy (
Facioscapulohumeral muscular dystrophy (FSHD) results from expression of a gene that is not typically expressed in somatic tissue. This happens because of an opening of the chromatin structure either as a result of loss of D4Z4 copy number repeats or hypomethylation of D4Z4 due to a heterozygous pathogenic variant in
Each 3.3-kb D4Z4 repeat unit has an open reading frame (named
Chromosome variants 4A and 4B (sometimes referred to as 4qA and 4qB) are almost equally common in the population and can be further divided into at least nine distinct haplotypes [
4A161 is the most common 4A permissive haplotype.
4A159, 4A163, 4A166H, and 4A168 are less common permissive haplotypes.
Contraction of the D4Z4 allele on 4A166, a less common 4A haplotype found in two Dutch families, is not associated with FSHD.
Contraction of the D4Z4 allele on 4B haplotypes is non-pathogenic.
In FSHD2, chromatin relaxation results from a heterozygous pathogenic variant in
• 4A161 is the most common 4A permissive haplotype.
• 4A159, 4A163, 4A166H, and 4A168 are less common permissive haplotypes.
• Contraction of the D4Z4 allele on 4A166, a less common 4A haplotype found in two Dutch families, is not associated with FSHD.
• Contraction of the D4Z4 allele on 4B haplotypes is non-pathogenic.
## Molecular Pathogenesis
Facioscapulohumeral muscular dystrophy (FSHD) results from expression of a gene that is not typically expressed in somatic tissue. This happens because of an opening of the chromatin structure either as a result of loss of D4Z4 copy number repeats or hypomethylation of D4Z4 due to a heterozygous pathogenic variant in
Each 3.3-kb D4Z4 repeat unit has an open reading frame (named
Chromosome variants 4A and 4B (sometimes referred to as 4qA and 4qB) are almost equally common in the population and can be further divided into at least nine distinct haplotypes [
4A161 is the most common 4A permissive haplotype.
4A159, 4A163, 4A166H, and 4A168 are less common permissive haplotypes.
Contraction of the D4Z4 allele on 4A166, a less common 4A haplotype found in two Dutch families, is not associated with FSHD.
Contraction of the D4Z4 allele on 4B haplotypes is non-pathogenic.
In FSHD2, chromatin relaxation results from a heterozygous pathogenic variant in
• 4A161 is the most common 4A permissive haplotype.
• 4A159, 4A163, 4A166H, and 4A168 are less common permissive haplotypes.
• Contraction of the D4Z4 allele on 4A166, a less common 4A haplotype found in two Dutch families, is not associated with FSHD.
• Contraction of the D4Z4 allele on 4B haplotypes is non-pathogenic.
## Chapter Notes
The authors would like to acknowledge the authors of the prior versions of this chapter (see
Denise A Figlewicz, PhD; University of Michigan Medical School (1998-2009)Richard JLF Lemmers, PhD; Leiden University Medical Center (2009-2020)Daniel G Miller, MD, PhD; University of Washington (2012-2020)Matthew K Preston, MD (2020-present)Rabi Tawil, MD (1998-2009; 2020-2025)Silvere M van der Maarel, MD; Leiden University Medical Center (2009-2020)Leo H Wang, MD, PhD (2020-present)
10 July 2025 (sw) Comprehensive update posted live
6 February 2020 (sw) Comprehensive update posted live
21 June 2012 (me) Comprehensive update posted live
9 July 2009 (me) Comprehensive update posted live
17 March 2005 (me) Comprehensive update posted live
18 March 2003 (me) Comprehensive update posted live
8 March 1999 (pb) Review posted live
10 July 1998 (df) Original submission
• 10 July 2025 (sw) Comprehensive update posted live
• 6 February 2020 (sw) Comprehensive update posted live
• 21 June 2012 (me) Comprehensive update posted live
• 9 July 2009 (me) Comprehensive update posted live
• 17 March 2005 (me) Comprehensive update posted live
• 18 March 2003 (me) Comprehensive update posted live
• 8 March 1999 (pb) Review posted live
• 10 July 1998 (df) Original submission
## Acknowledgments
The authors would like to acknowledge the authors of the prior versions of this chapter (see
## Author History
Denise A Figlewicz, PhD; University of Michigan Medical School (1998-2009)Richard JLF Lemmers, PhD; Leiden University Medical Center (2009-2020)Daniel G Miller, MD, PhD; University of Washington (2012-2020)Matthew K Preston, MD (2020-present)Rabi Tawil, MD (1998-2009; 2020-2025)Silvere M van der Maarel, MD; Leiden University Medical Center (2009-2020)Leo H Wang, MD, PhD (2020-present)
## Revision History
10 July 2025 (sw) Comprehensive update posted live
6 February 2020 (sw) Comprehensive update posted live
21 June 2012 (me) Comprehensive update posted live
9 July 2009 (me) Comprehensive update posted live
17 March 2005 (me) Comprehensive update posted live
18 March 2003 (me) Comprehensive update posted live
8 March 1999 (pb) Review posted live
10 July 1998 (df) Original submission
• 10 July 2025 (sw) Comprehensive update posted live
• 6 February 2020 (sw) Comprehensive update posted live
• 21 June 2012 (me) Comprehensive update posted live
• 9 July 2009 (me) Comprehensive update posted live
• 17 March 2005 (me) Comprehensive update posted live
• 18 March 2003 (me) Comprehensive update posted live
• 8 March 1999 (pb) Review posted live
• 10 July 1998 (df) Original submission
## References
Giardina E, Camaño P, Burton-Jones S, Ravenscroft G, Henning F, Magdinier F, van der Stoep N, van der Vliet PJ, Bernard R, Tomaselli PJ, Davis MR, Nishino I, Oflazer P, Race V, Vishnu VY, Williams V, Sobreira CFR, van der Maarel SM, Moore SA, Voermans NC, Lemmers RJLF. Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines. Clin Genet. 2024;106:13-26.
Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy. Neurology. 2015;85:357–64.
• Giardina E, Camaño P, Burton-Jones S, Ravenscroft G, Henning F, Magdinier F, van der Stoep N, van der Vliet PJ, Bernard R, Tomaselli PJ, Davis MR, Nishino I, Oflazer P, Race V, Vishnu VY, Williams V, Sobreira CFR, van der Maarel SM, Moore SA, Voermans NC, Lemmers RJLF. Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines. Clin Genet. 2024;106:13-26.
• Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy. Neurology. 2015;85:357–64.
## Published Guidelines / Consensus Statements
Giardina E, Camaño P, Burton-Jones S, Ravenscroft G, Henning F, Magdinier F, van der Stoep N, van der Vliet PJ, Bernard R, Tomaselli PJ, Davis MR, Nishino I, Oflazer P, Race V, Vishnu VY, Williams V, Sobreira CFR, van der Maarel SM, Moore SA, Voermans NC, Lemmers RJLF. Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines. Clin Genet. 2024;106:13-26.
Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy. Neurology. 2015;85:357–64.
• Giardina E, Camaño P, Burton-Jones S, Ravenscroft G, Henning F, Magdinier F, van der Stoep N, van der Vliet PJ, Bernard R, Tomaselli PJ, Davis MR, Nishino I, Oflazer P, Race V, Vishnu VY, Williams V, Sobreira CFR, van der Maarel SM, Moore SA, Voermans NC, Lemmers RJLF. Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines. Clin Genet. 2024;106:13-26.
• Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy. Neurology. 2015;85:357–64.
## Literature Cited
Schematic comparison of the structure of the normal D4Z4 allele and the pathogenic contracted D4Z4 allele that causes FSHD1. The normal D4Z4 allele has between 11 and 100 units of the 3.3-kb repeat sequence (depicted by triangles), whereas the pathogenic contracted FSHD1-causing D4Z4 allele has a contracted D4Z4 repeat array of between one and ten units on a permissive chromosome 4 haplotype (e.g., 4A161, 4A159, 4A168, 4A166H).
|
[] |
8/3/1999
|
10/7/2025
|
20/3/2014
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
ftd-chmp2b
|
ftd-chmp2b
|
[
"CHMP2B-FTD",
"Chromosome 3-Linked Frontotemporal Dementia",
"FTD-3",
"FTD-3",
"CHMP2B-FTD",
"Chromosome 3-Linked Frontotemporal Dementia",
"Charged multivesicular body protein 2b",
"CHMP2B",
"CHMP2B Frontotemporal Dementia"
] |
Peter Roos, Ida E Holm, Jørgen E Nielsen, Troels T Nielsen, Jeremy M Brown, Peter Johannsen, Adrian M Isaacs
|
Summary The diagnosis of
|
## Diagnosis
Frontotemporal dementia
A neuropsychological profile of a dysexecutive syndrome, behavioral changes, lack of emotional recognition, and dyscalculia
Generalized atrophy on neuroimaging:
Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical and central atrophy and ventricular enlargement [
Cerebral blood flow-positron emission tomography (CBF-PET) shows a global reduction in cortical CBF with sparing of the visual cortex and basal ganglia [
CBF-MRI shows a decreased CBF in occipital and parietal lobes in presymptomatic
Fluorodeoxyglucose (FDG)-PET shows globalized hypometabolism [
Family history of frontotemporal dementia in two or more first-degree relatives consistent with an autosomal dominant mode of inheritance
Neuropathology showing p62-positive, ubiquitin-positive, TDP-43-negative, and FUS-negative cytoplasmic intraneuronal inclusions in the hippocampal dentate granule cells and in neurons in the frontal and temporal cortex [
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and imaging findings suggest the diagnosis of
Note: Targeted analysis for
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by frontotemporal dementia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
The
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
C-terminal truncations of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Frontotemporal dementia
• A neuropsychological profile of a dysexecutive syndrome, behavioral changes, lack of emotional recognition, and dyscalculia
• Generalized atrophy on neuroimaging:
• Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical and central atrophy and ventricular enlargement [
• Cerebral blood flow-positron emission tomography (CBF-PET) shows a global reduction in cortical CBF with sparing of the visual cortex and basal ganglia [
• CBF-MRI shows a decreased CBF in occipital and parietal lobes in presymptomatic
• Fluorodeoxyglucose (FDG)-PET shows globalized hypometabolism [
• Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical and central atrophy and ventricular enlargement [
• Cerebral blood flow-positron emission tomography (CBF-PET) shows a global reduction in cortical CBF with sparing of the visual cortex and basal ganglia [
• CBF-MRI shows a decreased CBF in occipital and parietal lobes in presymptomatic
• Fluorodeoxyglucose (FDG)-PET shows globalized hypometabolism [
• Family history of frontotemporal dementia in two or more first-degree relatives consistent with an autosomal dominant mode of inheritance
• Neuropathology showing p62-positive, ubiquitin-positive, TDP-43-negative, and FUS-negative cytoplasmic intraneuronal inclusions in the hippocampal dentate granule cells and in neurons in the frontal and temporal cortex [
• Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical and central atrophy and ventricular enlargement [
• Cerebral blood flow-positron emission tomography (CBF-PET) shows a global reduction in cortical CBF with sparing of the visual cortex and basal ganglia [
• CBF-MRI shows a decreased CBF in occipital and parietal lobes in presymptomatic
• Fluorodeoxyglucose (FDG)-PET shows globalized hypometabolism [
• Note: Targeted analysis for
• For an introduction to multigene panels click
## Suggestive Findings
Frontotemporal dementia
A neuropsychological profile of a dysexecutive syndrome, behavioral changes, lack of emotional recognition, and dyscalculia
Generalized atrophy on neuroimaging:
Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical and central atrophy and ventricular enlargement [
Cerebral blood flow-positron emission tomography (CBF-PET) shows a global reduction in cortical CBF with sparing of the visual cortex and basal ganglia [
CBF-MRI shows a decreased CBF in occipital and parietal lobes in presymptomatic
Fluorodeoxyglucose (FDG)-PET shows globalized hypometabolism [
Family history of frontotemporal dementia in two or more first-degree relatives consistent with an autosomal dominant mode of inheritance
Neuropathology showing p62-positive, ubiquitin-positive, TDP-43-negative, and FUS-negative cytoplasmic intraneuronal inclusions in the hippocampal dentate granule cells and in neurons in the frontal and temporal cortex [
• Frontotemporal dementia
• A neuropsychological profile of a dysexecutive syndrome, behavioral changes, lack of emotional recognition, and dyscalculia
• Generalized atrophy on neuroimaging:
• Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical and central atrophy and ventricular enlargement [
• Cerebral blood flow-positron emission tomography (CBF-PET) shows a global reduction in cortical CBF with sparing of the visual cortex and basal ganglia [
• CBF-MRI shows a decreased CBF in occipital and parietal lobes in presymptomatic
• Fluorodeoxyglucose (FDG)-PET shows globalized hypometabolism [
• Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical and central atrophy and ventricular enlargement [
• Cerebral blood flow-positron emission tomography (CBF-PET) shows a global reduction in cortical CBF with sparing of the visual cortex and basal ganglia [
• CBF-MRI shows a decreased CBF in occipital and parietal lobes in presymptomatic
• Fluorodeoxyglucose (FDG)-PET shows globalized hypometabolism [
• Family history of frontotemporal dementia in two or more first-degree relatives consistent with an autosomal dominant mode of inheritance
• Neuropathology showing p62-positive, ubiquitin-positive, TDP-43-negative, and FUS-negative cytoplasmic intraneuronal inclusions in the hippocampal dentate granule cells and in neurons in the frontal and temporal cortex [
• Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical and central atrophy and ventricular enlargement [
• Cerebral blood flow-positron emission tomography (CBF-PET) shows a global reduction in cortical CBF with sparing of the visual cortex and basal ganglia [
• CBF-MRI shows a decreased CBF in occipital and parietal lobes in presymptomatic
• Fluorodeoxyglucose (FDG)-PET shows globalized hypometabolism [
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and imaging findings suggest the diagnosis of
Note: Targeted analysis for
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by frontotemporal dementia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
The
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
C-terminal truncations of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Note: Targeted analysis for
• For an introduction to multigene panels click
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of
Note: Targeted analysis for
For an introduction to multigene panels click
• Note: Targeted analysis for
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by frontotemporal dementia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
The
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
C-terminal truncations of
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
To date,
Symptoms usually start between ages 46 and 70 years, with an average age of onset of 57 years. Disease duration is from three to more than 20 years. The disease progresses over a few years into profound dementia with mutism [
Microscopic analysis reveals neuronal loss, gliosis, and spongiosis in the superficial cortical layers.
Immunohistochemical analysis shows pathologic accumulation of p62-positive, ubiquitin-positive, TDP-43-negative, and FUS-negative cytoplasmic inclusions in the hippocampal dentate granule cells and in a few cortical neurons [
No genotype-phenotype correlations have been identified.
Penetrance is age dependent and appears to be nearly complete in the Danish family.
Following identification of a causative pathogenic variant in
## Clinical Description
To date,
Symptoms usually start between ages 46 and 70 years, with an average age of onset of 57 years. Disease duration is from three to more than 20 years. The disease progresses over a few years into profound dementia with mutism [
Microscopic analysis reveals neuronal loss, gliosis, and spongiosis in the superficial cortical layers.
Immunohistochemical analysis shows pathologic accumulation of p62-positive, ubiquitin-positive, TDP-43-negative, and FUS-negative cytoplasmic inclusions in the hippocampal dentate granule cells and in a few cortical neurons [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Penetrance is age dependent and appears to be nearly complete in the Danish family.
## Nomenclature
Following identification of a causative pathogenic variant in
## Prevalence
## Genetically Related (Allelic) Disorders
In an English cohort, three different
In a Dutch cohort, four novel
A rare
## Differential Diagnosis
Pathogenic variants in
Pathogenic variants in
Genes of Interest in the Differential Diagnosis of
Mild behavioral changes
Prominent memory disturbance
Loss of initiative
Word-finding problems
May not be clinically distinguishable
Psychotic symptoms more common in
Familial ALS w/o FTD
Onset before 5th decade
Incomplete penetrance
Dementia
Extrapyramidal signs (rigidity, bradykinesia)
REM sleep disorders
Visual hallucinations
DaT scans abnormal
Adult-onset behavioral-variant FTD
Generally affects frontal & temporal cortex, → behavioral changes, executive dysfunction, & language disturbances
Parietal cortex & basal ganglia may be affected as well, resulting in parkinsonism, cortical basal syndrome, & memory impairment
Age of onset: 48-83 yrs
Clinically indistinguishable
Metabolic changes (on FDG-PET) preceding structural changes of frontal atrophy (on MRI)
Changes in personality (apathy or depression)
Cognitive decline
Dementia
Dystonia
Chorea
Delusions
Visual hallucinations
Adult-onset behavioral variant FTD
Extrapyramidal signs (rigidity, bradykinesia, supranuclear palsy, & saccadic eye movement disorders)
Symptoms usually start at ages 40-60 yrs but may occur earlier or later.
Disease progresses over few yrs to profound dementia w/mutism.
Clinically indistinguishable
Onset before 5th decade
Metabolic changes (on FDG-PET) preceding structural changes of frontal atrophy (on MRI)
Adult-onset behavioral variant FTD
Generalized cerebral atrophy on MRI
Early bulbar symptoms
Onset before 5th decade
Adult-onset behavioral variant FTD
Disinhibition as presenting symptom
Generalized cerebral atrophy on MRI
Extrapyramidal features at later stage of disease
Memory loss at early stage of disease
Incomplete penetrance
MND w/FTD
Choreic movements
Familial ALS w/o FTD
Early spastic paralysis, dysarthria, & dysphagia
Onset before 5th decade
Premature FTD
Early stages characterized by dysnomia, dyscalculia, comprehension deficits, paraphasic errors, & relative preservation of memory
Later stages characterized by inability to speak, auditory comprehension deficits for even 1-step commands, alexia, & agraphia
Mean age at FTD diagnosis: 56 yrs
Adult-onset proximal & distal muscle weakness
Muscle weakness progresses to involve other limb & respiratory muscles.
Cardiac failure & cardiomyopathy may be observed in later stages.
Early-onset PDB
AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; DiffDx = differential diagnosis; FDG-PET = fluorodeoxyglucose-positron emission tomography; FTD = frontotemporal dementia; MND = motor neuron disease; MOI = mode of inheritance; PDB = Paget disease of bone; XL = X-linked
It is likely that pathogenic variants in other genes causative of EOFAD will be identified because families with autosomal dominant FAD with no known pathogenic variants in
Adult-onset proximal and distal muscle weakness in inclusion body myopathy associated w/Paget disease of bone and/or FTD clinically resembles a limb-girdle muscular dystrophy syndrome.
PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion.
Structural imaging may show a frontal preponderance of the generalized atrophy and will exclude other treatable causes of dementia (e.g., frontal meningioma, chronic subdural hematoma).
Nongenetic acquired causes of dementia should always be considered.
• Mild behavioral changes
• Prominent memory disturbance
• Loss of initiative
• Word-finding problems
• May not be clinically distinguishable
• Psychotic symptoms more common in
• Familial ALS w/o FTD
• Onset before 5th decade
• Incomplete penetrance
• Dementia
• Extrapyramidal signs (rigidity, bradykinesia)
• REM sleep disorders
• Visual hallucinations
• DaT scans abnormal
• Adult-onset behavioral-variant FTD
• Generally affects frontal & temporal cortex, → behavioral changes, executive dysfunction, & language disturbances
• Parietal cortex & basal ganglia may be affected as well, resulting in parkinsonism, cortical basal syndrome, & memory impairment
• Age of onset: 48-83 yrs
• Clinically indistinguishable
• Metabolic changes (on FDG-PET) preceding structural changes of frontal atrophy (on MRI)
• Changes in personality (apathy or depression)
• Cognitive decline
• Dementia
• Dystonia
• Chorea
• Delusions
• Visual hallucinations
• Adult-onset behavioral variant FTD
• Extrapyramidal signs (rigidity, bradykinesia, supranuclear palsy, & saccadic eye movement disorders)
• Symptoms usually start at ages 40-60 yrs but may occur earlier or later.
• Disease progresses over few yrs to profound dementia w/mutism.
• Clinically indistinguishable
• Onset before 5th decade
• Metabolic changes (on FDG-PET) preceding structural changes of frontal atrophy (on MRI)
• Adult-onset behavioral variant FTD
• Generalized cerebral atrophy on MRI
• Early bulbar symptoms
• Onset before 5th decade
• Adult-onset behavioral variant FTD
• Disinhibition as presenting symptom
• Generalized cerebral atrophy on MRI
• Extrapyramidal features at later stage of disease
• Memory loss at early stage of disease
• Incomplete penetrance
• MND w/FTD
• Choreic movements
• Familial ALS w/o FTD
• Early spastic paralysis, dysarthria, & dysphagia
• Onset before 5th decade
• Premature FTD
• Early stages characterized by dysnomia, dyscalculia, comprehension deficits, paraphasic errors, & relative preservation of memory
• Later stages characterized by inability to speak, auditory comprehension deficits for even 1-step commands, alexia, & agraphia
• Mean age at FTD diagnosis: 56 yrs
• Adult-onset proximal & distal muscle weakness
• Muscle weakness progresses to involve other limb & respiratory muscles.
• Cardiac failure & cardiomyopathy may be observed in later stages.
• Early-onset PDB
• Structural imaging may show a frontal preponderance of the generalized atrophy and will exclude other treatable causes of dementia (e.g., frontal meningioma, chronic subdural hematoma).
• Nongenetic acquired causes of dementia should always be considered.
## Management
To establish the extent of disease and needs in an individual diagnosed with
A general medical history and family history
Physical and neurologic examination
Evaluation of the extent and profile of cognitive disturbance by neuropsychological examination
Discussion of capabilities for job and for driving
Consultation with a clinical geneticist and/or genetic counselor
Discussion of advanced care planning
Behavioral changes and the loss of insight and judgment in individuals with
Psychosocial support is essential in the management of FTD and should include occupational therapy and environmental and physical interventions.
The behavioral and psychological symptoms should be treated as in other types of FTD. There is no consensus treatment guideline for
Members of the Danish family with
See
Search
• A general medical history and family history
• Physical and neurologic examination
• Evaluation of the extent and profile of cognitive disturbance by neuropsychological examination
• Discussion of capabilities for job and for driving
• Consultation with a clinical geneticist and/or genetic counselor
• Discussion of advanced care planning
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
A general medical history and family history
Physical and neurologic examination
Evaluation of the extent and profile of cognitive disturbance by neuropsychological examination
Discussion of capabilities for job and for driving
Consultation with a clinical geneticist and/or genetic counselor
Discussion of advanced care planning
• A general medical history and family history
• Physical and neurologic examination
• Evaluation of the extent and profile of cognitive disturbance by neuropsychological examination
• Discussion of capabilities for job and for driving
• Consultation with a clinical geneticist and/or genetic counselor
• Discussion of advanced care planning
## Treatment of Manifestations
Behavioral changes and the loss of insight and judgment in individuals with
Psychosocial support is essential in the management of FTD and should include occupational therapy and environmental and physical interventions.
The behavioral and psychological symptoms should be treated as in other types of FTD. There is no consensus treatment guideline for
## Surveillance
Members of the Danish family with
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
To date, almost all individuals diagnosed with CHMP2B-FTD have an affected parent.
One individual with FTD and no clear family history of neurodegenerative disease was reported to have a
Molecular genetic testing and neurologic examination are recommended for the parents of a proband with an apparent
If the
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the
If the
If the parents have not been tested for the
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• To date, almost all individuals diagnosed with CHMP2B-FTD have an affected parent.
• One individual with FTD and no clear family history of neurodegenerative disease was reported to have a
• Molecular genetic testing and neurologic examination are recommended for the parents of a proband with an apparent
• If the
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with
• If a parent of the proband is affected and/or is known to have the
• If the
• If the parents have not been tested for the
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
To date, almost all individuals diagnosed with CHMP2B-FTD have an affected parent.
One individual with FTD and no clear family history of neurodegenerative disease was reported to have a
Molecular genetic testing and neurologic examination are recommended for the parents of a proband with an apparent
If the
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the
If the
If the parents have not been tested for the
• To date, almost all individuals diagnosed with CHMP2B-FTD have an affected parent.
• One individual with FTD and no clear family history of neurodegenerative disease was reported to have a
• Molecular genetic testing and neurologic examination are recommended for the parents of a proband with an apparent
• If the
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with
• If a parent of the proband is affected and/or is known to have the
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
United Kingdom
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•
•
• United Kingdom
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• United Kingdom
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## Molecular Genetics
CHMP2B Frontotemporal Dementia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CHMP2B Frontotemporal Dementia (
The
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
The Danish family is studied by the FReJA (Frontotemporal Dementia Research in Jutland Association) Consortium that includes the authors and the following:
Anders Gade, PhD Institute of Psychology Copenhagen UniversityCopenhagen, Denmark
Jette Stokholm, NeuropsychologistMemory Disorders Research GroupDepartment of Neurology, RigshospitaletCopenhagen University HospitalCopenhagen, Denmark
Susanne Gydesen, MD Psychiatric Center BallerupCopenhagen University HospitalBallerup, Denmark
Tove Thusgaard, RN Health and Social Services
Elisabet Englund, MD, PhD Department of Pathology University Hospital of LundLund, Sweden
John Collinge, MD MRC Prion Unit Department of Neurodegenerative Diseases Institute of Neurology University College LondonLondon, UK
Martin Rossor, MD and Elizabeth MC Fisher, PhD Department of Neurodegenerative Diseases Institute of Neurology University College LondonLondon, UK
2 July 2020 (sw) Comprehensive update posted live
4 October 2012 (me) Comprehensive update posted live
23 August 2007 (me) Review posted live
11 July 2007 (ih) Original submission
• 2 July 2020 (sw) Comprehensive update posted live
• 4 October 2012 (me) Comprehensive update posted live
• 23 August 2007 (me) Review posted live
• 11 July 2007 (ih) Original submission
## Acknowledgments
The Danish family is studied by the FReJA (Frontotemporal Dementia Research in Jutland Association) Consortium that includes the authors and the following:
Anders Gade, PhD Institute of Psychology Copenhagen UniversityCopenhagen, Denmark
Jette Stokholm, NeuropsychologistMemory Disorders Research GroupDepartment of Neurology, RigshospitaletCopenhagen University HospitalCopenhagen, Denmark
Susanne Gydesen, MD Psychiatric Center BallerupCopenhagen University HospitalBallerup, Denmark
Tove Thusgaard, RN Health and Social Services
Elisabet Englund, MD, PhD Department of Pathology University Hospital of LundLund, Sweden
John Collinge, MD MRC Prion Unit Department of Neurodegenerative Diseases Institute of Neurology University College LondonLondon, UK
Martin Rossor, MD and Elizabeth MC Fisher, PhD Department of Neurodegenerative Diseases Institute of Neurology University College LondonLondon, UK
## Revision History
2 July 2020 (sw) Comprehensive update posted live
4 October 2012 (me) Comprehensive update posted live
23 August 2007 (me) Review posted live
11 July 2007 (ih) Original submission
• 2 July 2020 (sw) Comprehensive update posted live
• 4 October 2012 (me) Comprehensive update posted live
• 23 August 2007 (me) Review posted live
• 11 July 2007 (ih) Original submission
## References
## Literature Cited
|
[] |
23/8/2007
|
2/7/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
ftd-grn
|
ftd-grn
|
[
"FTD-GRN",
"FTD-GRN",
"Progranulin",
"GRN",
"GRN Frontotemporal Dementia"
] |
Ging-Yuek Robin Hsiung, Howard H Feldman
|
Summary The spectrum of The diagnosis of
|
## Diagnosis
Clinical presentations of
Early behavioral disinhibition (including one of the following):
Socially inappropriate behavior
Loss of manners or decorum
Impulsive, rash, or careless actions
Early apathy or inertia (one of the following):
Apathy
Inertia
Early loss of sympathy or empathy (one of the following):
Diminished response to other people's needs and feelings
Diminished social interest, interrelatedness, or personal warmth
Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following):
Simple repetitive movements
Complex, compulsive, or ritualistic behaviors
Stereotypy of speech
Hyperorality and dietary changes (one of the following):
Altered food preferences
Binge eating, increased consumption of alcohol or cigarettes
Oral exploration or consumption of inedible objects
Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (
Deficits in executive tasks
Relative sparing of episodic memory
Relative sparing of visuospatial skills
Progressive nonfluent aphasia (PNFA, also known as nonfluent or agrammatic subtype of PPA)
Semantic dementia (SD)
Logopenic variant (logopenic PPA)
Note: To date, the logopenic variant has not been associated with
The majority of the literature describes PNFA to be the predominant form of PPA in
The currently proposed diagnostic algorithm for PNFA requires a two-step process. First, individuals must meet the criteria for PPA, and after the diagnosis of PPA is established, the main features of the speech and language abnormalities may be considered to subcategorize into each of the PPA variants.
The diagnostic criteria of PPA [
The most prominent clinical feature is difficulty with language.
Language deficits are the principal cause of impaired daily living activities.
Aphasia is the most prominent deficit at symptom onset and for the initial phases of the disease.
Note: The pattern of deficits cannot be accounted for by other nondegenerative diseases of the nervous system, medical disorders, or psychiatric diagnoses.
At least one of the following core features:
Agrammatism in language production
Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
At least two of the three following supportive features:
Impaired comprehension of syntactically complex sentences
Spared single-word comprehension
Spared object knowledge
Impaired confrontation naming
Impaired single-word comprehension
AND at least three of the following four additional diagnostic features:
Impaired object knowledge, particularly for low frequency or low-familiarity items
Surface dyslexia or dysgraphia
Spared repetition
Spared speech production (grammar and motor speech)
Bradykinesia
Rigidity
Gait instability
Resting tremor
Progressive asymmetric rigidity
Apraxia
Alien-limb phenomenon
Cortical sensory loss
Focal dystonia
Myoclonus
Dementia
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Gene-targeted testing (multigene panel) requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Because the phenotype of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
• Early behavioral disinhibition (including one of the following):
• Socially inappropriate behavior
• Loss of manners or decorum
• Impulsive, rash, or careless actions
• Socially inappropriate behavior
• Loss of manners or decorum
• Impulsive, rash, or careless actions
• Early apathy or inertia (one of the following):
• Apathy
• Inertia
• Apathy
• Inertia
• Early loss of sympathy or empathy (one of the following):
• Diminished response to other people's needs and feelings
• Diminished social interest, interrelatedness, or personal warmth
• Diminished response to other people's needs and feelings
• Diminished social interest, interrelatedness, or personal warmth
• Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following):
• Simple repetitive movements
• Complex, compulsive, or ritualistic behaviors
• Stereotypy of speech
• Simple repetitive movements
• Complex, compulsive, or ritualistic behaviors
• Stereotypy of speech
• Hyperorality and dietary changes (one of the following):
• Altered food preferences
• Binge eating, increased consumption of alcohol or cigarettes
• Oral exploration or consumption of inedible objects
• Altered food preferences
• Binge eating, increased consumption of alcohol or cigarettes
• Oral exploration or consumption of inedible objects
• Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (
• Deficits in executive tasks
• Relative sparing of episodic memory
• Relative sparing of visuospatial skills
• Deficits in executive tasks
• Relative sparing of episodic memory
• Relative sparing of visuospatial skills
• Socially inappropriate behavior
• Loss of manners or decorum
• Impulsive, rash, or careless actions
• Apathy
• Inertia
• Diminished response to other people's needs and feelings
• Diminished social interest, interrelatedness, or personal warmth
• Simple repetitive movements
• Complex, compulsive, or ritualistic behaviors
• Stereotypy of speech
• Altered food preferences
• Binge eating, increased consumption of alcohol or cigarettes
• Oral exploration or consumption of inedible objects
• Deficits in executive tasks
• Relative sparing of episodic memory
• Relative sparing of visuospatial skills
• Progressive nonfluent aphasia (PNFA, also known as nonfluent or agrammatic subtype of PPA)
• Semantic dementia (SD)
• Logopenic variant (logopenic PPA)
• Note: To date, the logopenic variant has not been associated with
• The most prominent clinical feature is difficulty with language.
• Language deficits are the principal cause of impaired daily living activities.
• Aphasia is the most prominent deficit at symptom onset and for the initial phases of the disease.
• At least one of the following core features:
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• At least two of the three following supportive features:
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• At least one of the following core features:
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• At least two of the three following supportive features:
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired confrontation naming
• Impaired single-word comprehension
• AND at least three of the following four additional diagnostic features:
• Impaired object knowledge, particularly for low frequency or low-familiarity items
• Surface dyslexia or dysgraphia
• Spared repetition
• Spared speech production (grammar and motor speech)
• Impaired confrontation naming
• Impaired single-word comprehension
• Impaired object knowledge, particularly for low frequency or low-familiarity items
• Surface dyslexia or dysgraphia
• Spared repetition
• Spared speech production (grammar and motor speech)
• At least one of the following core features:
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• At least two of the three following supportive features:
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired confrontation naming
• Impaired single-word comprehension
• Impaired object knowledge, particularly for low frequency or low-familiarity items
• Surface dyslexia or dysgraphia
• Spared repetition
• Spared speech production (grammar and motor speech)
• Bradykinesia
• Rigidity
• Gait instability
• Resting tremor
• Progressive asymmetric rigidity
• Apraxia
• Alien-limb phenomenon
• Cortical sensory loss
• Focal dystonia
• Myoclonus
• Dementia
## Suggestive Findings
Clinical presentations of
Early behavioral disinhibition (including one of the following):
Socially inappropriate behavior
Loss of manners or decorum
Impulsive, rash, or careless actions
Early apathy or inertia (one of the following):
Apathy
Inertia
Early loss of sympathy or empathy (one of the following):
Diminished response to other people's needs and feelings
Diminished social interest, interrelatedness, or personal warmth
Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following):
Simple repetitive movements
Complex, compulsive, or ritualistic behaviors
Stereotypy of speech
Hyperorality and dietary changes (one of the following):
Altered food preferences
Binge eating, increased consumption of alcohol or cigarettes
Oral exploration or consumption of inedible objects
Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (
Deficits in executive tasks
Relative sparing of episodic memory
Relative sparing of visuospatial skills
Progressive nonfluent aphasia (PNFA, also known as nonfluent or agrammatic subtype of PPA)
Semantic dementia (SD)
Logopenic variant (logopenic PPA)
Note: To date, the logopenic variant has not been associated with
The majority of the literature describes PNFA to be the predominant form of PPA in
The currently proposed diagnostic algorithm for PNFA requires a two-step process. First, individuals must meet the criteria for PPA, and after the diagnosis of PPA is established, the main features of the speech and language abnormalities may be considered to subcategorize into each of the PPA variants.
The diagnostic criteria of PPA [
The most prominent clinical feature is difficulty with language.
Language deficits are the principal cause of impaired daily living activities.
Aphasia is the most prominent deficit at symptom onset and for the initial phases of the disease.
Note: The pattern of deficits cannot be accounted for by other nondegenerative diseases of the nervous system, medical disorders, or psychiatric diagnoses.
At least one of the following core features:
Agrammatism in language production
Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
At least two of the three following supportive features:
Impaired comprehension of syntactically complex sentences
Spared single-word comprehension
Spared object knowledge
Impaired confrontation naming
Impaired single-word comprehension
AND at least three of the following four additional diagnostic features:
Impaired object knowledge, particularly for low frequency or low-familiarity items
Surface dyslexia or dysgraphia
Spared repetition
Spared speech production (grammar and motor speech)
Bradykinesia
Rigidity
Gait instability
Resting tremor
Progressive asymmetric rigidity
Apraxia
Alien-limb phenomenon
Cortical sensory loss
Focal dystonia
Myoclonus
Dementia
• Early behavioral disinhibition (including one of the following):
• Socially inappropriate behavior
• Loss of manners or decorum
• Impulsive, rash, or careless actions
• Socially inappropriate behavior
• Loss of manners or decorum
• Impulsive, rash, or careless actions
• Early apathy or inertia (one of the following):
• Apathy
• Inertia
• Apathy
• Inertia
• Early loss of sympathy or empathy (one of the following):
• Diminished response to other people's needs and feelings
• Diminished social interest, interrelatedness, or personal warmth
• Diminished response to other people's needs and feelings
• Diminished social interest, interrelatedness, or personal warmth
• Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following):
• Simple repetitive movements
• Complex, compulsive, or ritualistic behaviors
• Stereotypy of speech
• Simple repetitive movements
• Complex, compulsive, or ritualistic behaviors
• Stereotypy of speech
• Hyperorality and dietary changes (one of the following):
• Altered food preferences
• Binge eating, increased consumption of alcohol or cigarettes
• Oral exploration or consumption of inedible objects
• Altered food preferences
• Binge eating, increased consumption of alcohol or cigarettes
• Oral exploration or consumption of inedible objects
• Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (
• Deficits in executive tasks
• Relative sparing of episodic memory
• Relative sparing of visuospatial skills
• Deficits in executive tasks
• Relative sparing of episodic memory
• Relative sparing of visuospatial skills
• Socially inappropriate behavior
• Loss of manners or decorum
• Impulsive, rash, or careless actions
• Apathy
• Inertia
• Diminished response to other people's needs and feelings
• Diminished social interest, interrelatedness, or personal warmth
• Simple repetitive movements
• Complex, compulsive, or ritualistic behaviors
• Stereotypy of speech
• Altered food preferences
• Binge eating, increased consumption of alcohol or cigarettes
• Oral exploration or consumption of inedible objects
• Deficits in executive tasks
• Relative sparing of episodic memory
• Relative sparing of visuospatial skills
• Progressive nonfluent aphasia (PNFA, also known as nonfluent or agrammatic subtype of PPA)
• Semantic dementia (SD)
• Logopenic variant (logopenic PPA)
• Note: To date, the logopenic variant has not been associated with
• The most prominent clinical feature is difficulty with language.
• Language deficits are the principal cause of impaired daily living activities.
• Aphasia is the most prominent deficit at symptom onset and for the initial phases of the disease.
• At least one of the following core features:
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• At least two of the three following supportive features:
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• At least one of the following core features:
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• At least two of the three following supportive features:
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired confrontation naming
• Impaired single-word comprehension
• AND at least three of the following four additional diagnostic features:
• Impaired object knowledge, particularly for low frequency or low-familiarity items
• Surface dyslexia or dysgraphia
• Spared repetition
• Spared speech production (grammar and motor speech)
• Impaired confrontation naming
• Impaired single-word comprehension
• Impaired object knowledge, particularly for low frequency or low-familiarity items
• Surface dyslexia or dysgraphia
• Spared repetition
• Spared speech production (grammar and motor speech)
• At least one of the following core features:
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• At least two of the three following supportive features:
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired confrontation naming
• Impaired single-word comprehension
• Impaired object knowledge, particularly for low frequency or low-familiarity items
• Surface dyslexia or dysgraphia
• Spared repetition
• Spared speech production (grammar and motor speech)
• Bradykinesia
• Rigidity
• Gait instability
• Resting tremor
• Progressive asymmetric rigidity
• Apraxia
• Alien-limb phenomenon
• Cortical sensory loss
• Focal dystonia
• Myoclonus
• Dementia
## Clinical Presentations
Clinical presentations of
Early behavioral disinhibition (including one of the following):
Socially inappropriate behavior
Loss of manners or decorum
Impulsive, rash, or careless actions
Early apathy or inertia (one of the following):
Apathy
Inertia
Early loss of sympathy or empathy (one of the following):
Diminished response to other people's needs and feelings
Diminished social interest, interrelatedness, or personal warmth
Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following):
Simple repetitive movements
Complex, compulsive, or ritualistic behaviors
Stereotypy of speech
Hyperorality and dietary changes (one of the following):
Altered food preferences
Binge eating, increased consumption of alcohol or cigarettes
Oral exploration or consumption of inedible objects
Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (
Deficits in executive tasks
Relative sparing of episodic memory
Relative sparing of visuospatial skills
Progressive nonfluent aphasia (PNFA, also known as nonfluent or agrammatic subtype of PPA)
Semantic dementia (SD)
Logopenic variant (logopenic PPA)
Note: To date, the logopenic variant has not been associated with
The majority of the literature describes PNFA to be the predominant form of PPA in
The currently proposed diagnostic algorithm for PNFA requires a two-step process. First, individuals must meet the criteria for PPA, and after the diagnosis of PPA is established, the main features of the speech and language abnormalities may be considered to subcategorize into each of the PPA variants.
The diagnostic criteria of PPA [
The most prominent clinical feature is difficulty with language.
Language deficits are the principal cause of impaired daily living activities.
Aphasia is the most prominent deficit at symptom onset and for the initial phases of the disease.
Note: The pattern of deficits cannot be accounted for by other nondegenerative diseases of the nervous system, medical disorders, or psychiatric diagnoses.
At least one of the following core features:
Agrammatism in language production
Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
At least two of the three following supportive features:
Impaired comprehension of syntactically complex sentences
Spared single-word comprehension
Spared object knowledge
Impaired confrontation naming
Impaired single-word comprehension
AND at least three of the following four additional diagnostic features:
Impaired object knowledge, particularly for low frequency or low-familiarity items
Surface dyslexia or dysgraphia
Spared repetition
Spared speech production (grammar and motor speech)
Bradykinesia
Rigidity
Gait instability
Resting tremor
Progressive asymmetric rigidity
Apraxia
Alien-limb phenomenon
Cortical sensory loss
Focal dystonia
Myoclonus
Dementia
• Early behavioral disinhibition (including one of the following):
• Socially inappropriate behavior
• Loss of manners or decorum
• Impulsive, rash, or careless actions
• Socially inappropriate behavior
• Loss of manners or decorum
• Impulsive, rash, or careless actions
• Early apathy or inertia (one of the following):
• Apathy
• Inertia
• Apathy
• Inertia
• Early loss of sympathy or empathy (one of the following):
• Diminished response to other people's needs and feelings
• Diminished social interest, interrelatedness, or personal warmth
• Diminished response to other people's needs and feelings
• Diminished social interest, interrelatedness, or personal warmth
• Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following):
• Simple repetitive movements
• Complex, compulsive, or ritualistic behaviors
• Stereotypy of speech
• Simple repetitive movements
• Complex, compulsive, or ritualistic behaviors
• Stereotypy of speech
• Hyperorality and dietary changes (one of the following):
• Altered food preferences
• Binge eating, increased consumption of alcohol or cigarettes
• Oral exploration or consumption of inedible objects
• Altered food preferences
• Binge eating, increased consumption of alcohol or cigarettes
• Oral exploration or consumption of inedible objects
• Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (
• Deficits in executive tasks
• Relative sparing of episodic memory
• Relative sparing of visuospatial skills
• Deficits in executive tasks
• Relative sparing of episodic memory
• Relative sparing of visuospatial skills
• Socially inappropriate behavior
• Loss of manners or decorum
• Impulsive, rash, or careless actions
• Apathy
• Inertia
• Diminished response to other people's needs and feelings
• Diminished social interest, interrelatedness, or personal warmth
• Simple repetitive movements
• Complex, compulsive, or ritualistic behaviors
• Stereotypy of speech
• Altered food preferences
• Binge eating, increased consumption of alcohol or cigarettes
• Oral exploration or consumption of inedible objects
• Deficits in executive tasks
• Relative sparing of episodic memory
• Relative sparing of visuospatial skills
• Progressive nonfluent aphasia (PNFA, also known as nonfluent or agrammatic subtype of PPA)
• Semantic dementia (SD)
• Logopenic variant (logopenic PPA)
• Note: To date, the logopenic variant has not been associated with
• The most prominent clinical feature is difficulty with language.
• Language deficits are the principal cause of impaired daily living activities.
• Aphasia is the most prominent deficit at symptom onset and for the initial phases of the disease.
• At least one of the following core features:
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• At least two of the three following supportive features:
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• At least one of the following core features:
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• At least two of the three following supportive features:
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired confrontation naming
• Impaired single-word comprehension
• AND at least three of the following four additional diagnostic features:
• Impaired object knowledge, particularly for low frequency or low-familiarity items
• Surface dyslexia or dysgraphia
• Spared repetition
• Spared speech production (grammar and motor speech)
• Impaired confrontation naming
• Impaired single-word comprehension
• Impaired object knowledge, particularly for low frequency or low-familiarity items
• Surface dyslexia or dysgraphia
• Spared repetition
• Spared speech production (grammar and motor speech)
• At least one of the following core features:
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• At least two of the three following supportive features:
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Agrammatism in language production
• Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
• Impaired comprehension of syntactically complex sentences
• Spared single-word comprehension
• Spared object knowledge
• Impaired confrontation naming
• Impaired single-word comprehension
• Impaired object knowledge, particularly for low frequency or low-familiarity items
• Surface dyslexia or dysgraphia
• Spared repetition
• Spared speech production (grammar and motor speech)
• Bradykinesia
• Rigidity
• Gait instability
• Resting tremor
• Progressive asymmetric rigidity
• Apraxia
• Alien-limb phenomenon
• Cortical sensory loss
• Focal dystonia
• Myoclonus
• Dementia
## Neuroimaging
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Gene-targeted testing (multigene panel) requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Because the phenotype of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
## Clinical Characteristics
Comparison studies demonstrate that onset age in individuals with
Behavioral disturbances are the most common early feature, followed by progressive aphasia [
With impairment in executive function, there is loss of judgment and insight, which may manifest early in the disease course as, for example, making poor financial decisions, quitting jobs abruptly, or becoming unduly forward or rude to strangers. Alternatively, persons with predominant apathy may lose all interest and initiative with usual activities, appear socially withdrawn, give up all previous hobbies and interests, and be unable to complete tasks due to lack of persistence. Early in the course of the illness, affected individuals may be misdiagnosed as having psychiatric conditions such as depression, mania, or psychosis because of the unusual and bizarre nature of their behavior. Psychometric testing may demonstrate impairment on frontal executive tasks including the Trail-Making Test, proverb interpretation, descriptions of similarities, categorical naming, and abstract pattern recognition (e.g., Wisconsin Card Sort Test).
In contrast with PPA-PNFA, semantic dementia is characterized by impaired naming and comprehension, semantic paraphasias, and impaired recognition of familiar faces or objects. Although rare in
A number of studies have reported individuals with
Tau-negative alpha-synuclein-negative ubiquitin-positive "cat-eye" or lentiform-shaped neuronal intranuclear inclusions (NII), often found in the neocortex and striatum
Superficial laminar spongiosis with ubiquitin-positive neurites and neuronal cytoplasmic inclusions (NCI) in the neocortex
Granular appearance of the ubiquitin-immunoreactive (ub-ir) neurites in the striatum and the NCI in the hippocampus
Phosphorylation of S409/410 of TDP-43 in pathologic inclusions [
The major protein component of these ubiquitin inclusions is a TAR DNA-binding protein of 43 kd (TDP-43). TDP-43 is a nuclear factor involved in regulating transcription and alternative splicing [
It is now recognized that pathologically,
No obvious correlations between age of onset, disease duration, or clinical phenotype and specific
Penetrance of
A study of the common
In a large series in France, 3.2% of simplex cases (i.e., only one affected individual in a family) with FTD were found to have a
The term frontotemporal dementia (FTD) is used in this
Note that
Prior to the identification of
Frontotemporal dementia (FTD) accounts for 5%-10% of all individuals with dementia and 10%-20% of individuals with dementia with onset before age 65 years [
• Tau-negative alpha-synuclein-negative ubiquitin-positive "cat-eye" or lentiform-shaped neuronal intranuclear inclusions (NII), often found in the neocortex and striatum
• Superficial laminar spongiosis with ubiquitin-positive neurites and neuronal cytoplasmic inclusions (NCI) in the neocortex
• Granular appearance of the ubiquitin-immunoreactive (ub-ir) neurites in the striatum and the NCI in the hippocampus
• Phosphorylation of S409/410 of TDP-43 in pathologic inclusions [
• The major protein component of these ubiquitin inclusions is a TAR DNA-binding protein of 43 kd (TDP-43). TDP-43 is a nuclear factor involved in regulating transcription and alternative splicing [
## Clinical Description
Comparison studies demonstrate that onset age in individuals with
Behavioral disturbances are the most common early feature, followed by progressive aphasia [
With impairment in executive function, there is loss of judgment and insight, which may manifest early in the disease course as, for example, making poor financial decisions, quitting jobs abruptly, or becoming unduly forward or rude to strangers. Alternatively, persons with predominant apathy may lose all interest and initiative with usual activities, appear socially withdrawn, give up all previous hobbies and interests, and be unable to complete tasks due to lack of persistence. Early in the course of the illness, affected individuals may be misdiagnosed as having psychiatric conditions such as depression, mania, or psychosis because of the unusual and bizarre nature of their behavior. Psychometric testing may demonstrate impairment on frontal executive tasks including the Trail-Making Test, proverb interpretation, descriptions of similarities, categorical naming, and abstract pattern recognition (e.g., Wisconsin Card Sort Test).
In contrast with PPA-PNFA, semantic dementia is characterized by impaired naming and comprehension, semantic paraphasias, and impaired recognition of familiar faces or objects. Although rare in
A number of studies have reported individuals with
Tau-negative alpha-synuclein-negative ubiquitin-positive "cat-eye" or lentiform-shaped neuronal intranuclear inclusions (NII), often found in the neocortex and striatum
Superficial laminar spongiosis with ubiquitin-positive neurites and neuronal cytoplasmic inclusions (NCI) in the neocortex
Granular appearance of the ubiquitin-immunoreactive (ub-ir) neurites in the striatum and the NCI in the hippocampus
Phosphorylation of S409/410 of TDP-43 in pathologic inclusions [
The major protein component of these ubiquitin inclusions is a TAR DNA-binding protein of 43 kd (TDP-43). TDP-43 is a nuclear factor involved in regulating transcription and alternative splicing [
It is now recognized that pathologically,
• Tau-negative alpha-synuclein-negative ubiquitin-positive "cat-eye" or lentiform-shaped neuronal intranuclear inclusions (NII), often found in the neocortex and striatum
• Superficial laminar spongiosis with ubiquitin-positive neurites and neuronal cytoplasmic inclusions (NCI) in the neocortex
• Granular appearance of the ubiquitin-immunoreactive (ub-ir) neurites in the striatum and the NCI in the hippocampus
• Phosphorylation of S409/410 of TDP-43 in pathologic inclusions [
• The major protein component of these ubiquitin inclusions is a TAR DNA-binding protein of 43 kd (TDP-43). TDP-43 is a nuclear factor involved in regulating transcription and alternative splicing [
## Genotype-Phenotype Correlations
No obvious correlations between age of onset, disease duration, or clinical phenotype and specific
## Penetrance
Penetrance of
A study of the common
In a large series in France, 3.2% of simplex cases (i.e., only one affected individual in a family) with FTD were found to have a
## Nomenclature
The term frontotemporal dementia (FTD) is used in this
Note that
Prior to the identification of
## Prevalence
Frontotemporal dementia (FTD) accounts for 5%-10% of all individuals with dementia and 10%-20% of individuals with dementia with onset before age 65 years [
## Genetically Related (Allelic) Disorders
Individuals with biallelic
## Differential Diagnosis
Neuroimaging can evaluate for other conditions that mimic frontotemporal dementia (FTD) (e.g., white matter diseases, frontotemporal focal lesions, frontal lobe tumors, and cerebrovascular disease).
The clinical manifestations of
Up to 50% of individuals with FTD have a positive family history of dementia, usually with autosomal dominant inheritance.
Genes in the Differential Diagnosis of
AD= autosomal dominant; ALS = amyotrophic lateral sclerosis; DiffDx = differential diagnosis; FTD = frontotemporal dementia; bvFTD = behavioral variant FTD; FTDP = frontotemporal dementia with parkinsonism; FUS = fused in sarcoma; LGMD = limb-girdle muscular dystrophy; PNFA = progressive nonfluent aphasia; PDB = Paget disease of bone; PPA = primary progressive aphasia
See
Muscle weakness progresses to involve other limb & respiratory muscles; cardiac failure & cardiomyopathy have been observed in later stages of IBMPFD.
Paget disease of bone (PDB) involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones.
## Management
To establish the extent of disease and needs in an individual diagnosed with
Detailed general, neurologic, and family history
Physical examination
Neurologic examination
Cognitive examination. When clinical cognitive assessments are not informative enough, a neuropsychological assessment may be performed to provide a more comprehensive and objective view of a patient's cognitive function. Formal neuropsychological assessment requires comparison of the patient's raw score on a specific test to a large general population normative sample which is usually drawn from a population comparable to that of the person being examined. This allows for the patient's performance to be compared to a suitable control group, adjusted for age, sex, level of education, and/or ethnicity. While much more sensitive than bedside clinical cognitive examination, such assessment is resource intensive and time consuming.
Discussion of capabilities for job and for driving
Discussion of advanced care planning
Consultation with a clinical geneticist and/or genetic counselor
There is currently no known treatment for
However, some behavioral manifestations such as apathy, impulsivity, and compulsiveness may respond to selective serotonin reuptake inhibitors. Behavioral changes and the loss of insight and judgment in individuals with
The behavioral and psychological manifestations should be treated as in other types of FTD. There is no consensus treatment guideline for
Roaming, delusions, and hallucinations may respond to antipsychotic medications.
Although reports have suggested potential benefits with certain pharmacotherapy on management of FTD in general, evidence from randomized controlled trials is limited [
One double-blind placebo-controlled crossover trial suggests that trazodone, a serotonergic agent, may be beneficial in treating the symptoms of irritability, agitation, depression, and eating disorders in FTD [
While an open-label study suggested some benefits on behavioral symptoms with paroxetine, a double-blind placebo-controlled trial of ten subjects found worsening of performance on paired associates learning, reversal learning, and delayed pattern recognition [
A study of galantamine in bvFTD and primary progressive aphasia (PPA) found significant benefits in subjects with PPA but not in those with bvFTD [
A 12-month open-label rivastigmine trial showed improvement of behavioral symptoms and decreased caregiver burden in individuals with FTD; however, the treatment did not prevent cognitive decline [
A double-blind placebo-controlled crossover study of methylphenidate found attenuation of risk-taking behavior but worsening of spatial span [
A small clinical trial of dextroamphetamine treatment on eight individuals with bvFTD revealed improvement of behavioral symptoms [
A few open-label studies of memantine, a partial NMDA agonist, demonstrated an improvement on the frontal battery inventory in individuals with bvFTD after a six-month trial, but a decline in other cognitive performance [
Note: Donepezil treatment has been associated with exacerbation of disinhibition and compulsion symptoms [
Patients are often followed in a memory disorder clinic or a similar multidisciplinary clinic involving neurologic and psychiatric services and follow-up medical care.
See
Search
• Detailed general, neurologic, and family history
• Physical examination
• Neurologic examination
• Cognitive examination. When clinical cognitive assessments are not informative enough, a neuropsychological assessment may be performed to provide a more comprehensive and objective view of a patient's cognitive function. Formal neuropsychological assessment requires comparison of the patient's raw score on a specific test to a large general population normative sample which is usually drawn from a population comparable to that of the person being examined. This allows for the patient's performance to be compared to a suitable control group, adjusted for age, sex, level of education, and/or ethnicity. While much more sensitive than bedside clinical cognitive examination, such assessment is resource intensive and time consuming.
• Discussion of capabilities for job and for driving
• Discussion of advanced care planning
• Consultation with a clinical geneticist and/or genetic counselor
• One double-blind placebo-controlled crossover trial suggests that trazodone, a serotonergic agent, may be beneficial in treating the symptoms of irritability, agitation, depression, and eating disorders in FTD [
• While an open-label study suggested some benefits on behavioral symptoms with paroxetine, a double-blind placebo-controlled trial of ten subjects found worsening of performance on paired associates learning, reversal learning, and delayed pattern recognition [
• A study of galantamine in bvFTD and primary progressive aphasia (PPA) found significant benefits in subjects with PPA but not in those with bvFTD [
• A 12-month open-label rivastigmine trial showed improvement of behavioral symptoms and decreased caregiver burden in individuals with FTD; however, the treatment did not prevent cognitive decline [
• A double-blind placebo-controlled crossover study of methylphenidate found attenuation of risk-taking behavior but worsening of spatial span [
• A small clinical trial of dextroamphetamine treatment on eight individuals with bvFTD revealed improvement of behavioral symptoms [
• A few open-label studies of memantine, a partial NMDA agonist, demonstrated an improvement on the frontal battery inventory in individuals with bvFTD after a six-month trial, but a decline in other cognitive performance [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Detailed general, neurologic, and family history
Physical examination
Neurologic examination
Cognitive examination. When clinical cognitive assessments are not informative enough, a neuropsychological assessment may be performed to provide a more comprehensive and objective view of a patient's cognitive function. Formal neuropsychological assessment requires comparison of the patient's raw score on a specific test to a large general population normative sample which is usually drawn from a population comparable to that of the person being examined. This allows for the patient's performance to be compared to a suitable control group, adjusted for age, sex, level of education, and/or ethnicity. While much more sensitive than bedside clinical cognitive examination, such assessment is resource intensive and time consuming.
Discussion of capabilities for job and for driving
Discussion of advanced care planning
Consultation with a clinical geneticist and/or genetic counselor
• Detailed general, neurologic, and family history
• Physical examination
• Neurologic examination
• Cognitive examination. When clinical cognitive assessments are not informative enough, a neuropsychological assessment may be performed to provide a more comprehensive and objective view of a patient's cognitive function. Formal neuropsychological assessment requires comparison of the patient's raw score on a specific test to a large general population normative sample which is usually drawn from a population comparable to that of the person being examined. This allows for the patient's performance to be compared to a suitable control group, adjusted for age, sex, level of education, and/or ethnicity. While much more sensitive than bedside clinical cognitive examination, such assessment is resource intensive and time consuming.
• Discussion of capabilities for job and for driving
• Discussion of advanced care planning
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
There is currently no known treatment for
However, some behavioral manifestations such as apathy, impulsivity, and compulsiveness may respond to selective serotonin reuptake inhibitors. Behavioral changes and the loss of insight and judgment in individuals with
The behavioral and psychological manifestations should be treated as in other types of FTD. There is no consensus treatment guideline for
Roaming, delusions, and hallucinations may respond to antipsychotic medications.
Although reports have suggested potential benefits with certain pharmacotherapy on management of FTD in general, evidence from randomized controlled trials is limited [
One double-blind placebo-controlled crossover trial suggests that trazodone, a serotonergic agent, may be beneficial in treating the symptoms of irritability, agitation, depression, and eating disorders in FTD [
While an open-label study suggested some benefits on behavioral symptoms with paroxetine, a double-blind placebo-controlled trial of ten subjects found worsening of performance on paired associates learning, reversal learning, and delayed pattern recognition [
A study of galantamine in bvFTD and primary progressive aphasia (PPA) found significant benefits in subjects with PPA but not in those with bvFTD [
A 12-month open-label rivastigmine trial showed improvement of behavioral symptoms and decreased caregiver burden in individuals with FTD; however, the treatment did not prevent cognitive decline [
A double-blind placebo-controlled crossover study of methylphenidate found attenuation of risk-taking behavior but worsening of spatial span [
A small clinical trial of dextroamphetamine treatment on eight individuals with bvFTD revealed improvement of behavioral symptoms [
A few open-label studies of memantine, a partial NMDA agonist, demonstrated an improvement on the frontal battery inventory in individuals with bvFTD after a six-month trial, but a decline in other cognitive performance [
Note: Donepezil treatment has been associated with exacerbation of disinhibition and compulsion symptoms [
• One double-blind placebo-controlled crossover trial suggests that trazodone, a serotonergic agent, may be beneficial in treating the symptoms of irritability, agitation, depression, and eating disorders in FTD [
• While an open-label study suggested some benefits on behavioral symptoms with paroxetine, a double-blind placebo-controlled trial of ten subjects found worsening of performance on paired associates learning, reversal learning, and delayed pattern recognition [
• A study of galantamine in bvFTD and primary progressive aphasia (PPA) found significant benefits in subjects with PPA but not in those with bvFTD [
• A 12-month open-label rivastigmine trial showed improvement of behavioral symptoms and decreased caregiver burden in individuals with FTD; however, the treatment did not prevent cognitive decline [
• A double-blind placebo-controlled crossover study of methylphenidate found attenuation of risk-taking behavior but worsening of spatial span [
• A small clinical trial of dextroamphetamine treatment on eight individuals with bvFTD revealed improvement of behavioral symptoms [
• A few open-label studies of memantine, a partial NMDA agonist, demonstrated an improvement on the frontal battery inventory in individuals with bvFTD after a six-month trial, but a decline in other cognitive performance [
## Surveillance
Patients are often followed in a memory disorder clinic or a similar multidisciplinary clinic involving neurologic and psychiatric services and follow-up medical care.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most (95%) individuals diagnosed with
A proband with
Recommendations for the evaluation of parents of a proband with an apparent
If the
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the clinically unaffected parents have not been tested for the
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most (95%) individuals diagnosed with
• A proband with
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with
• If a parent of the proband is affected and/or is known to have the
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the clinically unaffected parents have not been tested for the
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
## Mode of Inheritance
## Risk to Family Members
Most (95%) individuals diagnosed with
A proband with
Recommendations for the evaluation of parents of a proband with an apparent
If the
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the clinically unaffected parents have not been tested for the
• Most (95%) individuals diagnosed with
• A proband with
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with
• If a parent of the proband is affected and/or is known to have the
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the clinically unaffected parents have not been tested for the
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
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## Molecular Genetics
GRN Frontotemporal Dementia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GRN Frontotemporal Dementia (
The granulins are a family of cysteine-rich polypeptides, some of which have growth-modulating activity. All four known human granulin-like peptides are produced from a single precursor, progranulin.
Progranulin, also known as PC-cell-derived growth factor, proepithelin, granulin-epithelin, or acrogranin, is a high-molecular-weight secreted mitogen. Progranulin mRNA is widely expressed in rapidly cycling epithelial cells, in the immune system, and in neurons such as cerebellar Purkinje cells, suggesting an important function in these tissues. Progranulin is involved in multiple physiologic processes such as cellular proliferation and survival as well as tissue repair, and pathologic processes including tumorigenesis [
Full-length progranulin has trophic and anti-inflammatory activity, while the cleaved granulin peptides promote inflammatory activity. In the periphery, progranulin is involved in wound healing responses and modulates inflammatory events. In the central nervous system, progranulin is expressed by neurons and microglia [
There is growing evidence that
Deletion of the progranulin locus can also lead to the same clinical presentation of
Notable
Most frequently found pathogenic variant
60% of individuals w/this variant were affected by age 60 yrs; >95% by age 70 yrs [
Haplotype analyses suggest a founder effect [
2nd most commonly reported pathogenic variant
Only 25% reported to have a family history, suggesting possible ↓ penetrance or
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Most frequently found pathogenic variant
• 60% of individuals w/this variant were affected by age 60 yrs; >95% by age 70 yrs [
• Haplotype analyses suggest a founder effect [
• 2nd most commonly reported pathogenic variant
• Only 25% reported to have a family history, suggesting possible ↓ penetrance or
## Molecular Pathogenesis
The granulins are a family of cysteine-rich polypeptides, some of which have growth-modulating activity. All four known human granulin-like peptides are produced from a single precursor, progranulin.
Progranulin, also known as PC-cell-derived growth factor, proepithelin, granulin-epithelin, or acrogranin, is a high-molecular-weight secreted mitogen. Progranulin mRNA is widely expressed in rapidly cycling epithelial cells, in the immune system, and in neurons such as cerebellar Purkinje cells, suggesting an important function in these tissues. Progranulin is involved in multiple physiologic processes such as cellular proliferation and survival as well as tissue repair, and pathologic processes including tumorigenesis [
Full-length progranulin has trophic and anti-inflammatory activity, while the cleaved granulin peptides promote inflammatory activity. In the periphery, progranulin is involved in wound healing responses and modulates inflammatory events. In the central nervous system, progranulin is expressed by neurons and microglia [
There is growing evidence that
Deletion of the progranulin locus can also lead to the same clinical presentation of
Notable
Most frequently found pathogenic variant
60% of individuals w/this variant were affected by age 60 yrs; >95% by age 70 yrs [
Haplotype analyses suggest a founder effect [
2nd most commonly reported pathogenic variant
Only 25% reported to have a family history, suggesting possible ↓ penetrance or
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Most frequently found pathogenic variant
• 60% of individuals w/this variant were affected by age 60 yrs; >95% by age 70 yrs [
• Haplotype analyses suggest a founder effect [
• 2nd most commonly reported pathogenic variant
• Only 25% reported to have a family history, suggesting possible ↓ penetrance or
## Chapter Notes
The authors gratefully acknowledge the funding received from the Canadian Institutes of Health Research operating grant #74580 and #179009 in support of their research on FTD as well as the collaborations of the investigators of the UBC FTD research team including Drs I Mackenzie, B Hallam, C Jacova, E Dwosh, and AD Sadovnick. Dr GYR Hsiung is supported by a CIHR Clinical Genetics Investigatorship.
6 February 2020 (bp) Comprehensive update posted live
14 March 2013 (me) Comprehensive update posted live
7 September 2007 (me) Review posted live
1 June 2007 (gyrh) Original submission
• 6 February 2020 (bp) Comprehensive update posted live
• 14 March 2013 (me) Comprehensive update posted live
• 7 September 2007 (me) Review posted live
• 1 June 2007 (gyrh) Original submission
## Acknowledgments
The authors gratefully acknowledge the funding received from the Canadian Institutes of Health Research operating grant #74580 and #179009 in support of their research on FTD as well as the collaborations of the investigators of the UBC FTD research team including Drs I Mackenzie, B Hallam, C Jacova, E Dwosh, and AD Sadovnick. Dr GYR Hsiung is supported by a CIHR Clinical Genetics Investigatorship.
## Revision History
6 February 2020 (bp) Comprehensive update posted live
14 March 2013 (me) Comprehensive update posted live
7 September 2007 (me) Review posted live
1 June 2007 (gyrh) Original submission
• 6 February 2020 (bp) Comprehensive update posted live
• 14 March 2013 (me) Comprehensive update posted live
• 7 September 2007 (me) Review posted live
• 1 June 2007 (gyrh) Original submission
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"C Pottier, X Zhou, RB Perkerson, M Baker, GD Jenkins, DJ Serie, R Ghidoni, L Benussi, G Binetti, A López de Munain, M Zulaica, F Moreno, I Le Ber, F Pasquier, D Hannequin, R Sánchez-Valle, A Antonell, A Lladó, TM Parsons, NA Finch, EC Finger, CF Lippa, ED Huey, M Neumann, P Heutink, M Synofzik, C Wilke, RA Rissman, J Slawek, E Sitek, P Johannsen, JE Nielsen, Y Ren, M van Blitterswijk, M DeJesus-Hernandez, E Christopher, ME Murray, KF Bieniek, BM Evers, C Ferrari, S Rollinson, A Richardson, E Scarpini, GG Fumagalli, A Padovani, J Hardy, P Momeni, R Ferrari, F Frangipane, R Maletta, M Anfossi, M Gallo, L Petrucelli, E Suh, OL Lopez, TH Wong, JGJ van Rooij, H Seelaar, S Mead, RJ Caselli, EM Reiman, M Noel Sabbagh, M Kjolby, A Nykjaer, AM Karydas, AL Boxer, LT Grinberg, J Grafman, S Spina, A Oblak, MM Mesulam, S Weintraub, C Geula, JR Hodges, O Piguet, WS Brooks, DJ Irwin, JQ Trojanowski, EB Lee, KA Josephs, JE Parisi, N Ertekin-Taner, DS Knopman, B Nacmias, I Piaceri, S Bagnoli, S Sorbi, M Gearing, J Glass, TG Beach, SE Black, M Masellis, E Rogaeva, JP Vonsattel, LS Honig, J Kofler, AC Bruni, J Snowden, D Mann, S Pickering-Brown, J Diehl-Schmid, J Winkelmann, D Galimberti, C Graff, L Öijerstedt, C Troakes, S Al-Sarraj, C Cruchaga, NJ Cairns, JD Rohrer, GM Halliday, JB Kwok, JC van Swieten, CL White, B Ghetti, JR Murell, IRA Mackenzie, GR Hsiung, B Borroni, G Rossi, F Tagliavini, ZK Wszolek, RC Petersen, EH Bigio, M Grossman, VM Van Deerlin, WW Seeley, BL Miller, NR Graff-Radford, BF Boeve, DW Dickson, JM Biernacka, R Rademakers. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.. Lancet Neurol. 2018;17:548-58",
"R Rademakers, M Baker, J Gass, J Adamson, ED Huey, P Momeni, S Spina, G Coppola, AM Karydas, H Stewart, N Johnson, GY Hsiung, B Kelley, K Kuntz, E Steinbart, EM Wood, CE Yu, K Josephs, E Sorenson, KB Womack, S Weintraub, SM Pickering-Brown, PR Schofield, WS Brooks, VM Van Deerlin, J Snowden, CM Clark, A Kertesz, K Boylan, B Ghetti, D Neary, GD Schellenberg, TG Beach, M Mesulam, D Mann, J Grafman, IR Mackenzie, H Feldman, T Bird, R Petersen, D Knopman, B Boeve, DH Geschwind, B Miller, Z Wszolek, C Lippa, EH Bigio, D Dickson, N Graff-Radford, M Hutton. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative.. Lancet Neurol. 2007;6:857-68",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Rahman, TW Robbins, JR Hodges, MA Mehta, PJ Nestor, L Clark, BJ Sahakian. Methylphenidate ('Ritalin') can ameliorate abnormal risk-taking behavior in the frontal variant of frontotemporal dementia.. Neuropsychopharmacology 2006;31:651-8",
"K Rascovsky, JR Hodges, D Knopman, MF Mendez, JH Kramer, J Neuhaus, JC van Swieten, H Seelaar, EG Dopper, CU Onyike, AE Hillis, KA Josephs, BF Boeve, A Kertesz, WW Seeley, KP Rankin, JK Johnson, ML Gorno-Tempini, H Rosen, CE Prioleau-Latham, A Lee, CM Kipps, P Lillo, O Piguet, JD Rohrer, MN Rossor, JD Warren, NC Fox, D Galasko, DP Salmon, SE Black, M Mesulam, S Weintraub, BC Dickerson, J Diehl-Schmid, F Pasquier, V Deramecourt, F Lebert, Y Pijnenburg, TW Chow, F Manes, J Grafman, SF Cappa, M Freedman, M Grossman, BL Miller. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.. Brain. 2011;134:2456-77",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"JD Rohrer, J Beck, V Plagnol, E Gordon, T Lashley, T Revesz, JC Janssen, NC Fox, JD Warren, MN Rossor, S Mead, JM Schott. Exome sequencing reveals a novel partial deletion in the progranulin gene causing primary progressive aphasia.. J Neurol Neurosurg Psychiatry. 2013;84:1411-2",
"JD Rohrer, JD Warren. Phenotypic signatures of genetic frontotemporal dementia.. Curr Opin Neurol. 2011;24:542-9",
"A Rovelet-Lecrux, V Deramecourt, S Legallic, CA Maurage, I Le Ber, A Brice, JC Lambert, T Frébourg, D Hannequin, F Pasquier, D Campion. Deletion of the progranulin gene in patients with frontotemporal lobar degeneration or Parkinson disease.. Neurobiol Dis. 2008;31:41-5",
"JC Schymick, Y Yang, PM Andersen, JP Vonsattel, M Greenway, P Momeni, J Elder, A Chio, G Restagno, W Robberecht, C Dahlberg, O Mukherjee, A Goate, N Graff-Radford, RJ Caselli, M Hutton, J Gass, A Cannon, R Rademakers, AB Singleton, O Hardiman, J Rothstein, J Hardy, BJ Traynor. Progranulin mutations and amyotrophic lateral sclerosis or amyotrophic lateral sclerosis-frontotemporal dementia phenotypes.. J Neurol Neurosurg Psychiatry 2007;78:754-6",
"WW Seeley, AM Bauer, BL Miller, ML Gorno-Tempini, JH Kramer, M Weiner, HJ Rosen. The natural history of temporal variant frontotemporal dementia.. Neurology. 2005;64:1384-90",
"M. Sendtner. TDP-43: multiple targets, multiple disease mechanisms?. Nat Neurosci. 2011;14:403-5",
"KR Smith, J Damiano, S Franceschetti, S Carpenter, L Canafoglia, M Morbin. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.. Am J Hum Genet. 2012;90:1102-7",
"S Spina, JR Murrell, ED Huey, EM Wassermann, P Pietrini, MA Baraibar, AG Barbeito, JC Troncoso, R Vidal, B Ghetti, J Grafman. Clinicopathologic features of frontotemporal dementia with progranulin sequence variation.. Neurology 2007;68:820-7",
"Y Tanaka, JK Chambers, T Matsuwaki, K Yamanouchi, M Nishihara. Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice.. Acta neuropathologica communications. 2014;2:78",
"RA Townley, BF Boeve, EE Benarroch. Progranulin: functions and neurologic correlations.. Neurology. 2018;90:118-25",
"C Valdez, D Ysselstein, TJ Young, J Zheng, D Krainc. Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity.. Hum Mol Genet. 2020;29:716-26",
"J van der Zee, I Le Ber, S Maurer-Stroh, S Engelborghs, I Gijselinck, A Camuzat, N Brouwers, R Vandenberghe, K Sleegers, D Hannequin, B Dermaut, J Schymkowitz, D Campion, P Santens, JJ Martin, L Lacomblez, T De Pooter, K Peeters, M Mattheijssens, M Vercelletto, M Van den Broeck, M Cruts, PP De Deyn, F Rousseau, A Brice, C Van Broeckhoven. Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia.. Hum Mutat 2007;28:416",
"T Van Langenhove, J van der Zee, I Gijselinck, S Engelborghs, R Vandenberghe, M Vandenbulcke, J De Bleecker, A Sieben, J Versijpt, A Ivanoiu, O Deryck, C Willems, L Dillen, S Philtjens, G Maes, V Bäumer, M Van Den Broeck, M Mattheijssens, K Peeters, JJ Martin, A Michotte, P Santens, P De Jonghe, P Cras, PP De Deyn, M Cruts, C Van Broeckhoven. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort.. JAMA Neurol. 2013;70:365-73",
"JL Whitwell, CR Jack, M Baker, R Rademakers, J Adamson, BF Boeve, DS Knopman, JF Parisi, RC Petersen, DW Dickson, ML Hutton, KA Josephs. Voxel-based morphometry in frontotemporal lobar degeneration with ubiquitin-positive inclusions with and without progranulin mutations.. Arch Neurol 2007;64:371-6",
"JL Whitwell, SD Weigand, JL Gunter, BF Boeve, R Rademakers, M Baker, DS Knopman, ZK Wszolek, RC Petersen, CR Jack, KA Josephs. Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN.. Neurology. 2011;77:393-8",
"X Zhou, DH Paushter, MD Pagan, D Kim, M Nunez Santos, RL Lieberman, HS Overkleeft, Y Sun, MB Smolka, F Hu. Progranulin deficiency leads to reduced glucocerebrosidase activity.. PLoS One. 2019;14",
"X Zhou, L Sun, O Bracko, JW Choi, Y Jia, AL Nana, OA Brady, JCC Hernandez, N Nishimura, WW Seeley, F Hu. Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations.. Nat Commun. 2017;8:15277"
] |
7/9/2007
|
6/2/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
ftdp-17
|
ftdp-17
|
[
"MAPT-Related Corticobasal Degeneration (CBD)",
"MAPT-Related Dementia with Epilepsy",
"Frontotemporal Dementia with Parkinsonism-17 (FTDP-17)",
"MAPT-Related Mild Late-Onset Parkinsonism",
"MAPT-Related Progressive Supranuclear Palsy (PSP)",
"Microtubule-associated protein tau",
"MAPT",
"MAPT-Related Frontotemporal Dementia"
] |
Jonathan Rohrer, Brigid Ryan, Rebekah Ahmed
|
Summary The spectrum of clinical manifestations of The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Age at onset ranges from 17 to 82 years; mean age of onset is 49.5 (SD: 10.0) years [
The most common initial manifestations are:
Behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) [
Parkinsonian features suggestive of either corticobasal syndrome [
Less common initial presentations include:
An amnesic presentation (which may be diagnosed as Alzheimer disease);
A language presentation (consistent with one of the primary progressive aphasia syndromes) [
A recent study showed at least two patterns of atrophy:
A "temporal" type in which atrophy initially predominantly involved the hippocampus, amygdala, anteromedial temporal cortex, and insula;
A "frontotemporal" type in which atrophy involved both the frontal lobe and temporal lobe more laterally than observed in the "temporal" type [
Absence of a known family history does not preclude the diagnosis.
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.
To date, only one individual with FTD has been described with a partial deletion of
To date, only ten individuals with FTD and a duplication of
• Age at onset ranges from 17 to 82 years; mean age of onset is 49.5 (SD: 10.0) years [
• The most common initial manifestations are:
• Behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) [
• Parkinsonian features suggestive of either corticobasal syndrome [
• Behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) [
• Parkinsonian features suggestive of either corticobasal syndrome [
• Less common initial presentations include:
• An amnesic presentation (which may be diagnosed as Alzheimer disease);
• A language presentation (consistent with one of the primary progressive aphasia syndromes) [
• An amnesic presentation (which may be diagnosed as Alzheimer disease);
• A language presentation (consistent with one of the primary progressive aphasia syndromes) [
• Behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) [
• Parkinsonian features suggestive of either corticobasal syndrome [
• An amnesic presentation (which may be diagnosed as Alzheimer disease);
• A language presentation (consistent with one of the primary progressive aphasia syndromes) [
• A recent study showed at least two patterns of atrophy:
• A "temporal" type in which atrophy initially predominantly involved the hippocampus, amygdala, anteromedial temporal cortex, and insula;
• A "frontotemporal" type in which atrophy involved both the frontal lobe and temporal lobe more laterally than observed in the "temporal" type [
• A "temporal" type in which atrophy initially predominantly involved the hippocampus, amygdala, anteromedial temporal cortex, and insula;
• A "frontotemporal" type in which atrophy involved both the frontal lobe and temporal lobe more laterally than observed in the "temporal" type [
•
• A "temporal" type in which atrophy initially predominantly involved the hippocampus, amygdala, anteromedial temporal cortex, and insula;
• A "frontotemporal" type in which atrophy involved both the frontal lobe and temporal lobe more laterally than observed in the "temporal" type [
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Age at onset ranges from 17 to 82 years; mean age of onset is 49.5 (SD: 10.0) years [
The most common initial manifestations are:
Behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) [
Parkinsonian features suggestive of either corticobasal syndrome [
Less common initial presentations include:
An amnesic presentation (which may be diagnosed as Alzheimer disease);
A language presentation (consistent with one of the primary progressive aphasia syndromes) [
A recent study showed at least two patterns of atrophy:
A "temporal" type in which atrophy initially predominantly involved the hippocampus, amygdala, anteromedial temporal cortex, and insula;
A "frontotemporal" type in which atrophy involved both the frontal lobe and temporal lobe more laterally than observed in the "temporal" type [
Absence of a known family history does not preclude the diagnosis.
• Age at onset ranges from 17 to 82 years; mean age of onset is 49.5 (SD: 10.0) years [
• The most common initial manifestations are:
• Behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) [
• Parkinsonian features suggestive of either corticobasal syndrome [
• Behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) [
• Parkinsonian features suggestive of either corticobasal syndrome [
• Less common initial presentations include:
• An amnesic presentation (which may be diagnosed as Alzheimer disease);
• A language presentation (consistent with one of the primary progressive aphasia syndromes) [
• An amnesic presentation (which may be diagnosed as Alzheimer disease);
• A language presentation (consistent with one of the primary progressive aphasia syndromes) [
• Behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) [
• Parkinsonian features suggestive of either corticobasal syndrome [
• An amnesic presentation (which may be diagnosed as Alzheimer disease);
• A language presentation (consistent with one of the primary progressive aphasia syndromes) [
• A recent study showed at least two patterns of atrophy:
• A "temporal" type in which atrophy initially predominantly involved the hippocampus, amygdala, anteromedial temporal cortex, and insula;
• A "frontotemporal" type in which atrophy involved both the frontal lobe and temporal lobe more laterally than observed in the "temporal" type [
• A "temporal" type in which atrophy initially predominantly involved the hippocampus, amygdala, anteromedial temporal cortex, and insula;
• A "frontotemporal" type in which atrophy involved both the frontal lobe and temporal lobe more laterally than observed in the "temporal" type [
•
• A "temporal" type in which atrophy initially predominantly involved the hippocampus, amygdala, anteromedial temporal cortex, and insula;
• A "frontotemporal" type in which atrophy involved both the frontal lobe and temporal lobe more laterally than observed in the "temporal" type [
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.
To date, only one individual with FTD has been described with a partial deletion of
To date, only ten individuals with FTD and a duplication of
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
The spectrum of clinical manifestations of
A recent retrospective study suggested that the majority of affected individuals have either behavioral variant FTD (bvFTD) or, less commonly, a parkinsonian syndrome (i.e., progressive supranuclear palsy, corticobasal syndrome, or Parkinson disease). Fewer than 5% of people with
+++ = most common, ++ = common, + = less common
bvFTD = behavioral variant frontotemporal dementia; CBS = corticobasal syndrome; PSP = progressive supranuclear palsy
Early behavioral disinhibition
Early apathy or inertia
Early loss of sympathy or empathy
Early perseverative stereotype or compulsive/ritualistic behavior
Hyperorality or dietary change
Neuropsychological profile of executive function difficulties with relative sparing of memory and visuospatial symptoms
Some individuals with
Progression of motor impairment in affected individuals results in some becoming chairbound and others bedbound.
The following genotype-phenotype correlations have been observed [
The common variants
The variant
A sizeable minority of individuals with the variant
The less common variants
The variants
The prevalence of
• Early behavioral disinhibition
• Early apathy or inertia
• Early loss of sympathy or empathy
• Early perseverative stereotype or compulsive/ritualistic behavior
• Hyperorality or dietary change
• Neuropsychological profile of executive function difficulties with relative sparing of memory and visuospatial symptoms
• The common variants
• The variant
• A sizeable minority of individuals with the variant
• The less common variants
• The variants
## Clinical Description
The spectrum of clinical manifestations of
A recent retrospective study suggested that the majority of affected individuals have either behavioral variant FTD (bvFTD) or, less commonly, a parkinsonian syndrome (i.e., progressive supranuclear palsy, corticobasal syndrome, or Parkinson disease). Fewer than 5% of people with
+++ = most common, ++ = common, + = less common
bvFTD = behavioral variant frontotemporal dementia; CBS = corticobasal syndrome; PSP = progressive supranuclear palsy
Early behavioral disinhibition
Early apathy or inertia
Early loss of sympathy or empathy
Early perseverative stereotype or compulsive/ritualistic behavior
Hyperorality or dietary change
Neuropsychological profile of executive function difficulties with relative sparing of memory and visuospatial symptoms
Some individuals with
Progression of motor impairment in affected individuals results in some becoming chairbound and others bedbound.
• Early behavioral disinhibition
• Early apathy or inertia
• Early loss of sympathy or empathy
• Early perseverative stereotype or compulsive/ritualistic behavior
• Hyperorality or dietary change
• Neuropsychological profile of executive function difficulties with relative sparing of memory and visuospatial symptoms
## Genotype-Phenotype Correlations
The following genotype-phenotype correlations have been observed [
The common variants
The variant
A sizeable minority of individuals with the variant
The less common variants
The variants
• The common variants
• The variant
• A sizeable minority of individuals with the variant
• The less common variants
• The variants
## Penetrance
## Nomenclature
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
A 17q21.31 deletion that includes
## Differential Diagnosis
The clinical characteristics of
Around 30% of individuals with FTD have familial FTD (i.e., a positive family history of dementia, usually with autosomal dominant inheritance).
Note: On rare occasions individuals with
Genes of Interest in the Differential Diagnosis of
AD= Alzheimer disease; ALS = amyotrophic lateral sclerosis; bvFTD = behavioral variant FTD; CBS = corticobasal syndrome; CNS = central nervous system; DiffDx = differential diagnosis; FTD = frontotemporal dementia; FUS = fused in sarcoma; HD = Huntington disease; LGMD = limb-girdle muscular dystrophy; PD = Parkinson disease; PDB = Paget disease of bone; PLS = primary lateral sclerosis; PPA = primary progressive aphasia
See
Paget disease of bone (PDB) involves focal areas of increased bone turnover that typically leads to spine and/or hip pain and localized enlargement and deformity of the long bones.
Muscle weakness progresses to involve other limb and respiratory muscles; cardiac failure and cardiomyopathy have been observed in later stages of IBMPFD.
It is likely that pathogenic variants in other genes causative of early-onset familial Alzheimer disease will be identified because kindreds with autosomal dominant familial Alzheimer disease with no known pathogenic variants in
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
PT needs
Need for assistive walking devices (e.g., cane, walker, walker w/wheels, walker w/seat, wheelchair)
Fine motor function (e.g., hands, feet, face, fingers, & toes)
Home adaptations for ADL & safety
Community or
Social work involvement for parental support;
Home nursing referral.
Early discussion of advanced care planning is warranted.
The affected individual's perspective & burden must be taken into account for clinical decision making.
The presence of cognitive impairment may raise ethical concerns.
ADL = activities of daily living; CDR = Clinical Dementia Rating
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
When severe manifestations (agitation, aggressiveness, psychosis) are refractory to SSRIs, often a temporizing measure is used until persons become more apathetic.
Note: Risk of iatrogenic extrapyramidal syndrome
PT = physical therapy; SSRIs = selective serotonin reuptake inhibitors
See
Search
• Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• PT needs
• Need for assistive walking devices (e.g., cane, walker, walker w/wheels, walker w/seat, wheelchair)
• Fine motor function (e.g., hands, feet, face, fingers, & toes)
• Home adaptations for ADL & safety
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Early discussion of advanced care planning is warranted.
• The affected individual's perspective & burden must be taken into account for clinical decision making.
• The presence of cognitive impairment may raise ethical concerns.
• When severe manifestations (agitation, aggressiveness, psychosis) are refractory to SSRIs, often a temporizing measure is used until persons become more apathetic.
• Note: Risk of iatrogenic extrapyramidal syndrome
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
PT needs
Need for assistive walking devices (e.g., cane, walker, walker w/wheels, walker w/seat, wheelchair)
Fine motor function (e.g., hands, feet, face, fingers, & toes)
Home adaptations for ADL & safety
Community or
Social work involvement for parental support;
Home nursing referral.
Early discussion of advanced care planning is warranted.
The affected individual's perspective & burden must be taken into account for clinical decision making.
The presence of cognitive impairment may raise ethical concerns.
ADL = activities of daily living; CDR = Clinical Dementia Rating
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• PT needs
• Need for assistive walking devices (e.g., cane, walker, walker w/wheels, walker w/seat, wheelchair)
• Fine motor function (e.g., hands, feet, face, fingers, & toes)
• Home adaptations for ADL & safety
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Early discussion of advanced care planning is warranted.
• The affected individual's perspective & burden must be taken into account for clinical decision making.
• The presence of cognitive impairment may raise ethical concerns.
## Treatment of Manifestations
There is no cure for
When severe manifestations (agitation, aggressiveness, psychosis) are refractory to SSRIs, often a temporizing measure is used until persons become more apathetic.
Note: Risk of iatrogenic extrapyramidal syndrome
PT = physical therapy; SSRIs = selective serotonin reuptake inhibitors
• When severe manifestations (agitation, aggressiveness, psychosis) are refractory to SSRIs, often a temporizing measure is used until persons become more apathetic.
• Note: Risk of iatrogenic extrapyramidal syndrome
## Surveillance
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals diagnosed with
A proband with a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with
If a parent of the proband is affected or is known to have a
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. For more information, see the National Society of Genetic Counselors
• Most individuals diagnosed with
• A proband with a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected or is known to have a
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
## Mode of Inheritance
## Risk to Family Members
Most individuals diagnosed with
A proband with a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with
If a parent of the proband is affected or is known to have a
If the
• Most individuals diagnosed with
• A proband with a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected or is known to have a
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Predictive testing for at-risk relatives is possible once the
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once the
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. For more information, see the National Society of Genetic Counselors
## Resources
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## Molecular Genetics
MAPT-Related Frontotemporal Dementia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MAPT-Related Frontotemporal Dementia (
Tau protein, encoded by
Notable
Variants listed in the table have been provided by the authors.
Nucleotide change is predicted to disrupt splicing [
## Molecular Pathogenesis
Tau protein, encoded by
Notable
Variants listed in the table have been provided by the authors.
Nucleotide change is predicted to disrupt splicing [
## Chapter Notes
Jonathan Rohrer is a Professor of Neurology at the Dementia Research Centre in the Queen Square UCL Institute of Neurology as well as a Consultant Neurologist at the National Hospital for Neurology and Neurosurgery. He is also a Clinical Co-Investigator at the UK Dementia Research Institute. After a Natural Sciences degree at the University of Cambridge he went on to study medicine at the University of Oxford and UCL. He started as a Wellcome Trust Clinical Research Fellow in 2005 at UCL, where he first began to study frontotemporal dementia (FTD) including the neuroimaging of genetic FTD, and completed his
The authors would like to thank the patients and family members who take part in the
Rebekah Ahmed, FRACP, PhD (2022-present)Peter Heutink, PhD, Vrije Universiteit Medical Center, Amsterdam (2000-2022)Jonathan Rohrer, FRCP, PhD (2022-present)Sonia M Rosso, MD, PhD, Havenziekenhuis, Rotterdam (2000-2022)Brigid Ryan, PhD (2022-present)John C van Swieten, MD, PhD, Erasmus Medical Center, Rotterdam (2000-2022)
18 August 2022 (bp) Comprehensive update posted live
26 October 2010 (me) Comprehensive update posted live
18 November 2005 (me) Comprehensive update posted to live Web site
5 August 2003 (me) Comprehensive update posted to live Web site
7 November 2000 (me) Review posted live
30 June 2000 (jvs) Original submission
• 18 August 2022 (bp) Comprehensive update posted live
• 26 October 2010 (me) Comprehensive update posted live
• 18 November 2005 (me) Comprehensive update posted to live Web site
• 5 August 2003 (me) Comprehensive update posted to live Web site
• 7 November 2000 (me) Review posted live
• 30 June 2000 (jvs) Original submission
## Author Notes
Jonathan Rohrer is a Professor of Neurology at the Dementia Research Centre in the Queen Square UCL Institute of Neurology as well as a Consultant Neurologist at the National Hospital for Neurology and Neurosurgery. He is also a Clinical Co-Investigator at the UK Dementia Research Institute. After a Natural Sciences degree at the University of Cambridge he went on to study medicine at the University of Oxford and UCL. He started as a Wellcome Trust Clinical Research Fellow in 2005 at UCL, where he first began to study frontotemporal dementia (FTD) including the neuroimaging of genetic FTD, and completed his
## Acknowledgments
The authors would like to thank the patients and family members who take part in the
## Author History
Rebekah Ahmed, FRACP, PhD (2022-present)Peter Heutink, PhD, Vrije Universiteit Medical Center, Amsterdam (2000-2022)Jonathan Rohrer, FRCP, PhD (2022-present)Sonia M Rosso, MD, PhD, Havenziekenhuis, Rotterdam (2000-2022)Brigid Ryan, PhD (2022-present)John C van Swieten, MD, PhD, Erasmus Medical Center, Rotterdam (2000-2022)
## Revision History
18 August 2022 (bp) Comprehensive update posted live
26 October 2010 (me) Comprehensive update posted live
18 November 2005 (me) Comprehensive update posted to live Web site
5 August 2003 (me) Comprehensive update posted to live Web site
7 November 2000 (me) Review posted live
30 June 2000 (jvs) Original submission
• 18 August 2022 (bp) Comprehensive update posted live
• 26 October 2010 (me) Comprehensive update posted live
• 18 November 2005 (me) Comprehensive update posted to live Web site
• 5 August 2003 (me) Comprehensive update posted to live Web site
• 7 November 2000 (me) Review posted live
• 30 June 2000 (jvs) Original submission
## References
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"B Ghetti, AL Oblak, BF Boeve, KA Johnson, BC Dickerson, M Goedert. Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging.. Neuropathol Appl Neurobiol. 2015;41:24-46",
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"SY Im, YE Kim, YJ Kim. Genetics of progressive supranuclear palsy.. J Mov Disord. 2015;8:122-9",
"E Mioshi, S Hsieh, S Savage, M Hornberger, JR Hodges. Neurology. 2010;74:1591-7",
"T Miyagawa, D Brushaber, J Syrjanen, W Kremers, J Fields, LK Forsberg, HW Heuer, D Knopman, J Kornak, A Boxer, HJ Rosen, BF Boeve, B Appleby, Y Bordelon, J Bove, P Brannelly, C Caso, G Coppola, R Dever, C Dheel, B Dickerson, S Dickinson, S Dominguez, K Domoto-Reilly, K Faber, J Ferrell, A Fishman, J Fong, T Foroud, R Gavrilova, D Gearhart, B Ghazanfari, N Ghoshal, JS Goldman, J Graff-Radford, N Graff-Radford, I Grant, M Grossman, D Haley, R Hsiung, E Huey, D Irwin, D Jones, L Jones, K Kantarci, A Karydas, D Kaufer, D Kerwin, R Kraft, J Kramer, W Kukull, I Litvan, D Lucente, C Lungu, I Mackenzie, M Maldonado, M Manoochehri, S McGinnis, E McKinley, MF Mendez, B Miller, N Multani, C Onyike, J Padmanabhan, A Pantelyat, R Pearlman, L Petrucelli, M Potter, R Rademakers, EM Ramos, K Rankin, K Rascovsky, ED Roberson, E Rogalski, P Sengdy, L Shaw, MC Tartaglia, N Tatton, J Taylor, A Toga, JQ Trojanowski, P Wang, S Weintraub, B Wong, Z Wszolek. Alzheimers Dement. 2020;16:106-17",
"KM Moore, J Nicholas, M Grossman, CT McMillan, DJ Irwin, L Massimo, VM Van Deerlin, JD Warren, NC Fox, MN Rossor, S Mead, M Bocchetta, BF Boeve, DS Knopman, NR Graff-Radford, LK Forsberg, R Rademakers, ZK Wszolek, JC van Swieten, LC Jiskoot, LH Meeter, EG Dopper, JM Papma, JS Snowden, J Saxon, M Jones, S Pickering-Brown, I Le Ber, A Camuzat, A Brice, P Caroppo, R Ghidoni, M Pievani, L Benussi, G Binetti, BC Dickerson, D Lucente, S Krivensky, C Graff, L Oijerstedt, M Fallstrom, H Thonberg, N Ghoshal, JC Morris, B Borroni, A Benussi, A Padovani, D Galimberti, E Scarpini, GG Fumagalli, IR Mackenzie, GR Hsiung, P Sengdy, AL Boxer, H Rosen, JB Taylor, M Synofzik, C Wilke, P Sulzer, JR Hodges, G Halliday, J Kwok, R Sanchez-Valle, A Llado, S Borrego-Ecija, I Santana, MR Almeida, M Tabuas-Pereira, F Moreno, M Barandiaran, B Indakoetxea, J Levin, A Danek, JB Rowe, TE Cope, M Otto, S Anderl-Straub, A de Mendonca, C Maruta, M Masellis, SE Black, P Couratier, G Lautrette, ED Huey, S Sorbi, B Nacmias, R Laforce, ML Tremblay, R Vandenberghe, PV Damme, EJ Rogalski, S Weintraub, A Gerhard, CU Onyike, S Ducharme, SG Papageorgiou, ASL Ng, A Brodtmann, E Finger, R Guerreiro, J Bras, JD Rohrer. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.. Lancet Neurol. 2020;19:145-56",
"DG Munoz, R Ros, M Fatas, F Bermejo, JG de Yebenes. Progressive nonfluent aphasia associated with a new mutation V363I in tau gene.. Am J Alzheimers Dis Other Demen. 2007;22:294-9",
"K Rascovsky, JR Hodges, D Knopman, MF Mendez, JH Kramer, J Neuhaus, JC van Swieten, H Seelaar, EG Dopper, CU Onyike, AE Hillis, KA Josephs, BF Boeve, A Kertesz, WW Seeley, KP Rankin, JK Johnson, ML Gorno-Tempini, H Rosen, CE Prioleau-Latham, A Lee, CM Kipps, P Lillo, O Piguet, JD Rohrer, MN Rossor, JD Warren, NC Fox, D Galasko, DP Salmon, SE Black, M Mesulam, S Weintraub, BC Dickerson, J Diehl-Schmid, F Pasquier, V Deramecourt, F Lebert, Y Pijnenburg, TW Chow, F Manes, J Grafman, SF Cappa, M Freedman, M Grossman, BL Miller. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.. Brain. 2011;134:2456-77",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"A Rovelet-Lecrux, M Lecourtois, C Thomas-Anterion, I Le Ber, A Brice, T Frebourg, D Hannequin, D Campion. Partial deletion of the MAPT gene: a novel mechanism of FTDP-17.. Hum Mutat 2009;30:E591-602",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"H Tubeuf, C Charbonnier, O Soukarieh, A Blavier, A Lefebvre, H Dauchel, T Frebourg, P Gaildrat, A Martins. Large-scale comparative evaluation of user-friendly tools for predicting variant-induced alterations of splicing regulatory elements.. Hum Mutat. 2020;41:1811-29",
"RR Valentino, S Koga, RL Walton, AI Soto-Beasley, N Kouri, MA DeTure, ME Murray, PW Johnson, RC Petersen, BF Boeve, RJ Uitti, ZK Wszolek, DW Dickson, OA Ross, MG Heckman. MAPT subhaplotypes in corticobasal degeneration: assessing associations with disease risk, severity of tau pathology, and clinical features.. Acta Neuropathol Commun. 2020;8:218",
"C Villa, L Ghezzi, AM Pietroboni, C Fenoglio, F Cortini, M Serpente, C Cantoni, E Ridolfi, A Marcone, L Benussi, R Ghidoni, F Jacini, A Arighi, GG Fumagalli, A Mandelli, G Binetti, S Cappa, N Bresolin, E Scarpini, D Galimberti. A novel MAPT mutation associated with the clinical phenotype of progressive nonfluent aphasia.. J Alzheimers Dis. 2011;26:19-26",
"D Wallon, S Boluda, A Rovelet-Lecrux, M Thierry, J Lagarde, L Miguel, M Lecourtois, A Bonnevalle, M Sarazin, M Bottlaender, M Mula, S Marty, N Nakamura, C Schramm, F Sellal, T Jonveaux, C Heitz, I Le Ber, S Epelbaum, E Magnin, A Zarea, S Rousseau, O Quenez, D Hannequin, F Clavaguera, D Campion, C Duyckaerts, G. Nicolas. Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers.. Acta Neuropathol. 2021;142:259-78",
"AL Young, M Bocchetta, LL Russell, RS Convery, G Peakman, E Todd, DM Cash, CV Greaves, J van Swieten, L Jiskoot, H Seelaar, F Moreno, R Sanchez-Valle, B Borroni, R Laforce, M Masellis, MC Tartaglia, C Graff, D Galimberti, JB Rowe, E Finger, M Synofzik, R Vandenberghe, A de Mendonca, F Tagliavini, I Santana, S Ducharme, C Butler, A Gerhard, J Levin, A Danek, M Otto, S Sorbi, SC Williams, DC Alexander, JD Rohrer. Characterizing the clinical features and atrophy patterns of MAPT-related frontotemporal dementia with disease progression modeling.. Neurology. 2021;97:e941-e952"
] |
7/11/2000
|
18/8/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
fum
|
fum
|
[
"Fumarase Deficiency",
"Fumaric Aciduria",
"Fumaric Aciduria",
"Fumarase Deficiency",
"Fumarate hydratase, mitochondrial",
"FH",
"Fumarate Hydratase Deficiency"
] |
Fumarate Hydratase Deficiency
|
David Coman, Kamil R Kranc, John Christodoulou
|
Summary Fumarate hydratase (FH) deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are nonverbal and nonambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported. Isolated increased fumaric acid and alpha-ketoglutarate on urine organic acid analysis, combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency. The diagnosis of FH deficiency is established in a proband with reduced fumarate hydratase enzyme activity in fibroblasts or leukocytes and/or biallelic pathogenic variants in FH deficiency is inherited in an autosomal recessive manner. When both parents are known to be heterozygous for an
|
## Diagnosis
Fumarate hydratase (FH) deficiency
Neonatal and early-infantile severe encephalopathy, which may include poor feeding, hypotonia, and decreased levels of consciousness (lethargy, stupor, and coma)
Seizures, present in many but not all affected individuals
Intellectual disability / developmental delay
Dysmorphic facial features including frontal bossing, depressed nasal bridge, and widely spaced eyes
Finding of isolated increased fumaric acid and alpha-ketoglutarate on urine organic acid analysis combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency.
Reduced fumarate hydratase enzyme activity. Fumarate hydratase enzyme activity can be measured in fibroblasts or leukocytes. Fumarate hydratase enzyme activity in severely affected individuals is often less than 10% of the control mean; however, residual fumarate hydratase enzyme activity in some affected individuals can be 11%-35% of the control mean. FH deficiency is evident in both isozymes – the mitochondrial form and the cytosolic form (see
The diagnosis of FH deficiency
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FH deficiency is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of FH deficiency, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and/or intellectual disability,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fumarate Hydratase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A whole-gene deletion in an individual with fumarate hydratase deficiency was reported by
• Neonatal and early-infantile severe encephalopathy, which may include poor feeding, hypotonia, and decreased levels of consciousness (lethargy, stupor, and coma)
• Seizures, present in many but not all affected individuals
• Intellectual disability / developmental delay
• Dysmorphic facial features including frontal bossing, depressed nasal bridge, and widely spaced eyes
• Finding of isolated increased fumaric acid and alpha-ketoglutarate on urine organic acid analysis combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency.
• Reduced fumarate hydratase enzyme activity. Fumarate hydratase enzyme activity can be measured in fibroblasts or leukocytes. Fumarate hydratase enzyme activity in severely affected individuals is often less than 10% of the control mean; however, residual fumarate hydratase enzyme activity in some affected individuals can be 11%-35% of the control mean. FH deficiency is evident in both isozymes – the mitochondrial form and the cytosolic form (see
• For an introduction to multigene panels click
## Suggestive Findings
Fumarate hydratase (FH) deficiency
Neonatal and early-infantile severe encephalopathy, which may include poor feeding, hypotonia, and decreased levels of consciousness (lethargy, stupor, and coma)
Seizures, present in many but not all affected individuals
Intellectual disability / developmental delay
Dysmorphic facial features including frontal bossing, depressed nasal bridge, and widely spaced eyes
Finding of isolated increased fumaric acid and alpha-ketoglutarate on urine organic acid analysis combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency.
Reduced fumarate hydratase enzyme activity. Fumarate hydratase enzyme activity can be measured in fibroblasts or leukocytes. Fumarate hydratase enzyme activity in severely affected individuals is often less than 10% of the control mean; however, residual fumarate hydratase enzyme activity in some affected individuals can be 11%-35% of the control mean. FH deficiency is evident in both isozymes – the mitochondrial form and the cytosolic form (see
• Neonatal and early-infantile severe encephalopathy, which may include poor feeding, hypotonia, and decreased levels of consciousness (lethargy, stupor, and coma)
• Seizures, present in many but not all affected individuals
• Intellectual disability / developmental delay
• Dysmorphic facial features including frontal bossing, depressed nasal bridge, and widely spaced eyes
• Finding of isolated increased fumaric acid and alpha-ketoglutarate on urine organic acid analysis combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency.
• Reduced fumarate hydratase enzyme activity. Fumarate hydratase enzyme activity can be measured in fibroblasts or leukocytes. Fumarate hydratase enzyme activity in severely affected individuals is often less than 10% of the control mean; however, residual fumarate hydratase enzyme activity in some affected individuals can be 11%-35% of the control mean. FH deficiency is evident in both isozymes – the mitochondrial form and the cytosolic form (see
## Establishing the Diagnosis
The diagnosis of FH deficiency
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of FH deficiency is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of FH deficiency, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and/or intellectual disability,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fumarate Hydratase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A whole-gene deletion in an individual with fumarate hydratase deficiency was reported by
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of FH deficiency, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by seizures and/or intellectual disability,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Fumarate Hydratase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A whole-gene deletion in an individual with fumarate hydratase deficiency was reported by
## Clinical Characteristics
To date, approximately 50 individuals have been identified with fumarate hydratase (FH) deficiency [
Select Features of Fumarate Hydratase Deficiency
DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth retardation
Note: Some infants died in the neonatal period.
Few clinical reports comment on complications of affected pregnancies. However, polyhydramnios, oligohydramnios, intrauterine growth retardation, and premature birth (typically at 33-36 weeks' gestation) are reported in approximately one third of affected pregnancies [
Newborns with FH deficiency may be symptomatic immediately following delivery or may appear normal at birth and be discharged home from the nursery without recognized problems [
Epileptic seizures are common (40%-80%), with variable age of onset and seizure type [
Abnormal facial features with a spectrum of specific findings have been widely reported and should be regarded as a hallmark feature of this condition (although perhaps not universal). Common features (>50% of affected individuals) include depressed nasal bridge, frontal bossing, and widely spaced eyes [
Head size has been reported as microcephalic in 36% of all affected individuals [
The most common finding is a small brain, representative of cerebral underdevelopment. This may be described by the neuroradiologist as cerebral atrophy (73% of all individuals summarized by
Additional findings on MRI can include nonspecific white matter abnormalities, described as either delayed myelination or hypomyelination [
Acute metabolic crises with findings such as hypoglycemia, ketosis, hyperammonemia, or acidosis are rarely observed in individuals with FH deficiency [
Other findings can include neonatal polycythemia [
The clinical outcome for individuals with FH deficiency is not favorable. Many individuals do not survive infancy, or may die of secondary complications (e.g., respiratory failure) during the first decade of life [
Over time, severely affected children (usually nonverbal and nonambulatory) develop evidence of spasticity, and consequently are at risk for contractures and orthopedic deformities including scoliosis. Extrapyramidal motor features, including athetosis and dystonic posturing, can also be observed. Epileptic seizures often become more frequent and less responsive to treatment. Seizures may occur daily in some individuals.
However, less severely affected children, who may be ambulatory and capable of engaging in special needs school programs (despite the presence of bilateral polymicrogyria), have also been reported [
Most heterozygous parents are healthy. However, the finding of cutaneous leiomyomata without uterine fibroids in the mother of an affected child [
No genotype-phenotype correlations have been identified.
FH deficiency is rare. Fewer than 100 individuals have been reported. The disorder occurs in individuals of different ethnic backgrounds.
## Clinical Description
To date, approximately 50 individuals have been identified with fumarate hydratase (FH) deficiency [
Select Features of Fumarate Hydratase Deficiency
DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth retardation
Note: Some infants died in the neonatal period.
Few clinical reports comment on complications of affected pregnancies. However, polyhydramnios, oligohydramnios, intrauterine growth retardation, and premature birth (typically at 33-36 weeks' gestation) are reported in approximately one third of affected pregnancies [
Newborns with FH deficiency may be symptomatic immediately following delivery or may appear normal at birth and be discharged home from the nursery without recognized problems [
Epileptic seizures are common (40%-80%), with variable age of onset and seizure type [
Abnormal facial features with a spectrum of specific findings have been widely reported and should be regarded as a hallmark feature of this condition (although perhaps not universal). Common features (>50% of affected individuals) include depressed nasal bridge, frontal bossing, and widely spaced eyes [
Head size has been reported as microcephalic in 36% of all affected individuals [
The most common finding is a small brain, representative of cerebral underdevelopment. This may be described by the neuroradiologist as cerebral atrophy (73% of all individuals summarized by
Additional findings on MRI can include nonspecific white matter abnormalities, described as either delayed myelination or hypomyelination [
Acute metabolic crises with findings such as hypoglycemia, ketosis, hyperammonemia, or acidosis are rarely observed in individuals with FH deficiency [
Other findings can include neonatal polycythemia [
The clinical outcome for individuals with FH deficiency is not favorable. Many individuals do not survive infancy, or may die of secondary complications (e.g., respiratory failure) during the first decade of life [
Over time, severely affected children (usually nonverbal and nonambulatory) develop evidence of spasticity, and consequently are at risk for contractures and orthopedic deformities including scoliosis. Extrapyramidal motor features, including athetosis and dystonic posturing, can also be observed. Epileptic seizures often become more frequent and less responsive to treatment. Seizures may occur daily in some individuals.
However, less severely affected children, who may be ambulatory and capable of engaging in special needs school programs (despite the presence of bilateral polymicrogyria), have also been reported [
Most heterozygous parents are healthy. However, the finding of cutaneous leiomyomata without uterine fibroids in the mother of an affected child [
## Fetal Manifestations
Few clinical reports comment on complications of affected pregnancies. However, polyhydramnios, oligohydramnios, intrauterine growth retardation, and premature birth (typically at 33-36 weeks' gestation) are reported in approximately one third of affected pregnancies [
## Neonatal and Early-Infantile Encephalopathy
Newborns with FH deficiency may be symptomatic immediately following delivery or may appear normal at birth and be discharged home from the nursery without recognized problems [
Epileptic seizures are common (40%-80%), with variable age of onset and seizure type [
## Dysmorphic Facial Features
Abnormal facial features with a spectrum of specific findings have been widely reported and should be regarded as a hallmark feature of this condition (although perhaps not universal). Common features (>50% of affected individuals) include depressed nasal bridge, frontal bossing, and widely spaced eyes [
## Head Size
Head size has been reported as microcephalic in 36% of all affected individuals [
## Brain Imaging Findings
The most common finding is a small brain, representative of cerebral underdevelopment. This may be described by the neuroradiologist as cerebral atrophy (73% of all individuals summarized by
Additional findings on MRI can include nonspecific white matter abnormalities, described as either delayed myelination or hypomyelination [
## Acute Metabolic Derangements
Acute metabolic crises with findings such as hypoglycemia, ketosis, hyperammonemia, or acidosis are rarely observed in individuals with FH deficiency [
## Other Clinical Features
Other findings can include neonatal polycythemia [
## Clinical Course
The clinical outcome for individuals with FH deficiency is not favorable. Many individuals do not survive infancy, or may die of secondary complications (e.g., respiratory failure) during the first decade of life [
Over time, severely affected children (usually nonverbal and nonambulatory) develop evidence of spasticity, and consequently are at risk for contractures and orthopedic deformities including scoliosis. Extrapyramidal motor features, including athetosis and dystonic posturing, can also be observed. Epileptic seizures often become more frequent and less responsive to treatment. Seizures may occur daily in some individuals.
However, less severely affected children, who may be ambulatory and capable of engaging in special needs school programs (despite the presence of bilateral polymicrogyria), have also been reported [
## Heterozygotes
Most heterozygous parents are healthy. However, the finding of cutaneous leiomyomata without uterine fibroids in the mother of an affected child [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
FH deficiency is rare. Fewer than 100 individuals have been reported. The disorder occurs in individuals of different ethnic backgrounds.
## Genetically Related (Allelic) Disorders
Sporadic tumors occurring as single tumors in the absence of any other findings of hereditary leiomyomatosis and renal cell cancer were found to have biallelic somatic pathogenic variants in
## Differential Diagnosis
Increased excretion of fumaric acid along with other citric acid intermediates is seen in mitochondrial disorders, including subacute necrotizing encephalomyelopathy (see
## Management
To establish the extent of disease and needs in an individual diagnosed with fumarate hydratase (FH) deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fumarate Hydratase Deficiency
Treatment of Manifestations in Individuals with Fumarate Hydratase Deficiency
Ketogenic diet is considered contraindicated.
Seizures are often difficult to control.
One individual with FH deficiency has been treated with a high-fat/low-carbohydrate diet with 60% of the dietary energy goals coming from fat, 30% from carbohydrate, and 10% from protein [
Recommended Surveillance for Individuals with Fumarate Hydratase Deficiency
The ketogenic diet is usually considered to be contraindicated for treating epilepsy associated with FH deficiency or other enzymatic defects within the Krebs tricarboxylic acid cycle.
If the
See
Increasingly sophisticated models of mitochondrial function are being used to study the metabolic derangements associated with identified defects of intermediary metabolism, including FH deficiency [
Search
No significant clinical or biochemical improvement was noted by treatment with a protein-restricted diet [unpublished data]. A brief therapeutic trial of a low-protein diet in one mildly affected individual with FH deficiency did not alter urinary excretion of fumaric acid or improve clinical signs [
• Ketogenic diet is considered contraindicated.
• Seizures are often difficult to control.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with fumarate hydratase (FH) deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Fumarate Hydratase Deficiency
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Fumarate Hydratase Deficiency
Ketogenic diet is considered contraindicated.
Seizures are often difficult to control.
• Ketogenic diet is considered contraindicated.
• Seizures are often difficult to control.
## Prevention of Primary Manifestations
One individual with FH deficiency has been treated with a high-fat/low-carbohydrate diet with 60% of the dietary energy goals coming from fat, 30% from carbohydrate, and 10% from protein [
## Surveillance
Recommended Surveillance for Individuals with Fumarate Hydratase Deficiency
## Agents/Circumstances to Avoid
The ketogenic diet is usually considered to be contraindicated for treating epilepsy associated with FH deficiency or other enzymatic defects within the Krebs tricarboxylic acid cycle.
## Evaluation of Relatives at Risk
If the
See
## Therapies Under Investigation
Increasingly sophisticated models of mitochondrial function are being used to study the metabolic derangements associated with identified defects of intermediary metabolism, including FH deficiency [
Search
## Other
No significant clinical or biochemical improvement was noted by treatment with a protein-restricted diet [unpublished data]. A brief therapeutic trial of a low-protein diet in one mildly affected individual with FH deficiency did not alter urinary excretion of fumaric acid or improve clinical signs [
## Genetic Counseling
Fumarate hydratase (FH) deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for one
A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's
In another family, FH deficiency resulted from partial uniparental isodisomy of chromosome 1 [
The heterozygous parents of a proband are at risk of developing
If both parents are known to be heterozygous for an
Each sib of an affected individual has at conception a 25% chance of having FH deficiency and a 25% chance of having no pathogenic variant in
Heterozygotes are at risk of developing HLRCC.
When FH deficiency occurs as the result of an unusual mechanism (e.g., a
See Management,
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygous or are at risk of being heterozygous.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for one
• A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's
• In another family, FH deficiency resulted from partial uniparental isodisomy of chromosome 1 [
• A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's
• In another family, FH deficiency resulted from partial uniparental isodisomy of chromosome 1 [
• The heterozygous parents of a proband are at risk of developing
• A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's
• In another family, FH deficiency resulted from partial uniparental isodisomy of chromosome 1 [
• If both parents are known to be heterozygous for an
• Each sib of an affected individual has at conception a 25% chance of having FH deficiency and a 25% chance of having no pathogenic variant in
• Heterozygotes are at risk of developing HLRCC.
• Each sib of an affected individual has at conception a 25% chance of having FH deficiency and a 25% chance of having no pathogenic variant in
• Heterozygotes are at risk of developing HLRCC.
• When FH deficiency occurs as the result of an unusual mechanism (e.g., a
• Each sib of an affected individual has at conception a 25% chance of having FH deficiency and a 25% chance of having no pathogenic variant in
• Heterozygotes are at risk of developing HLRCC.
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygous or are at risk of being heterozygous.
## Mode of Inheritance
Fumarate hydratase (FH) deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for one
A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's
In another family, FH deficiency resulted from partial uniparental isodisomy of chromosome 1 [
The heterozygous parents of a proband are at risk of developing
If both parents are known to be heterozygous for an
Each sib of an affected individual has at conception a 25% chance of having FH deficiency and a 25% chance of having no pathogenic variant in
Heterozygotes are at risk of developing HLRCC.
When FH deficiency occurs as the result of an unusual mechanism (e.g., a
• The parents of an affected child are presumed to be heterozygous for one
• A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's
• In another family, FH deficiency resulted from partial uniparental isodisomy of chromosome 1 [
• A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's
• In another family, FH deficiency resulted from partial uniparental isodisomy of chromosome 1 [
• The heterozygous parents of a proband are at risk of developing
• A father whose paternity was confirmed by haplotyping had normal fumarate hydratase enzyme activity and no evidence of either of his child's
• In another family, FH deficiency resulted from partial uniparental isodisomy of chromosome 1 [
• If both parents are known to be heterozygous for an
• Each sib of an affected individual has at conception a 25% chance of having FH deficiency and a 25% chance of having no pathogenic variant in
• Heterozygotes are at risk of developing HLRCC.
• Each sib of an affected individual has at conception a 25% chance of having FH deficiency and a 25% chance of having no pathogenic variant in
• Heterozygotes are at risk of developing HLRCC.
• When FH deficiency occurs as the result of an unusual mechanism (e.g., a
• Each sib of an affected individual has at conception a 25% chance of having FH deficiency and a 25% chance of having no pathogenic variant in
• Heterozygotes are at risk of developing HLRCC.
## Heterozygote Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygous or are at risk of being heterozygous.
• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygous or are at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
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•
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• United Kingdom
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## Molecular Genetics
Fumarate Hydratase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Fumarate Hydratase Deficiency (
FH deficiency results in a genetic block in Krebs cycle and the inability of cells to metabolize fumarate in the cytosol. As a consequence, fumarate is substantially accumulated intracellularly and extracellularly and in excessive levels it is toxic to the cells, thus causing multiple developmental defects.
The p.Lys477dup variant is the variant most frequently associated with FH deficiency [
Notable
Variants listed in the table have been provided by the authors.
The numbering system for the
Sporadic tumors (including 2 early-onset uterine leiomyomas and a soft tissue sarcoma of the lower limb) occurring as single tumors in the absence of any other findings of hereditary leiomyomatosis and renal cell cancer were found to have biallelic somatic pathogenic variants in
Loss of FH enzymatic activity leads to the accumulation of intracellular fumarate, which is thought to function as an oncometabolite, an intermediate of cellular metabolism that promotes cancer formation. Fumarate is known to competitively inhibit 2-oxoglutarate (2OG)-dependent oxygenases, including HIF prolyl hydroxylases, thus resulting in an increased stability of HIFs, which are thought to be oncogenic drivers in certain tumors. High levels of cytoplasmic fumarate also result in the modification of protein cysteine residues, forming S-(2-succinyl)-cysteine, in the process called succination, thereby affecting multiple cellular pathways. Furthermore, elevated fumarate succinates glutathione (GSH; a major cellular protection against reactive oxygen species), and by depleting the GSH pool it causes oxidative stress, a common feature of many cancers. While the exact causal mechanism by which elevated fumarate promotes cancer formation is not well defined, it is highly likely that fumarate synergistically affects multiple cellular pathways to exert its pathogenic effects.
## Molecular Pathogenesis
FH deficiency results in a genetic block in Krebs cycle and the inability of cells to metabolize fumarate in the cytosol. As a consequence, fumarate is substantially accumulated intracellularly and extracellularly and in excessive levels it is toxic to the cells, thus causing multiple developmental defects.
The p.Lys477dup variant is the variant most frequently associated with FH deficiency [
Notable
Variants listed in the table have been provided by the authors.
The numbering system for the
## Cancer and Benign Tumors
Sporadic tumors (including 2 early-onset uterine leiomyomas and a soft tissue sarcoma of the lower limb) occurring as single tumors in the absence of any other findings of hereditary leiomyomatosis and renal cell cancer were found to have biallelic somatic pathogenic variants in
Loss of FH enzymatic activity leads to the accumulation of intracellular fumarate, which is thought to function as an oncometabolite, an intermediate of cellular metabolism that promotes cancer formation. Fumarate is known to competitively inhibit 2-oxoglutarate (2OG)-dependent oxygenases, including HIF prolyl hydroxylases, thus resulting in an increased stability of HIFs, which are thought to be oncogenic drivers in certain tumors. High levels of cytoplasmic fumarate also result in the modification of protein cysteine residues, forming S-(2-succinyl)-cysteine, in the process called succination, thereby affecting multiple cellular pathways. Furthermore, elevated fumarate succinates glutathione (GSH; a major cellular protection against reactive oxygen species), and by depleting the GSH pool it causes oxidative stress, a common feature of many cancers. While the exact causal mechanism by which elevated fumarate promotes cancer formation is not well defined, it is highly likely that fumarate synergistically affects multiple cellular pathways to exert its pathogenic effects.
## References
## Literature Cited
## Chapter Notes
Kirk Aleck, MD; Phoenix Children's Hospital (2013-2020)John Christodoulou, MBBS, PhD (2020-present)David Coman, MBBS, MPhil, FRAC (2020-present)Clifton Ewbank, MD; University of California San Francisco – East Bay (2013-2020)John F Kerrigan, MD; Phoenix Children's Hospital (2013-2020)Kamil R Kranc, MD, DPhil (2020-present)Roseann Mandell, BA; Massachusetts General Hospital (2006-2013)Vivian E Shih, MD; Massachusetts General Hospital (2006-2013)
23 April 2020 (sw) Comprehensive update posted live
4 April 2013 (me) Comprehensive update posted live
2 June 2009 (me) Comprehensive update posted live
10 August 2006 (cd) Revision: Prenatal diagnosis clinically available by enzyme assay and molecular testing
5 July 2006 (me) Review posted live
2 February 2005 (ves) Original submission
• 23 April 2020 (sw) Comprehensive update posted live
• 4 April 2013 (me) Comprehensive update posted live
• 2 June 2009 (me) Comprehensive update posted live
• 10 August 2006 (cd) Revision: Prenatal diagnosis clinically available by enzyme assay and molecular testing
• 5 July 2006 (me) Review posted live
• 2 February 2005 (ves) Original submission
## Author History
Kirk Aleck, MD; Phoenix Children's Hospital (2013-2020)John Christodoulou, MBBS, PhD (2020-present)David Coman, MBBS, MPhil, FRAC (2020-present)Clifton Ewbank, MD; University of California San Francisco – East Bay (2013-2020)John F Kerrigan, MD; Phoenix Children's Hospital (2013-2020)Kamil R Kranc, MD, DPhil (2020-present)Roseann Mandell, BA; Massachusetts General Hospital (2006-2013)Vivian E Shih, MD; Massachusetts General Hospital (2006-2013)
## Revision History
23 April 2020 (sw) Comprehensive update posted live
4 April 2013 (me) Comprehensive update posted live
2 June 2009 (me) Comprehensive update posted live
10 August 2006 (cd) Revision: Prenatal diagnosis clinically available by enzyme assay and molecular testing
5 July 2006 (me) Review posted live
2 February 2005 (ves) Original submission
• 23 April 2020 (sw) Comprehensive update posted live
• 4 April 2013 (me) Comprehensive update posted live
• 2 June 2009 (me) Comprehensive update posted live
• 10 August 2006 (cd) Revision: Prenatal diagnosis clinically available by enzyme assay and molecular testing
• 5 July 2006 (me) Review posted live
• 2 February 2005 (ves) Original submission
|
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"R Lehtonen, M Kiuru, S Vanharanta, J Sjöberg, LM Aaltonen, K Aittomäki, J Arola, R Butzow, C Eng, K Husgafvel-Pursiainen, J Isola, H Järvinen, P Koivisto, JP Mecklin, P Peltomäki, R Salovaara, VM Wasenius, A Karhu, V Launonen, NN Nupponen, LA Aaltonen. Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors.. Am J Pathol. 2004;164:17-22",
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"AR Mroch, M Laudenschlager, JD Flanagan. Detection of a novel FH whole gene deletion in the propositus leading to subsequent prenatal diagnosis in a sibship with fumarase deficiency.. Am J Med Genet A. 2012;158A:155-8",
"C Ottolenghi, L Hubert, Y Allanore, A Brassier, C Altuzarra, C Mellot-Draznieks, S Bekri, A Goldenberg, S Veyrieres, N Boddaert, V Barbier, V Valayannopoulos, A Slama, D Chrétien, D Ricquier, S Marret, T Frebourg, D Rabier, A Munnich, Y de Keyzer, H Toulhoat, P. de Lonlay. Clinical and biochemical heterogeneity associated with fumarase deficiency.. Hum Mutat. 2011;32:1046-52",
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"L Zhang, MF Walsh, S Jairam, D Mandelker, Y Zhong, Y Kemel, YB Chen, D Musheyev, A Zehir, G Jayakumaran, E Brzostowski, O Birsoy, C Yang, Y Li, J Somar, D DeLair, N Pradhan, MF Berger, K Cadoo, MI Carlo, ME Robson, ZK Stadler, CA Iacobuzio-Donahue, V Joseph, K Offit. Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma.. Hum Mutat. 2020;41:103-9"
] |
5/7/2006
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23/4/2020
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10/8/2006
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
g6pc3-def
|
g6pc3-def
|
[
"Ubiquitous Glucose-6-Phosphatase Deficiency",
"Ubiquitous Glucose-6-Phosphatase Deficiency",
"Nonsyndromic Severe Congenital Neutropenia Due to G6PC3 Deficiency",
"Classic G6PC3 Deficiency (Severe Congenital Neutropenia Type 4)",
"Severe G6PC3 Deficiency (Dursun Syndrome)",
"Glucose-6-phosphatase 3",
"G6PC3",
"G6PC3 Deficiency"
] |
G6PC3 Deficiency
|
Siddharth Banka
|
Summary G6PC3 deficiency is characterized by severe congenital neutropenia which occurs in a phenotypic continuum that includes the following: Isolated severe congenital neutropenia (nonsyndromic) Classic G6PC3 deficiency (severe congenital neutropenia plus cardiovascular and/or urogenital abnormalities) Severe G6PC3 deficiency (classic G6PC3 deficiency plus involvement of non-myeloid hematopoietic cell lines, additional extra-hematologic features, and pulmonary hypertension; known as Dursun syndrome) Neutropenia usually presents with recurrent bacterial infections in the first few months of life. Intrauterine growth restriction (IUGR), failure to thrive (FTT), and poor postnatal growth are common. Other findings in classic and severe G6PC3 deficiency can include inflammatory bowel disease (IBD) resembling Crohn disease, and endocrine disorders (growth hormone deficiency, hypogonadotropic hypogonadism, and delayed puberty). The diagnosis of G6PC3 deficiency is established in a proband with severe congenital neutropenia and biallelic (homozygous or compound heterozygous) G6PC3 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the
|
Nonsyndromic severe congenital neutropenia due to G6PC3 deficiency
Classic G6PC3 deficiency (severe congenital neutropenia type 4)
Severe G6PC3 deficiency (Dursun syndrome)
• Nonsyndromic severe congenital neutropenia due to G6PC3 deficiency
• Classic G6PC3 deficiency (severe congenital neutropenia type 4)
• Severe G6PC3 deficiency (Dursun syndrome)
## Diagnosis
Consensus diagnostic criteria for G6PC3 deficiency have not been established.
G6PC3 deficiency should be suspected in individuals with the following:
Severe congenital neutropenia defined as an absolute neutrophil count <0.5 x 10
Note: Although maturation arrest of myeloid cells was initially thought to be the typical finding on bone marrow examination [
A family history consistent with autosomal recessive inheritance [
To date all individuals with G6PC3 deficiency have had severe congenital neutropenia; the phenotypic spectrum is a continuum that ranges from nonsyndromic (isolated severe congenital neutropenia) to classic (severe congenital neutropenia plus cardiovascular and/or urogenital abnormalities) to severe (classic G6PC3 deficiency plus involvement of non-myeloid hematopoietic cell lines and additional extra-hematologic features).
Other hematologic abnormalities: intermittent thrombocytopenia (66%)
Cardiovascular defects
Congenital heart defects (~77%) (See
Prominent superficial venous pattern (66%) which may not be visible at birth but tends to gradually develop with age
Urogenital defects (44%), especially in males in whom cryptorchidism is the most common anomaly
Primary pulmonary hypertension (PPH) developing in the newborn period
Non-myeloid cell involvement: severe lymphopenia
Thymic hypoplasia
The diagnosis of G6PC3 deficiency is established in a proband with severe congenital neutropenia and biallelic (homozygous or compound heterozygous)
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in G6PC3 Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
An estimate based on a single nonsystematic study in which
To date more than 91 individuals with molecularly confirmed G6PC3 deficiency have been reported [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Severe congenital neutropenia defined as an absolute neutrophil count <0.5 x 10
• Note: Although maturation arrest of myeloid cells was initially thought to be the typical finding on bone marrow examination [
• A family history consistent with autosomal recessive inheritance [
• Other hematologic abnormalities: intermittent thrombocytopenia (66%)
• Cardiovascular defects
• Congenital heart defects (~77%) (See
• Prominent superficial venous pattern (66%) which may not be visible at birth but tends to gradually develop with age
• Congenital heart defects (~77%) (See
• Prominent superficial venous pattern (66%) which may not be visible at birth but tends to gradually develop with age
• Urogenital defects (44%), especially in males in whom cryptorchidism is the most common anomaly
• Congenital heart defects (~77%) (See
• Prominent superficial venous pattern (66%) which may not be visible at birth but tends to gradually develop with age
• Primary pulmonary hypertension (PPH) developing in the newborn period
• Non-myeloid cell involvement: severe lymphopenia
• Thymic hypoplasia
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
G6PC3 deficiency should be suspected in individuals with the following:
Severe congenital neutropenia defined as an absolute neutrophil count <0.5 x 10
Note: Although maturation arrest of myeloid cells was initially thought to be the typical finding on bone marrow examination [
A family history consistent with autosomal recessive inheritance [
To date all individuals with G6PC3 deficiency have had severe congenital neutropenia; the phenotypic spectrum is a continuum that ranges from nonsyndromic (isolated severe congenital neutropenia) to classic (severe congenital neutropenia plus cardiovascular and/or urogenital abnormalities) to severe (classic G6PC3 deficiency plus involvement of non-myeloid hematopoietic cell lines and additional extra-hematologic features).
Other hematologic abnormalities: intermittent thrombocytopenia (66%)
Cardiovascular defects
Congenital heart defects (~77%) (See
Prominent superficial venous pattern (66%) which may not be visible at birth but tends to gradually develop with age
Urogenital defects (44%), especially in males in whom cryptorchidism is the most common anomaly
Primary pulmonary hypertension (PPH) developing in the newborn period
Non-myeloid cell involvement: severe lymphopenia
Thymic hypoplasia
• Severe congenital neutropenia defined as an absolute neutrophil count <0.5 x 10
• Note: Although maturation arrest of myeloid cells was initially thought to be the typical finding on bone marrow examination [
• A family history consistent with autosomal recessive inheritance [
• Other hematologic abnormalities: intermittent thrombocytopenia (66%)
• Cardiovascular defects
• Congenital heart defects (~77%) (See
• Prominent superficial venous pattern (66%) which may not be visible at birth but tends to gradually develop with age
• Congenital heart defects (~77%) (See
• Prominent superficial venous pattern (66%) which may not be visible at birth but tends to gradually develop with age
• Urogenital defects (44%), especially in males in whom cryptorchidism is the most common anomaly
• Congenital heart defects (~77%) (See
• Prominent superficial venous pattern (66%) which may not be visible at birth but tends to gradually develop with age
• Primary pulmonary hypertension (PPH) developing in the newborn period
• Non-myeloid cell involvement: severe lymphopenia
• Thymic hypoplasia
## Establishing the Diagnosis
The diagnosis of G6PC3 deficiency is established in a proband with severe congenital neutropenia and biallelic (homozygous or compound heterozygous)
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in G6PC3 Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
An estimate based on a single nonsystematic study in which
To date more than 91 individuals with molecularly confirmed G6PC3 deficiency have been reported [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
G6PC3 deficiency is highly variable in its severity and associated clinical features. Individuals with "nonsyndromic" disease have only severe congenital neutropenia. The majority of persons with G6PC3 deficiency have cardiovascular and/or urogenital features (so-called classic G6PC3 deficiency). Of those with classic disease, a subset are more severely affected (so-called Dursun syndrome) because of the additional involvement of myeloid cells, primary pulmonary hypertension developing in the newborn period, and minor dysmorphic features.
While it is estimated that nearly 10% of G6CP3 deficiency is the nonsyndromic form, this could be an underestimate due to ascertainment bias (i.e., selection of more severe phenotypes for testing of
G6PC3 deficiency usually presents in the first few months of life with recurrent bacterial infections. A range of bacterial infections have been reported [
Intermittent thrombocytopenia is seen frequently but usually does not cause symptoms.
Lymphopenia associated with hypoplasia of the thymus can be seen in more severely affected individuals [
A prominent superficial venous pattern begins to emerge between late infancy and early childhood in most affected children [
In Dursun syndrome early-onset primary pulmonary hypertension can be difficult to control [
Hydronephrosis, poor renal cortico-medullary differentiation, small kidneys, and vesico-uretric reflux are observed in some affected individuals. Other features include inguinal hernia, ambiguous genitalia in undervirilized males, and urachal fistula.
Hypogonadotropic hypogonadism and delayed puberty have been reported in both males and females [
Hypothyroidism has been reported in three individuals [
Minor dysmorphic features in some young children, such as a triangular face, depressed nasal bridge, thick lips, and prognathism [
Neurodevelopmental involvement:
Mild learning difficulties were initially described in four affected individuals from a single family [
Recently a study from the French Neutropenia Registry reported neurodevelopmental difficulties in seven of 14 individuals with pathogenic variants in
Skeletal involvement, such as scoliosis and pectus carinatum [
Cutis laxa, described in at least seven individuals [
Microcephaly [
Myopathy:
One individual with a single episode of myositis [
One sib pair with proximal muscle weakness [
Two individuals reported with nonspecific myopathy but no clinical details [
Myelodysplasia followed by acute myelogeneous leukemia with translocation (18, 21) (with no exposure to G-CSF) reported in one affected individual age 14 years [
Mild to moderate bilateral sensorineural hearing loss which may be asymptomatic and is sometimes only detected on audiometry [
Congenital ptosis [
Cleft palate [
Low HDL serum levels and persistently increased amylase activity described in one individual [
If neutropenia is untreated, G6PC3 deficiency can lead to death in early childhood from infections [
Four deaths in the 14 individuals in the French Severe Congenital Neutropenia Registry were reported: one at age five years with sepsis, one at age 19 years from pulmonary insufficiency, and two from sudden death of unknown cause during sleep at age 30 years.
No obvious genotype-phenotype correlations explain the difference between the marked cellularity of myeloid cells in the bone marrow of individuals with G6PC3 deficiency [
Based on limited data, certain pathogenic variants (e.g., p.Phe44Ser) appear to be more often (or only) associated with nonsyndromic neutropenia [
To date more than 91 individuals with the molecularly proven diagnosis of G6PC3 deficiency have been reported [
The prevalence is likely to vary significantly from population to population based on the presence of founder variants in certain populations [
The French Neutropenia Registry has estimated incidence at birth at 0.4:1,000,000 [
• Minor dysmorphic features in some young children, such as a triangular face, depressed nasal bridge, thick lips, and prognathism [
• Neurodevelopmental involvement:
• Mild learning difficulties were initially described in four affected individuals from a single family [
• Recently a study from the French Neutropenia Registry reported neurodevelopmental difficulties in seven of 14 individuals with pathogenic variants in
• Mild learning difficulties were initially described in four affected individuals from a single family [
• Recently a study from the French Neutropenia Registry reported neurodevelopmental difficulties in seven of 14 individuals with pathogenic variants in
• Skeletal involvement, such as scoliosis and pectus carinatum [
• Cutis laxa, described in at least seven individuals [
• Microcephaly [
• Myopathy:
• One individual with a single episode of myositis [
• One sib pair with proximal muscle weakness [
• Two individuals reported with nonspecific myopathy but no clinical details [
• One individual with a single episode of myositis [
• One sib pair with proximal muscle weakness [
• Two individuals reported with nonspecific myopathy but no clinical details [
• Mild learning difficulties were initially described in four affected individuals from a single family [
• Recently a study from the French Neutropenia Registry reported neurodevelopmental difficulties in seven of 14 individuals with pathogenic variants in
• One individual with a single episode of myositis [
• One sib pair with proximal muscle weakness [
• Two individuals reported with nonspecific myopathy but no clinical details [
• Myelodysplasia followed by acute myelogeneous leukemia with translocation (18, 21) (with no exposure to G-CSF) reported in one affected individual age 14 years [
• Mild to moderate bilateral sensorineural hearing loss which may be asymptomatic and is sometimes only detected on audiometry [
• Congenital ptosis [
• Cleft palate [
• Low HDL serum levels and persistently increased amylase activity described in one individual [
## Clinical Description
G6PC3 deficiency is highly variable in its severity and associated clinical features. Individuals with "nonsyndromic" disease have only severe congenital neutropenia. The majority of persons with G6PC3 deficiency have cardiovascular and/or urogenital features (so-called classic G6PC3 deficiency). Of those with classic disease, a subset are more severely affected (so-called Dursun syndrome) because of the additional involvement of myeloid cells, primary pulmonary hypertension developing in the newborn period, and minor dysmorphic features.
While it is estimated that nearly 10% of G6CP3 deficiency is the nonsyndromic form, this could be an underestimate due to ascertainment bias (i.e., selection of more severe phenotypes for testing of
G6PC3 deficiency usually presents in the first few months of life with recurrent bacterial infections. A range of bacterial infections have been reported [
Intermittent thrombocytopenia is seen frequently but usually does not cause symptoms.
Lymphopenia associated with hypoplasia of the thymus can be seen in more severely affected individuals [
A prominent superficial venous pattern begins to emerge between late infancy and early childhood in most affected children [
In Dursun syndrome early-onset primary pulmonary hypertension can be difficult to control [
Hydronephrosis, poor renal cortico-medullary differentiation, small kidneys, and vesico-uretric reflux are observed in some affected individuals. Other features include inguinal hernia, ambiguous genitalia in undervirilized males, and urachal fistula.
Hypogonadotropic hypogonadism and delayed puberty have been reported in both males and females [
Hypothyroidism has been reported in three individuals [
Minor dysmorphic features in some young children, such as a triangular face, depressed nasal bridge, thick lips, and prognathism [
Neurodevelopmental involvement:
Mild learning difficulties were initially described in four affected individuals from a single family [
Recently a study from the French Neutropenia Registry reported neurodevelopmental difficulties in seven of 14 individuals with pathogenic variants in
Skeletal involvement, such as scoliosis and pectus carinatum [
Cutis laxa, described in at least seven individuals [
Microcephaly [
Myopathy:
One individual with a single episode of myositis [
One sib pair with proximal muscle weakness [
Two individuals reported with nonspecific myopathy but no clinical details [
Myelodysplasia followed by acute myelogeneous leukemia with translocation (18, 21) (with no exposure to G-CSF) reported in one affected individual age 14 years [
Mild to moderate bilateral sensorineural hearing loss which may be asymptomatic and is sometimes only detected on audiometry [
Congenital ptosis [
Cleft palate [
Low HDL serum levels and persistently increased amylase activity described in one individual [
If neutropenia is untreated, G6PC3 deficiency can lead to death in early childhood from infections [
Four deaths in the 14 individuals in the French Severe Congenital Neutropenia Registry were reported: one at age five years with sepsis, one at age 19 years from pulmonary insufficiency, and two from sudden death of unknown cause during sleep at age 30 years.
• Minor dysmorphic features in some young children, such as a triangular face, depressed nasal bridge, thick lips, and prognathism [
• Neurodevelopmental involvement:
• Mild learning difficulties were initially described in four affected individuals from a single family [
• Recently a study from the French Neutropenia Registry reported neurodevelopmental difficulties in seven of 14 individuals with pathogenic variants in
• Mild learning difficulties were initially described in four affected individuals from a single family [
• Recently a study from the French Neutropenia Registry reported neurodevelopmental difficulties in seven of 14 individuals with pathogenic variants in
• Skeletal involvement, such as scoliosis and pectus carinatum [
• Cutis laxa, described in at least seven individuals [
• Microcephaly [
• Myopathy:
• One individual with a single episode of myositis [
• One sib pair with proximal muscle weakness [
• Two individuals reported with nonspecific myopathy but no clinical details [
• One individual with a single episode of myositis [
• One sib pair with proximal muscle weakness [
• Two individuals reported with nonspecific myopathy but no clinical details [
• Mild learning difficulties were initially described in four affected individuals from a single family [
• Recently a study from the French Neutropenia Registry reported neurodevelopmental difficulties in seven of 14 individuals with pathogenic variants in
• One individual with a single episode of myositis [
• One sib pair with proximal muscle weakness [
• Two individuals reported with nonspecific myopathy but no clinical details [
• Myelodysplasia followed by acute myelogeneous leukemia with translocation (18, 21) (with no exposure to G-CSF) reported in one affected individual age 14 years [
• Mild to moderate bilateral sensorineural hearing loss which may be asymptomatic and is sometimes only detected on audiometry [
• Congenital ptosis [
• Cleft palate [
• Low HDL serum levels and persistently increased amylase activity described in one individual [
## Genotype-Phenotype Correlations
No obvious genotype-phenotype correlations explain the difference between the marked cellularity of myeloid cells in the bone marrow of individuals with G6PC3 deficiency [
Based on limited data, certain pathogenic variants (e.g., p.Phe44Ser) appear to be more often (or only) associated with nonsyndromic neutropenia [
## Prevalence
To date more than 91 individuals with the molecularly proven diagnosis of G6PC3 deficiency have been reported [
The prevalence is likely to vary significantly from population to population based on the presence of founder variants in certain populations [
The French Neutropenia Registry has estimated incidence at birth at 0.4:1,000,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Severe congenital neutropenia is genetically heterogeneous [
Charcot-Marie-Tooth disease caused by mutation of
Griscelli syndrome type 2 (OMIM
Immunodeficiency due to defect in MAPBP-interacting protein (P14 deficiency) (OMIM
WHIM syndrome (OMIM
•
•
• Charcot-Marie-Tooth disease caused by mutation of
•
•
•
•
• Griscelli syndrome type 2 (OMIM
•
• Immunodeficiency due to defect in MAPBP-interacting protein (P14 deficiency) (OMIM
•
•
• WHIM syndrome (OMIM
•
## Inherited Conditions in which Neutropenia Predominates
## Inherited Conditions in which Neutropenia May be Part of a Multisystem Disorder
Charcot-Marie-Tooth disease caused by mutation of
Griscelli syndrome type 2 (OMIM
Immunodeficiency due to defect in MAPBP-interacting protein (P14 deficiency) (OMIM
WHIM syndrome (OMIM
•
•
• Charcot-Marie-Tooth disease caused by mutation of
•
•
•
•
• Griscelli syndrome type 2 (OMIM
•
• Immunodeficiency due to defect in MAPBP-interacting protein (P14 deficiency) (OMIM
•
•
• WHIM syndrome (OMIM
•
## Management
To establish the extent of disease and needs in an individual diagnosed with G6PC3 deficiency, the following evaluations are recommended:
Full blood count to look for evidence of other hematologic involvement (i.e., intermittent thrombocytopenia and/or lymphopenia)
Immunologic evaluation for T-cell subsets in individuals with a more severe presentation and unusual non-bacterial infections
Consultation with a cardiologist to evaluate for congenital heart disease
Renal and pelvic ultrasound examination to look for urogenital malformations
Growth parameters in children and pubertal development in adolescents
Age appropriate endocrine assessment for evidence of the hormone deficiencies reported (i.e., growth hormone, gonadotropins, thyroid hormone)
Biochemical investigations to look for abnormalities in the lipid profile
Consultation with a clinical geneticist and/or genetic counselor
A few mildly affected individuals have been reported to be adequately managed with prophylactic antibiotics alone [
Fevers and infections require prompt treatment with antibiotics.
Routine management of congenital heart disease, renal and urinary tract malformations
Routine management of hormone deficiencies
Consideration of oral steroids for inflammatory bowel disease [
Consideration of pancreatic enzyme supplementation if steatorrhea is present [
Chemotherapy and hematopoietic stem cell transplantation for acute myelogeneous leukemia
Good dental hygiene, including careful brushing and flossing and regular visits to the dentist, helps decrease the potential for infection. Prophylactic antibiotics should be considered with dental procedures, including routine dental repair and cleaning, especially in individuals with heart defects.
The following are appropriate:
Frequent follow up by a hematologist or immunologist to monitor infection frequency and neutrophil counts to ensure an adequate response to G-CSF (i.e., absolute neutrophil counts above 0.5x109/L)
Monitoring of growth in children and pubertal development in adolescents
Biochemical profile including lipid profile
Monitoring for development of varicose veins, especially in adults
Monitoring for osteopenia/osteoporosis
It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early diagnosis and management of the hematologic, cardiac, renal, and endocrine abnormalities of G6PC3 deficiency.
If the
If the
See
Search
• Full blood count to look for evidence of other hematologic involvement (i.e., intermittent thrombocytopenia and/or lymphopenia)
• Immunologic evaluation for T-cell subsets in individuals with a more severe presentation and unusual non-bacterial infections
• Consultation with a cardiologist to evaluate for congenital heart disease
• Renal and pelvic ultrasound examination to look for urogenital malformations
• Growth parameters in children and pubertal development in adolescents
• Age appropriate endocrine assessment for evidence of the hormone deficiencies reported (i.e., growth hormone, gonadotropins, thyroid hormone)
• Biochemical investigations to look for abnormalities in the lipid profile
• Consultation with a clinical geneticist and/or genetic counselor
• Routine management of congenital heart disease, renal and urinary tract malformations
• Routine management of hormone deficiencies
• Consideration of oral steroids for inflammatory bowel disease [
• Consideration of pancreatic enzyme supplementation if steatorrhea is present [
• Chemotherapy and hematopoietic stem cell transplantation for acute myelogeneous leukemia
• Frequent follow up by a hematologist or immunologist to monitor infection frequency and neutrophil counts to ensure an adequate response to G-CSF (i.e., absolute neutrophil counts above 0.5x109/L)
• Monitoring of growth in children and pubertal development in adolescents
• Biochemical profile including lipid profile
• Monitoring for development of varicose veins, especially in adults
• Monitoring for osteopenia/osteoporosis
• If the
• If the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with G6PC3 deficiency, the following evaluations are recommended:
Full blood count to look for evidence of other hematologic involvement (i.e., intermittent thrombocytopenia and/or lymphopenia)
Immunologic evaluation for T-cell subsets in individuals with a more severe presentation and unusual non-bacterial infections
Consultation with a cardiologist to evaluate for congenital heart disease
Renal and pelvic ultrasound examination to look for urogenital malformations
Growth parameters in children and pubertal development in adolescents
Age appropriate endocrine assessment for evidence of the hormone deficiencies reported (i.e., growth hormone, gonadotropins, thyroid hormone)
Biochemical investigations to look for abnormalities in the lipid profile
Consultation with a clinical geneticist and/or genetic counselor
• Full blood count to look for evidence of other hematologic involvement (i.e., intermittent thrombocytopenia and/or lymphopenia)
• Immunologic evaluation for T-cell subsets in individuals with a more severe presentation and unusual non-bacterial infections
• Consultation with a cardiologist to evaluate for congenital heart disease
• Renal and pelvic ultrasound examination to look for urogenital malformations
• Growth parameters in children and pubertal development in adolescents
• Age appropriate endocrine assessment for evidence of the hormone deficiencies reported (i.e., growth hormone, gonadotropins, thyroid hormone)
• Biochemical investigations to look for abnormalities in the lipid profile
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
A few mildly affected individuals have been reported to be adequately managed with prophylactic antibiotics alone [
Fevers and infections require prompt treatment with antibiotics.
Routine management of congenital heart disease, renal and urinary tract malformations
Routine management of hormone deficiencies
Consideration of oral steroids for inflammatory bowel disease [
Consideration of pancreatic enzyme supplementation if steatorrhea is present [
Chemotherapy and hematopoietic stem cell transplantation for acute myelogeneous leukemia
• Routine management of congenital heart disease, renal and urinary tract malformations
• Routine management of hormone deficiencies
• Consideration of oral steroids for inflammatory bowel disease [
• Consideration of pancreatic enzyme supplementation if steatorrhea is present [
• Chemotherapy and hematopoietic stem cell transplantation for acute myelogeneous leukemia
## Prevention of Secondary Complications
Good dental hygiene, including careful brushing and flossing and regular visits to the dentist, helps decrease the potential for infection. Prophylactic antibiotics should be considered with dental procedures, including routine dental repair and cleaning, especially in individuals with heart defects.
## Surveillance
The following are appropriate:
Frequent follow up by a hematologist or immunologist to monitor infection frequency and neutrophil counts to ensure an adequate response to G-CSF (i.e., absolute neutrophil counts above 0.5x109/L)
Monitoring of growth in children and pubertal development in adolescents
Biochemical profile including lipid profile
Monitoring for development of varicose veins, especially in adults
Monitoring for osteopenia/osteoporosis
• Frequent follow up by a hematologist or immunologist to monitor infection frequency and neutrophil counts to ensure an adequate response to G-CSF (i.e., absolute neutrophil counts above 0.5x109/L)
• Monitoring of growth in children and pubertal development in adolescents
• Biochemical profile including lipid profile
• Monitoring for development of varicose veins, especially in adults
• Monitoring for osteopenia/osteoporosis
## Evaluation of Relatives at Risk
It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early diagnosis and management of the hematologic, cardiac, renal, and endocrine abnormalities of G6PC3 deficiency.
If the
If the
See
• If the
• If the
## Therapies Under Investigation
Search
## Genetic Counseling
G6PC3 deficiency is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of the sib being a carrier of a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of the sib being a carrier of a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
G6PC3 deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of the sib being a carrier of a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of the sib being a carrier of a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
## Molecular Genetics
G6PC3 Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for G6PC3 Deficiency (
G6PC3 deficiency causes decreased cytoplasmic glucose and glucose-6-phosphate levels [
A number of founder variants have been identified, including:
p.Phe44Ser in individuals of Pakistani origin [
p.Arg253His in individuals from diverse backgrounds in the Middle East [
p.Gly260Arg in individuals with European ancestry [
Other pathogenic variants detected in two or more unrelated individuals of the same ancestry include p.Phe71SerfsTer46 ("Hispanic"), p.Gly277Ter (European), and p.Asn313GlnfsTer74 (Iranian) [
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
• p.Phe44Ser in individuals of Pakistani origin [
• p.Arg253His in individuals from diverse backgrounds in the Middle East [
• p.Gly260Arg in individuals with European ancestry [
## Molecular Pathogenesis
G6PC3 deficiency causes decreased cytoplasmic glucose and glucose-6-phosphate levels [
A number of founder variants have been identified, including:
p.Phe44Ser in individuals of Pakistani origin [
p.Arg253His in individuals from diverse backgrounds in the Middle East [
p.Gly260Arg in individuals with European ancestry [
Other pathogenic variants detected in two or more unrelated individuals of the same ancestry include p.Phe71SerfsTer46 ("Hispanic"), p.Gly277Ter (European), and p.Asn313GlnfsTer74 (Iranian) [
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
• p.Phe44Ser in individuals of Pakistani origin [
• p.Arg253His in individuals from diverse backgrounds in the Middle East [
• p.Gly260Arg in individuals with European ancestry [
## Chapter Notes
16 April 2015 (me) Review posted live
10 September 2014 (sb) Original submission
• 16 April 2015 (me) Review posted live
• 10 September 2014 (sb) Original submission
## Revision History
16 April 2015 (me) Review posted live
10 September 2014 (sb) Original submission
• 16 April 2015 (me) Review posted live
• 10 September 2014 (sb) Original submission
## References
## Literature Cited
|
[
"AA Alangari, A Alsultan, ME Osman, S Anazi, FS Alkuraya. A novel homozygous mutation in G6PC3 presenting as cyclic neutropenia and severe congenital neutropenia in the same family.. J Clin Immunol. 2013;33:1403-6",
"Z Alizadeh, MR Fazlollahi, P Eshghi, AA Hamidieh, M Ghadami, Z Pourpak. Two cases of syndromic neutropenia with a report of novel mutation in G6PC3.. Iran J Allergy Asthma Immunol. 2011;10:227-30",
"T Arikoglu, N Kuyucu, M Germeshausen, S. Kuyucu. Author information A novel G6PC3 gene mutation in severe congenital neutropenia: pancytopenia and variable bone marrow phenotype can also be part of this syndrome.. Eur J Haematol. 2015;94:79-82",
"C Aytekin, M Germeshausen, N Tuygun, F Dogu, A. Ikinciogullari. A novel G6PC3 gene mutation in a patient with severe congenital neutropenia.. J. Pediatr Hematol Oncol. 2013;35:e81-3",
"S Banka, E Chervinsky, WG Newman, YJ Crow, S Yeganeh, J Yacobovich, D Donnai, S Shalev. Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3.. Eur J Hum Genet. 2011a;19:18-22",
"S Banka, WG Newman, RK Özgül, A Dursun. Mutations in the G6PC3 gene cause Dursun syndrome.. Am J Med Genet A. 2010;152A:2609-11",
"S Banka, WG Newman. A clinical and molecular review of ubiquitous glucose-6-phosphatase deficiency caused by G6PC3 mutations.. Orphanet J Rare Dis. 2013;8:84",
"S Banka, R Wynn, H Byers, PD Arkwright, WG Newman. G6PC3 mutations cause non-syndromic severe congenital neutropenia.. Mol Genet Metab. 2013;108:138-41",
"S Banka, R Wynn, WG Newman. Variability of bone marrow morphology in G6PC3 mutations: Is there a genotype-phenotype correlation or age-dependent relationship?. Am J Hematol. 2011b;86:235-7",
"P Bégin, N Patey, P Mueller, A Rasquin, A Sirard, C Klein, E Haddad, É Drouin, F. Le Deist. Inflammatory bowel disease and T cell lymphopenia in G6PC3 deficiency.. J Clin Immunol. 2013;33:520-5",
"K Boztug, G Appaswamy, A Ashikov, AA Schäffer, U Salzer, J Diestelhorst, M Germeshausen, G Brandes, J Lee-Gossler, F Noyan. a syndrome with congenital neutropenia and mutations in G6PC3.. N Engl J Med. 2009;360:32-43",
"K Boztug, PM Järvinen, E Salzer, T Racek, S Mönch, W Garncarz, EM Gertz, AA Schäffer, A Antonopoulos, SM Haslam, L Schieck, J Puchałka, J Diestelhorst, G Appaswamy, B Lescoeur, R Giambruno, JW Bigenzahn, U Elling, D Pfeifer, CD Conde, MH Albert, K Welte, G Brandes, R Sherkat, J van der Werff ten Bosch, N Rezaei, A Etzioni, C Bellanné-Chantelot, G Superti-Furga, JM Penninger, KL Bennett, J von Blume, A Dell, J Donadieu, C Klein. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia.. Nat Genet. 2014;46:1021-7",
"K Boztug, PS Rosenberg, M Dorda, S Banka, T Moulton, J Curtin, N Rezaei, J Corns, JW Innis, Z Avci, HC Tran, I Pellier, P Pierani, R Fruge, N Parvaneh, S Mamishi, R Mody, P Darbyshire, J Motwani, J Murray, GR Buchanan, WG Newman, BP Alter, LA Boxer, J Donadieu, K Welte, C Klein. Extended spectrum of human glucose-6-phosphatase catalytic subunit 3 deficiency: novel genotypes and phenotypic variability in severe congenital neutropenia.. J Pediatr. 2012;160:679-683.e2",
"AR Cullinane, T Vilboux, K O'Brien, JA Curry, DM Maynard, H Carlson-Donohoe, C Ciccone, TC Markello, M Gunay-Aygun, M Huizing, WA Gahl. Homozygosity mapping and whole-exome sequencing to detect SLC45A2 and G6PC3 mutations in a single patient with oculocutaneous albinism and neutropenia.. J Invest Dermatol. 2011;131:2017-25",
"DC Dale, RE Person, AA Bolyard, AG Aprikyan, C Bos, MA Bonilla, LA Boxer, G Kannourakis, C Zeidler, K Welte, KF Benson, M Horwitz. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia.. Blood. 2000;96:2317-22",
"C Desplantes, M Fremond, B Beaupain, J Harousseau, A Buzyn, I Pellier, G Roques, P Morville, C Paillard, J Bruneau, L Pinson, E Jeziorski, J Vannier, C Picard, F Bellanger, N Romero, L de Pontual, H Lapillonne, P Lutz, C Chantelot, J. Donadieu. Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French severe congenital neutropenia registry.. Orphanet J Rare Dis. 2014;9:183",
"J Donadieu, O Fenneteau, B Beaupain, N Mahlaoui, C. Bellanne Chantelot. Congenital neutropenia: diagnosis, molecular bases and patient management.. Orphanet J Rare Dis. 2011;6:26",
"A Dursun, RK Ozgul, A Soydas, T Tugrul, A Gurgey, A Celiker, RJ Barst, JA Knowles, M Mahesh, JH Morse. Familial pulmonary arterial hypertension, leucopenia, and atrial septal defect: a probable new familial syndrome with multisystem involvement.. Clin Dysmorphol. 2009;18:19-23",
"OA Estévez, C Ortega, Á Tejero, S Fernández, R Aguado, JI Aróstegui, E González-Roca, J Peña, M Santamaría. A novel phenotype variant of severe congenital neutropenia caused by G6PC3 deficiency.. Pediatr Blood Cancer. 2013;60:E29-31",
"BA Fernandez, JS Green, F Bursey, B Barrett, A MacMillan, S McColl, S Fernandez, P Rahman, K Mahoney, SL Pereira, SW Scherer, KM Boycott, MO Woods. Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype.. BMC Med Genet. 2012;13:111",
"S Gatti, K Boztug, A Pedini, C Pasqualini, V Albano, C Klein, P. Pierani. A Case of syndromic neutropenia and mutation in G6PC3.. J Pediatr Hematol Oncol. 2011;33:138",
"M Germeshausen, C Zeidler, M Stuhrmann, M Lanciotti, M Ballmaier, K Welte. Digenic mutations in severe congenital neutropenia.. Haematologica. 2010;95:1207-10",
"HS Jun, YY Cheung, YM Lee, BC Mansfield, JY Chou. Glucose-6-phosphatase-β, implicated in a congenital neutropenia syndrome, is essential for macrophage energy homeostasis and functionality.. Blood. 2012;119:4047-55",
"HS Jun, YM Lee, KD Song, BC Mansfield, JY Chou. G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis.. Blood 2011;117:3881-92",
"Z Kaya, O Eğritaş, M Albayrak, PU Göçün, U Koçak, B Dalgiç, T Gürsel. Resolution of inflammatory colitis with pegfilgrastim treatment in a case of severe congenital neutropenia due to glucose 6 phosphatase catalytic subunit-3 deficiency.. J Pediatr Hematol Oncol. 2014;36:e316-8",
"C Klein, M Grudzien, G Appaswamy, M Germeshausen, I Sandrock, AA Schaffer, C Rathinam, K Boztug, B Schwinzer, N Rezaei, G Bohn, M Melin, G Carlsson, B Fadeel, N Dahl, J Palmblad, J-I Henter, C Zeidler, B Grimbacher, K Welte. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease).. Nat Genet. 2007;39:86-92",
"C. Klein. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes.. Annu Rev Immunol. 2011;29:399-413",
"C. Klein. Molecular basis of congenital neutropenia.. Haematologica. 2009;94:1333-6",
"A Lebel, J Yacobovich, T Krasnov, A Koren, C Levin, C Kaplinsky, S Ravel-Vilk, R Laor, D Attias, AB Barak, D Shtager, J Stein, A Kuperman, H Miskin, O Dgany, N Giri, BP Alter, H Tamary. Genetic analysis and clinical picture of severe congenital neutropenia in Israel.. Pediatr Blood Cancer. 2015;62:103-8",
"DH McDermott, SS De Ravin, HS Jun, Q Liu, DAL Priel, P Noel, CM Takemoto, T Ojode, SM Paul, KP Dunsmore, D Hilligoss, M Marquesen, J Ulrick, DB Kuhns, JY Chou, HL Malech, PM Murphy. Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis.. Blood 2010;116:2793-802",
"LD Notarangelo, G Savoldi, S Cavagnini, V Bennato, S Vasile, A Pilotta, A Plebani, F Porta. Severe congenital neutropenia due to G6PC3 deficiency: early and delayed phenotype in two patients with two novel mutations.. Ital J Pediatr. 2014;40:80",
"RK Ozgül, D Yücel-Yılmaz, A Dursun. Dursun syndrome due to G6PC3 gene defect has a fluctuating pattern in all blood cell lines.. J Clin Immunol. 2014;34:265-6",
"RE Person, F-Q Li, Z Duan, KF Benson, J Wechsler, HA Papadaki, G Eliopoulos, C Kaufman, SJ Bertolone, B Nakamoto, T Papayannopoulou, HL Grimes, M Horwitz. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.. Nat Genet. 2003;34:308-12",
"T Racek, J Puchalka, N Kohistani, C. Klein. Novel NGS-based platforms for molecular diagnosis of severe congenital neutropenia.. Blood. 2013;122",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"BN Smith, C Evans, A Ali, PJ Ancliff, B Hayee, AW Segal, G Hall, Z Kaya, AR Shakoori, DC Linch, RE Gale. Phenotypic heterogeneity and evidence of a founder effect associated with G6PC3 mutations in patients with severe congenital neutropenia.. Br J Haematol. 2012;158:146-9",
"B Tavil, M Cetin, F Gumruk. Sea-blue histiocytes in the bone marrow of a boy with severe congenital neutropenia associated with G6PC3 mutation.. Br J Haematol. 2014;165:426",
"T Vilboux, A Lev, MC Malicdan, AJ Simon, P Järvinen, T Racek, J Puchalka, R Sood, B Carrington, K Bishop, J Mullikin, M Huizing, BZ Garty, E Eyal, B Wolach, R Gavrieli, A Toren, M Soudack, OM Atawneh, T Babushkin, G Schiby, A Cullinane, C Avivi, S Polak-Charcon, I Barshack, N Amariglio, G Rechavi, J van der Werff ten Bosch, Y Anikster, C Klein, WA Gahl, R Somech. A congenital neutrophil defect syndrome associated with mutations in VPS45.. N Engl J Med. 2013;369:54-65",
"Y Yeshayahu, R Asaf, G Dubnov-Raz, G Schiby, AJ Simon, A Lev, R Somech. Testicular failure in a patient with G6PC3 deficiency.. Pediatr Res. 2014;76:197-201"
] |
16/4/2015
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
gabriele-devries
|
gabriele-devries
|
[
"YY1 Intellectual Disability Syndrome",
"YY1 Intellectual Disability Syndrome",
"Transcriptional repressor protein YY1",
"YY1",
"Gabriele-de Vries Syndrome"
] |
Gabriele-de Vries Syndrome
|
Maria J Nabais Sá, Michele Gabriele, Giuseppe Testa, Bert BA de Vries
|
Summary Gabriele-de Vries syndrome is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals and a wide spectrum of functional and morphologic abnormalities. Intrauterine growth restriction or low birth weight and feeding difficulties are common. Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies have also been reported. About half of affected individuals have neurologic manifestations, including hypotonia and gait abnormalities. Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder. The diagnosis of Gabriele-de Vries syndrome is established in a proband by the identification of a heterozygous pathogenic variant involving Gabriele-de Vries syndrome is inherited in an autosomal dominant manner. All probands reported to date with Gabriele-de Vries syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
|
## Diagnosis
No formal clinical diagnostic criteria exist for Gabriele-de Vries syndrome.
The clinical spectrum of Gabriele-de Vries syndrome is variable. Gabriele-de Vries syndrome
Mild-to-profound developmental delay
Any of the following features presenting in infancy or childhood:
Craniofacial dysmorphisms (See
Intrauterine growth restriction / low birth weight
Feeding difficulties
Neurologic abnormalities (hypotonia, abnormalities of movement, gait abnormalities)
Behavioral problems (attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, schizoaffective disorder)
Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies (See
The diagnosis of Gabriele-de Vries syndrome
A heterozygous pathogenic (or likely pathogenic) variant involving
A heterozygous deletion of 14q32.2 involving
Note: (1) See
Note: To date, most individuals with a
For an introduction to multigene panels click
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Gabriele-de Vries Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Targeted deletion testing is not appropriate for an individual in whom a pathogenic
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Mild-to-profound developmental delay
• Any of the following features presenting in infancy or childhood:
• Craniofacial dysmorphisms (See
• Intrauterine growth restriction / low birth weight
• Feeding difficulties
• Neurologic abnormalities (hypotonia, abnormalities of movement, gait abnormalities)
• Behavioral problems (attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, schizoaffective disorder)
• Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies (See
• Craniofacial dysmorphisms (See
• Intrauterine growth restriction / low birth weight
• Feeding difficulties
• Neurologic abnormalities (hypotonia, abnormalities of movement, gait abnormalities)
• Behavioral problems (attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, schizoaffective disorder)
• Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies (See
• Craniofacial dysmorphisms (See
• Intrauterine growth restriction / low birth weight
• Feeding difficulties
• Neurologic abnormalities (hypotonia, abnormalities of movement, gait abnormalities)
• Behavioral problems (attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, schizoaffective disorder)
• Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies (See
• A heterozygous pathogenic (or likely pathogenic) variant involving
• A heterozygous deletion of 14q32.2 involving
• Note: To date, most individuals with a
• For an introduction to multigene panels click
• If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
The clinical spectrum of Gabriele-de Vries syndrome is variable. Gabriele-de Vries syndrome
Mild-to-profound developmental delay
Any of the following features presenting in infancy or childhood:
Craniofacial dysmorphisms (See
Intrauterine growth restriction / low birth weight
Feeding difficulties
Neurologic abnormalities (hypotonia, abnormalities of movement, gait abnormalities)
Behavioral problems (attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, schizoaffective disorder)
Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies (See
• Mild-to-profound developmental delay
• Any of the following features presenting in infancy or childhood:
• Craniofacial dysmorphisms (See
• Intrauterine growth restriction / low birth weight
• Feeding difficulties
• Neurologic abnormalities (hypotonia, abnormalities of movement, gait abnormalities)
• Behavioral problems (attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, schizoaffective disorder)
• Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies (See
• Craniofacial dysmorphisms (See
• Intrauterine growth restriction / low birth weight
• Feeding difficulties
• Neurologic abnormalities (hypotonia, abnormalities of movement, gait abnormalities)
• Behavioral problems (attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, schizoaffective disorder)
• Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies (See
• Craniofacial dysmorphisms (See
• Intrauterine growth restriction / low birth weight
• Feeding difficulties
• Neurologic abnormalities (hypotonia, abnormalities of movement, gait abnormalities)
• Behavioral problems (attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, schizoaffective disorder)
• Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies (See
## Establishing the Diagnosis
The diagnosis of Gabriele-de Vries syndrome
A heterozygous pathogenic (or likely pathogenic) variant involving
A heterozygous deletion of 14q32.2 involving
Note: (1) See
Note: To date, most individuals with a
For an introduction to multigene panels click
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Gabriele-de Vries Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Targeted deletion testing is not appropriate for an individual in whom a pathogenic
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• A heterozygous pathogenic (or likely pathogenic) variant involving
• A heterozygous deletion of 14q32.2 involving
• Note: To date, most individuals with a
• For an introduction to multigene panels click
• If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date, ten individuals with a
Generalized facial asymmetry, with mild discrepancy in the size of one side of the face compared to the other
Broad forehead
Fullness of upper eyelids
Downslanted palpebral fissures
Bulbous nose
Malar flattening
Indentation of the vermilion of the upper lip resembling a ginkgo leaf
Thick vermilion of the lower lip
Pointed chin
External ear malformations are common and include the following:
Abnormally shaped ears
Simple ears
Posteriorly rotated ears
Low-set ears
Protruding ears
Rare craniofacial findings have included the following:
Abnormalities of the lacrimal duct, specifically lacrimal duct stenosis and hypoplastic lacrimal duct
Craniosynostosis in one affected individual (suture not specified)
Pierre Robin sequence with a cleft palate in one affected individual
Abnormalities of the subarachnoid space (widened subarachnoid space)
Delayed myelination
Frontal gliosis
Cortical dysplasia
Focal areas of encephalomalacia
Unilateral and/or bilateral dilatation of the lateral ventricles
Abnormalities of cerebral white matter (cerebral white matter atrophy, subcortical bifrontal white matter foci)
Abnormalities of the corpus callosum (ranging from hypoplasia of the corpus callosum to agenesis of corpus callosum)
Each of the reported CNS morphologic abnormalities was observed in one or two individuals (occurring alone or concomitantly with another neuroimaging abnormality) and is not exclusive to Gabriele-de Vries syndrome.
Unilateral hemihypotrophy of lower limb
Patella luxations
Increased laxity of fingers
Long fingers
Sydney crease *
Sandal gap
Hallux valgus
Distal arthrogryposis
* Note: The Sydney crease is a proximal transverse (5-finger) crease that starts on the radial side of the hand near the base of the index finger and extends completely to the ulnar margin of the palm.
Recurrent infections
Breast hypoplasia
Hyperextensible skin
Childhood-onset neuroblastoma
Given the small number of affected individuals reported in the literature, no genotype-phenotype correlations are currently known.
Gabriele-de Vries syndrome is a rare condition. So far, ten affected individuals worldwide have been described in the medical literature with a
The prevalence of Gabriele-de Vries syndrome is yet to be determined. To date,
Since individuals have been recruited via large exome sequencing projects, it is expected that more affected individuals will be diagnosed with Gabriele-de Vries syndrome as the use of genomic testing increases.
• Generalized facial asymmetry, with mild discrepancy in the size of one side of the face compared to the other
• Broad forehead
• Fullness of upper eyelids
• Downslanted palpebral fissures
• Bulbous nose
• Malar flattening
• Indentation of the vermilion of the upper lip resembling a ginkgo leaf
• Thick vermilion of the lower lip
• Pointed chin
• Abnormally shaped ears
• Simple ears
• Posteriorly rotated ears
• Low-set ears
• Protruding ears
• Abnormalities of the lacrimal duct, specifically lacrimal duct stenosis and hypoplastic lacrimal duct
• Craniosynostosis in one affected individual (suture not specified)
• Pierre Robin sequence with a cleft palate in one affected individual
• Abnormalities of the subarachnoid space (widened subarachnoid space)
• Delayed myelination
• Frontal gliosis
• Cortical dysplasia
• Focal areas of encephalomalacia
• Unilateral and/or bilateral dilatation of the lateral ventricles
• Abnormalities of cerebral white matter (cerebral white matter atrophy, subcortical bifrontal white matter foci)
• Abnormalities of the corpus callosum (ranging from hypoplasia of the corpus callosum to agenesis of corpus callosum)
• Unilateral hemihypotrophy of lower limb
• Patella luxations
• Increased laxity of fingers
• Long fingers
• Sydney crease *
• Sandal gap
• Hallux valgus
• Distal arthrogryposis
• Unilateral hemihypotrophy of lower limb
• Patella luxations
• Increased laxity of fingers
• Long fingers
• Sydney crease *
• Sandal gap
• Hallux valgus
• Distal arthrogryposis
• Unilateral hemihypotrophy of lower limb
• Patella luxations
• Increased laxity of fingers
• Long fingers
• Sydney crease *
• Sandal gap
• Hallux valgus
• Distal arthrogryposis
• Recurrent infections
• Breast hypoplasia
• Hyperextensible skin
• Childhood-onset neuroblastoma
## Clinical Description
To date, ten individuals with a
Generalized facial asymmetry, with mild discrepancy in the size of one side of the face compared to the other
Broad forehead
Fullness of upper eyelids
Downslanted palpebral fissures
Bulbous nose
Malar flattening
Indentation of the vermilion of the upper lip resembling a ginkgo leaf
Thick vermilion of the lower lip
Pointed chin
External ear malformations are common and include the following:
Abnormally shaped ears
Simple ears
Posteriorly rotated ears
Low-set ears
Protruding ears
Rare craniofacial findings have included the following:
Abnormalities of the lacrimal duct, specifically lacrimal duct stenosis and hypoplastic lacrimal duct
Craniosynostosis in one affected individual (suture not specified)
Pierre Robin sequence with a cleft palate in one affected individual
Abnormalities of the subarachnoid space (widened subarachnoid space)
Delayed myelination
Frontal gliosis
Cortical dysplasia
Focal areas of encephalomalacia
Unilateral and/or bilateral dilatation of the lateral ventricles
Abnormalities of cerebral white matter (cerebral white matter atrophy, subcortical bifrontal white matter foci)
Abnormalities of the corpus callosum (ranging from hypoplasia of the corpus callosum to agenesis of corpus callosum)
Each of the reported CNS morphologic abnormalities was observed in one or two individuals (occurring alone or concomitantly with another neuroimaging abnormality) and is not exclusive to Gabriele-de Vries syndrome.
Unilateral hemihypotrophy of lower limb
Patella luxations
Increased laxity of fingers
Long fingers
Sydney crease *
Sandal gap
Hallux valgus
Distal arthrogryposis
* Note: The Sydney crease is a proximal transverse (5-finger) crease that starts on the radial side of the hand near the base of the index finger and extends completely to the ulnar margin of the palm.
Recurrent infections
Breast hypoplasia
Hyperextensible skin
Childhood-onset neuroblastoma
• Generalized facial asymmetry, with mild discrepancy in the size of one side of the face compared to the other
• Broad forehead
• Fullness of upper eyelids
• Downslanted palpebral fissures
• Bulbous nose
• Malar flattening
• Indentation of the vermilion of the upper lip resembling a ginkgo leaf
• Thick vermilion of the lower lip
• Pointed chin
• Abnormally shaped ears
• Simple ears
• Posteriorly rotated ears
• Low-set ears
• Protruding ears
• Abnormalities of the lacrimal duct, specifically lacrimal duct stenosis and hypoplastic lacrimal duct
• Craniosynostosis in one affected individual (suture not specified)
• Pierre Robin sequence with a cleft palate in one affected individual
• Abnormalities of the subarachnoid space (widened subarachnoid space)
• Delayed myelination
• Frontal gliosis
• Cortical dysplasia
• Focal areas of encephalomalacia
• Unilateral and/or bilateral dilatation of the lateral ventricles
• Abnormalities of cerebral white matter (cerebral white matter atrophy, subcortical bifrontal white matter foci)
• Abnormalities of the corpus callosum (ranging from hypoplasia of the corpus callosum to agenesis of corpus callosum)
• Unilateral hemihypotrophy of lower limb
• Patella luxations
• Increased laxity of fingers
• Long fingers
• Sydney crease *
• Sandal gap
• Hallux valgus
• Distal arthrogryposis
• Unilateral hemihypotrophy of lower limb
• Patella luxations
• Increased laxity of fingers
• Long fingers
• Sydney crease *
• Sandal gap
• Hallux valgus
• Distal arthrogryposis
• Unilateral hemihypotrophy of lower limb
• Patella luxations
• Increased laxity of fingers
• Long fingers
• Sydney crease *
• Sandal gap
• Hallux valgus
• Distal arthrogryposis
• Recurrent infections
• Breast hypoplasia
• Hyperextensible skin
• Childhood-onset neuroblastoma
## Genotype-Phenotype Correlations
Given the small number of affected individuals reported in the literature, no genotype-phenotype correlations are currently known.
## Prevalence
Gabriele-de Vries syndrome is a rare condition. So far, ten affected individuals worldwide have been described in the medical literature with a
The prevalence of Gabriele-de Vries syndrome is yet to be determined. To date,
Since individuals have been recruited via large exome sequencing projects, it is expected that more affected individuals will be diagnosed with Gabriele-de Vries syndrome as the use of genomic testing increases.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
The phenotype of those with contiguous gene deletions including
## Differential Diagnosis
The phenotypic features associated with Gabriele-de Vries syndrome are not sufficient to diagnose this condition clinically; therefore, all disorders with intellectual disability and congenital anomalies should be considered in the differential diagnosis. See
## Management
Evaluation by a multidisciplinary team can be beneficial.
To establish the extent of disease and needs in an individual diagnosed with Gabriele-de Vries syndrome, the evaluations summarized
Note: Some evaluations are age dependent and may not be relevant at the time of initial diagnosis.
Recommended Evaluations Following Initial Diagnosis of Gabriele-de Vries Syndrome
Refer to occupational or speech therapist for feeding therapy.
Consider referral to gastroenterologist, if severe, to assess need for gastrostomy tube.
W/consideration of EEG &/or brain MRI
Consider referral to pediatric neurologist.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Including plastic surgeons, neurosurgeons, speech pathologists, geneticists, pediatricians, orthodontists, and other craniofacial specialists
Assessment of hypotonia, movement disorders, gait abnormalities, and history of possible seizures
Treatment of Manifestations in Individuals with Gabriele-de Vries Syndrome
ASM = anti-seizure medication
Including plastic surgeons, pediatricians, orthodontists, and other craniofacial specialists
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
A developmental pediatrician or a geneticist should coordinate the follow up of a child with Gabriele-de Vries syndrome. Surveillance of gastrointestinal, craniofacial, cardiac, renal, genital, skeletal, and endocrine abnormalities should be tailored to the affected individual according to the specific problems identified at diagnosis.
Long-term follow up by other specialists is also recommended and includes the following.
Recommended Surveillance for Individuals with Gabriele-de Vries Syndrome
See
Search
• Refer to occupational or speech therapist for feeding therapy.
• Consider referral to gastroenterologist, if severe, to assess need for gastrostomy tube.
• W/consideration of EEG &/or brain MRI
• Consider referral to pediatric neurologist.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations and Referrals Following Initial Diagnosis
Evaluation by a multidisciplinary team can be beneficial.
To establish the extent of disease and needs in an individual diagnosed with Gabriele-de Vries syndrome, the evaluations summarized
Note: Some evaluations are age dependent and may not be relevant at the time of initial diagnosis.
Recommended Evaluations Following Initial Diagnosis of Gabriele-de Vries Syndrome
Refer to occupational or speech therapist for feeding therapy.
Consider referral to gastroenterologist, if severe, to assess need for gastrostomy tube.
W/consideration of EEG &/or brain MRI
Consider referral to pediatric neurologist.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Including plastic surgeons, neurosurgeons, speech pathologists, geneticists, pediatricians, orthodontists, and other craniofacial specialists
Assessment of hypotonia, movement disorders, gait abnormalities, and history of possible seizures
• Refer to occupational or speech therapist for feeding therapy.
• Consider referral to gastroenterologist, if severe, to assess need for gastrostomy tube.
• W/consideration of EEG &/or brain MRI
• Consider referral to pediatric neurologist.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Gabriele-de Vries Syndrome
ASM = anti-seizure medication
Including plastic surgeons, pediatricians, orthodontists, and other craniofacial specialists
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
## Surveillance
A developmental pediatrician or a geneticist should coordinate the follow up of a child with Gabriele-de Vries syndrome. Surveillance of gastrointestinal, craniofacial, cardiac, renal, genital, skeletal, and endocrine abnormalities should be tailored to the affected individual according to the specific problems identified at diagnosis.
Long-term follow up by other specialists is also recommended and includes the following.
Recommended Surveillance for Individuals with Gabriele-de Vries Syndrome
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Gabriele-de Vries syndrome is inherited in an autosomal dominant manner and is typically caused by a
All probands reported to date with Gabriele-de Vries syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Theoretically, if the parent is the individual in whom the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• All probands reported to date with Gabriele-de Vries syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Theoretically, if the parent is the individual in whom the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals
## Mode of Inheritance
Gabriele-de Vries syndrome is inherited in an autosomal dominant manner and is typically caused by a
## Risk to Family Members
All probands reported to date with Gabriele-de Vries syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Theoretically, if the parent is the individual in whom the
• All probands reported to date with Gabriele-de Vries syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Theoretically, if the parent is the individual in whom the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals
## Prenatal Testing and Preimplantation Genetic Testing
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
## Molecular Genetics
Gabriele-de Vries Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Gabriele-de Vries Syndrome (
See
According to the capability of YY1 to mediate chromatin loops between enhancers and promoters [
In support of this hypothesis,
YY1 is overexpressed in several sporadic tumors including hepatocellular carcinoma [
## Cancer and Benign Tumors
YY1 is overexpressed in several sporadic tumors including hepatocellular carcinoma [
## Chapter Notes
The authors also recommend the following resource:
To gain further insight, and expand the clinical phenotype of pathogenic variants within the complete coding region of the
We acknowledge all individuals and their parents who participated in the study described in
30 May 2019 (ma) Review posted live
23 April 2018 (gt, bdv) Original submission
• 30 May 2019 (ma) Review posted live
• 23 April 2018 (gt, bdv) Original submission
## Author Notes
The authors also recommend the following resource:
To gain further insight, and expand the clinical phenotype of pathogenic variants within the complete coding region of the
## Acknowledgments
We acknowledge all individuals and their parents who participated in the study described in
## Revision History
30 May 2019 (ma) Review posted live
23 April 2018 (gt, bdv) Original submission
• 30 May 2019 (ma) Review posted live
• 23 April 2018 (gt, bdv) Original submission
## References
## Literature Cited
|
[
"ML Atchison. Function of YY1 in long-distance DNA interactions.. Front Immunol. 2014;5:45",
"JA Beagan, MT Duong, KR Titus, L Zhou, Z Cao, J Ma, CV Lachanski, DR Gillis, JE Phillips-Cremins. YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment.. Genome Res. 2017;27:1139-52",
"Y Cao, Z Gao, L Li, X Jiang, A Shan, J Cai, Y Peng, Y Li, X Jiang, X Huang, J Wang, Q Wei, G Qin, J Zhao, X Jin, L Liu, Y Li, W Wang, J Wang, G. Ning. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1.. Nat Commun. 2013;4:2810",
"AA Cho, B Bonavida. Targeting the overexpressed YY1 in cancer inhibits EMT and metastasis.. Crit Rev Oncog. 2017;22:49-61",
"ME Donohoe, X Zhang, L McGinnis, J Biggers, E Li, Y Shi. Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality.. Mol Cell Biol. 1999;19:7237-44",
"M Gabriele, A Lopez Tobon, G D'Agostino, G. Testa. The chromatin basis of neurodevelopmental disorders: rethinking dysfunction along the molecular and temporal axes.. Prog Neuropsychopharmacol Biol Psychiatry. 2018;84:306-27",
"M Gabriele, AT Vulto-van Silfhout, PL Germain, A Vitriolo, R Kumar, E Douglas, E Haan, K Kosaki, T Takenouchi, A Rauch, K Steindl, E Frengen, D Misceo, CRJ Pedurupillay, P Stromme, JA Rosenfeld, Y Shao, WJ Craigen, CP Schaaf, D Rodriguez-Buritica, L Farach, J Friedman, P Thulin, SD McLean, KM Nugent, J Morton, J Nicholl, J Andrieux, A Stray-Pedersen, P Chambon, S Patrier, SA Lynch, S Kjaergaard, PM Tørring, C Brasch-Andersen, A Ronan, A van Haeringen, PJ Anderson, Z Powis, HG Brunner, R Pfundt, JHM Schuurs-Hoeijmakers, BWM van Bon, S Lelieveld, C Gilissen, WM Nillesen, LELM Vissers, J Gecz, DA Koolen, G Testa, BBA de Vries. YY1 haploinsufficiency causes an intellectual disability syndrome featuring transcriptional and chromatin dysfunction.. Am J Hum Genet. 2017;100:907-25",
"T Gerasimova, C Guo, A Ghosh, X Qiu, L Montefiori, J Verma-Gaur, NM Choi, AJ Feeney, R Sen. A structural hierarchy mediated by multiple nuclear factors establishes IgH locus conformation.. Genes Dev. 2015;29:1683-95",
"Y He, P. Casaccia-Bonnefil. The Yin and Yang of YY1 in the nervous system.. J Neurochem. 2008;106:1493-502",
"Y He, J Dupree, J Wang, J Sandoval, J Li, H Liu, Y Shi, KA Nave, P Casaccia-Bonnefil. The transcription factor Yin Yang 1 is essential for oligodendrocyte progenitor differentiation.. Neuron. 2007;55:217-30",
"LM Khachigian. The Yin and Yang of YY1 in tumor growth and suppression.. Int J Cancer. 2018;143:460-5",
"UD Lichtenauer, G Di Dalmazi, EP Slater, T Wieland, A Kuebart, A Schmittfull, T Schwarzmayr, S Diener, D Wiese, WE Thasler, M Reincke, T Meitinger, M Schott, M Fassnacht, DK Bartsch, TM Strom, F Beuschlein. Frequency and clinical correlates of somatic Ying Yang 1 mutations in sporadic insulinomas.. J Clin Endocrinol Metab. 2015;100:E776-82",
"J Medvedovic, A Ebert, H Tagoh, IM Tamir, TA Schwickert, M Novatchkova, Q Sun, PJ Huis In 't Veld, C Guo, HS Yoon, Y Denizot, SJ Holwerda, W de Laat, M Cogné, Y Shi, FW Alt, M Busslinger. Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire.. Immunity. 2013;39:229-44",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"Y Shi, E Seto, LS Chang, T Shenk. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein.. Cell. 1991;67:377-88",
"LE Vissers, J de Ligt, C Gilissen, I Janssen, M Steehouwer, P de Vries, B van Lier, P Arts, N Wieskamp, M del Rosario, BW van Bon, A Hoischen, BB de Vries, HG Brunner, JA Veltman. A de novo paradigm for mental retardation.. Nat Genet. 2010;42:1109-12",
"AS Weintraub, CH Li, AV Zamudio, AA Sigova, NM Hannett, DS Day, BJ Abraham, MA Cohen, B Nabet, DL Buckley, YE Guo, D Hnisz, R Jaenisch, JE Bradner, NS Gray, RA Young. YY1 is a structural regulator of enhancer-promoter loops.. Cell. 2017;171:1573-88.e28",
"A Zaravinos, DA Spandidos. Yin yang 1 expression in human tumors.. Cell Cycle. 2010;9:512-22",
"S Zhang, T Jiang, L Feng, J Sun, H Lu, Q Wang, M Pan, D Huang, X Wang, L Wang, H. Jin. Yin Yang-1 suppresses differentiation of hepatocellular carcinoma cells through the downregulation of CCAAT/enhancer-binding protein alpha.. J Mol Med (Berl) 2012;90:1069-77"
] |
30/5/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
gaci
|
gaci
|
[
"GACI",
"Idiopathic Infantile Arterial Calcification (IIAC)",
"GACI",
"Idiopathic Infantile Arterial Calcification (IIAC)",
"ATP-binding cassette sub-family C member 6",
"Ectonucleotide pyrophosphatase/phosphodiesterase family member 1",
"ABCC6",
"ENPP1",
"Generalized Arterial Calcification of Infancy"
] |
Generalized Arterial Calcification of Infancy
|
Shira G Ziegler, William A Gahl, Carlos R Ferreira
|
Summary Generalized arterial calcification of infancy (GACI) is characterized by infantile onset of widespread arterial calcification and/or narrowing of large and medium-sized vessels resulting in cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly). Additional findings can include typical skin and retinal manifestations of pseudoxanthoma elasticum (PXE), periarticular calcifications, development of rickets after infancy, cervical spine fusion, and hearing loss. While mortality in infancy is high, survival into the third and fourth decades has occurred. The diagnosis of GACI is established in a proband with cardiovascular symptoms during infancy associated with widespread arterial calcification on imaging (once secondary causes have been ruled out) and biallelic pathogenic variants in GACI is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GACI-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither pathogenic variant. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.
|
## Diagnosis
No consensus clinical diagnostic criteria for generalized arterial calcification of infancy (GACI) have been published.
GACI should be suspected in individuals with a combination of the following.
Typical cardiovascular findings including heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly
Characteristic
Appearance of typical clinical and histologic skin findings of
Development of hypophosphatemic rickets after infancy
Detect echobrightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch;
Detect the presence of left ventricular hypertrophy and/or pericardial effusion.
The diagnosis of GACI is established in a proband with cardiovascular symptoms during infancy associated with widespread arterial calcification on imaging once secondary causes have been ruled out (see
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Generalized Arterial Calcification of Infancy (GACI)
Genes are listed in alphabetic order.
See
While a majority of cases of GACI are caused by biallelic pathogenic variants in
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
22 of 92 individuals with GACI reported by
• Typical cardiovascular findings including heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly
• Characteristic
• Appearance of typical clinical and histologic skin findings of
• Development of hypophosphatemic rickets after infancy
• Detect echobrightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch;
• Detect the presence of left ventricular hypertrophy and/or pericardial effusion.
• Detect echobrightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch;
• Detect the presence of left ventricular hypertrophy and/or pericardial effusion.
• Detect echobrightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch;
• Detect the presence of left ventricular hypertrophy and/or pericardial effusion.
## Suggestive Findings
GACI should be suspected in individuals with a combination of the following.
Typical cardiovascular findings including heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly
Characteristic
Appearance of typical clinical and histologic skin findings of
Development of hypophosphatemic rickets after infancy
Detect echobrightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch;
Detect the presence of left ventricular hypertrophy and/or pericardial effusion.
• Typical cardiovascular findings including heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly
• Characteristic
• Appearance of typical clinical and histologic skin findings of
• Development of hypophosphatemic rickets after infancy
• Detect echobrightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch;
• Detect the presence of left ventricular hypertrophy and/or pericardial effusion.
• Detect echobrightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch;
• Detect the presence of left ventricular hypertrophy and/or pericardial effusion.
• Detect echobrightness of the arteries near the heart, including the coronary and pulmonary arteries, ascending aorta and aortic arch, and large arteries originating from the aortic arch;
• Detect the presence of left ventricular hypertrophy and/or pericardial effusion.
## Establishing the Diagnosis
The diagnosis of GACI is established in a proband with cardiovascular symptoms during infancy associated with widespread arterial calcification on imaging once secondary causes have been ruled out (see
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Generalized Arterial Calcification of Infancy (GACI)
Genes are listed in alphabetic order.
See
While a majority of cases of GACI are caused by biallelic pathogenic variants in
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
22 of 92 individuals with GACI reported by
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Generalized Arterial Calcification of Infancy (GACI)
Genes are listed in alphabetic order.
See
While a majority of cases of GACI are caused by biallelic pathogenic variants in
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
22 of 92 individuals with GACI reported by
## Clinical Characteristics
Generalized arterial calcification of infancy (GACI) can result either from ENPP1 deficiency (ENPP1-GACI), or from ABCC6 deficiency (ABCC6-GACI) associated with biallelic pathogenic variants in
GACI: Frequency of Select Features
A review of published information on 161 individuals with GACI [
A bimodal age of presentation. 48% had early onset (i.e., in utero or within the first week of life) and 52% had late onset (median age three months).
In early-onset GACI, the most common initial findings were fetal distress (46%), heart failure (44%), polyhydramnios (38%), hypertension (33%), respiratory distress (30%), hydrops fetalis (28%), edema (24%), "visceral" effusions (20%), cyanosis (22%), cardiomegaly (17%), and ascites (13%).
In late-onset GACI, the most common presenting findings were respiratory distress (66%), cyanosis (43%), refusal to feed (34%), heart failure (29%), vomiting (24%), irritability (21%), failure to thrive (17%), fever (16%), hypertension (12%), and edema (7%).
Males and females were affected with similar frequency: 43% of those with early-onset GACI and 48% of late-onset GACI were female.
For individuals with fetal involvement, arterial calcifications are commonly detected at the time of prenatal ultrasound (most commonly in the third trimester, but imaging diagnosis in the second trimester is also possible). For infants with postnatal late-onset GACI, the presenting findings (respiratory distress, cyanosis, refusal to feed, heart failure) lead to imaging studies such as echocardiography and/or CT, and the detection of arterial calcification suggests the diagnosis.
Autopsy studies (reviewed by
In a cohort of long-term survivors of GACI, the most common sites of arterial calcification were the aorta (14/16), and renal (11/16), mesenteric (11/16), coronary (10/16), iliac (10/16), and pulmonary (10/16) arteries [
Although generally spared, the cerebral arteries have been involved in several reported individuals [
Peripheral arterial calcifications can present with decreased peripheral pulses; in exceptional cases, gangrene has occurred in the distal extremities [
Pulmonary hypertension refractory to medical therapy is possible [
Spontaneous resolution of calcification has been reported in several individuals [
Arterial calcifications or intimal proliferation may also explain the high frequency of recurrent pregnancy loss (≥4 miscarriages per family in 25% vs in 1%-2% in the general population) and hematochezia (15% vs 2% in the general population) [
Periarticular calcifications have been noted in eight of 16 surviving individuals with GACI [
Other sites of extravascular calcification include the ear lobes [
Individuals with GACI can manifest PXE-like changes; these were seen in four of 20 survivors, with onset between ages two and 43 years [
It has been speculated that children with GACI and findings of PXE were not reported until recently because most died before they developed typical signs of PXE, and many features of PXE (e.g., angioid streaks and skin lesions) are frequently overlooked in the clinical examination of individuals with GACI [
Individuals with GACI caused by pathogenic variants in
The average age for the development of hypophosphatemia was 1.6 years [
There are no reports of hypophosphatemia in individuals with GACI caused by pathogenic variants of
Bilateral medullary nephrocalcinosis was seen in five of ten individuals with ENPP1 deficiency who received standard treatment for hypophosphatemic rickets/osteomalacia, while it was not detected in any of seven individuals who were naïve to treatment. Cortical nephrocalcinosis can be seen in the absence of treatment. While medullary nephrocalcinosis is likely a complication from treatment of rickets/osteomalacia (and thus seen only in ENPP1 deficiency), cortical nephrocalcinosis likely represents a consequence of ischemia (and can be seen either with ENPP1 or ABCC6 deficiency) [
Fusion of the posterior elements of the cervical spine (posterior vertebral bodies, articular processes, laminae) was seen in four of 16 individuals with ENPP1 deficiency [
In GACI, hearing loss can be conductive, sensorineural, or mixed, and can present as early as in the neonatal period [
Sensorineural hearing loss is presumably due to calcifications of the arteries supplying the inner ear [
Although cognitive development has not been formally assessed in a cohort of individuals with GACI, the majority appear to have normal development. However, the authors are aware of a few individuals with severe global developmental delay in the setting of prior strokes or encephalomalacia. In individuals with periarticular calcifications, motor milestones can be delayed due to pain around the affected joints [Authors, personal observation].
In one family in which the father and son were homozygous for the same
In a series of 55 children, the mortality rate at age six months was 30 of 55 (55%) despite intensive therapy [
Long-term survivors, with several in their 20s, include twins age 21 years [
Bisphosphonate treatment was associated with survival beyond infancy in 11 of 17 individuals, while 18 of 26 individuals not treated with bisphosphonates died in infancy [
Marked phenotypic heterogeneity, even among surviving sibs with identical genotypes, argues against a genotype-phenotype correlation in GACI [
In the past, generalized arterial calcification of infancy (GACI) has been variously referred to as idiopathic obliterative arteriopathy, infantile calcifying arteriopathy, occlusive infantile arteriopathy, medial coronary sclerosis of infancy, diffuse arterial calcifying elastopathy of infancy, and arteriopathia calcificans infantum.
GACI shows no ethnic or racial predilection, and has been described throughout the world.
The disease frequency is estimated at one in 200,000 pregnancies, and the carrier frequency at one in 223 individuals [
• A bimodal age of presentation. 48% had early onset (i.e., in utero or within the first week of life) and 52% had late onset (median age three months).
• In early-onset GACI, the most common initial findings were fetal distress (46%), heart failure (44%), polyhydramnios (38%), hypertension (33%), respiratory distress (30%), hydrops fetalis (28%), edema (24%), "visceral" effusions (20%), cyanosis (22%), cardiomegaly (17%), and ascites (13%).
• In late-onset GACI, the most common presenting findings were respiratory distress (66%), cyanosis (43%), refusal to feed (34%), heart failure (29%), vomiting (24%), irritability (21%), failure to thrive (17%), fever (16%), hypertension (12%), and edema (7%).
• Males and females were affected with similar frequency: 43% of those with early-onset GACI and 48% of late-onset GACI were female.
## Clinical Description
Generalized arterial calcification of infancy (GACI) can result either from ENPP1 deficiency (ENPP1-GACI), or from ABCC6 deficiency (ABCC6-GACI) associated with biallelic pathogenic variants in
GACI: Frequency of Select Features
A review of published information on 161 individuals with GACI [
A bimodal age of presentation. 48% had early onset (i.e., in utero or within the first week of life) and 52% had late onset (median age three months).
In early-onset GACI, the most common initial findings were fetal distress (46%), heart failure (44%), polyhydramnios (38%), hypertension (33%), respiratory distress (30%), hydrops fetalis (28%), edema (24%), "visceral" effusions (20%), cyanosis (22%), cardiomegaly (17%), and ascites (13%).
In late-onset GACI, the most common presenting findings were respiratory distress (66%), cyanosis (43%), refusal to feed (34%), heart failure (29%), vomiting (24%), irritability (21%), failure to thrive (17%), fever (16%), hypertension (12%), and edema (7%).
Males and females were affected with similar frequency: 43% of those with early-onset GACI and 48% of late-onset GACI were female.
For individuals with fetal involvement, arterial calcifications are commonly detected at the time of prenatal ultrasound (most commonly in the third trimester, but imaging diagnosis in the second trimester is also possible). For infants with postnatal late-onset GACI, the presenting findings (respiratory distress, cyanosis, refusal to feed, heart failure) lead to imaging studies such as echocardiography and/or CT, and the detection of arterial calcification suggests the diagnosis.
Autopsy studies (reviewed by
In a cohort of long-term survivors of GACI, the most common sites of arterial calcification were the aorta (14/16), and renal (11/16), mesenteric (11/16), coronary (10/16), iliac (10/16), and pulmonary (10/16) arteries [
Although generally spared, the cerebral arteries have been involved in several reported individuals [
Peripheral arterial calcifications can present with decreased peripheral pulses; in exceptional cases, gangrene has occurred in the distal extremities [
Pulmonary hypertension refractory to medical therapy is possible [
Spontaneous resolution of calcification has been reported in several individuals [
Arterial calcifications or intimal proliferation may also explain the high frequency of recurrent pregnancy loss (≥4 miscarriages per family in 25% vs in 1%-2% in the general population) and hematochezia (15% vs 2% in the general population) [
Periarticular calcifications have been noted in eight of 16 surviving individuals with GACI [
Other sites of extravascular calcification include the ear lobes [
Individuals with GACI can manifest PXE-like changes; these were seen in four of 20 survivors, with onset between ages two and 43 years [
It has been speculated that children with GACI and findings of PXE were not reported until recently because most died before they developed typical signs of PXE, and many features of PXE (e.g., angioid streaks and skin lesions) are frequently overlooked in the clinical examination of individuals with GACI [
Individuals with GACI caused by pathogenic variants in
The average age for the development of hypophosphatemia was 1.6 years [
There are no reports of hypophosphatemia in individuals with GACI caused by pathogenic variants of
Bilateral medullary nephrocalcinosis was seen in five of ten individuals with ENPP1 deficiency who received standard treatment for hypophosphatemic rickets/osteomalacia, while it was not detected in any of seven individuals who were naïve to treatment. Cortical nephrocalcinosis can be seen in the absence of treatment. While medullary nephrocalcinosis is likely a complication from treatment of rickets/osteomalacia (and thus seen only in ENPP1 deficiency), cortical nephrocalcinosis likely represents a consequence of ischemia (and can be seen either with ENPP1 or ABCC6 deficiency) [
Fusion of the posterior elements of the cervical spine (posterior vertebral bodies, articular processes, laminae) was seen in four of 16 individuals with ENPP1 deficiency [
In GACI, hearing loss can be conductive, sensorineural, or mixed, and can present as early as in the neonatal period [
Sensorineural hearing loss is presumably due to calcifications of the arteries supplying the inner ear [
Although cognitive development has not been formally assessed in a cohort of individuals with GACI, the majority appear to have normal development. However, the authors are aware of a few individuals with severe global developmental delay in the setting of prior strokes or encephalomalacia. In individuals with periarticular calcifications, motor milestones can be delayed due to pain around the affected joints [Authors, personal observation].
In one family in which the father and son were homozygous for the same
In a series of 55 children, the mortality rate at age six months was 30 of 55 (55%) despite intensive therapy [
Long-term survivors, with several in their 20s, include twins age 21 years [
Bisphosphonate treatment was associated with survival beyond infancy in 11 of 17 individuals, while 18 of 26 individuals not treated with bisphosphonates died in infancy [
• A bimodal age of presentation. 48% had early onset (i.e., in utero or within the first week of life) and 52% had late onset (median age three months).
• In early-onset GACI, the most common initial findings were fetal distress (46%), heart failure (44%), polyhydramnios (38%), hypertension (33%), respiratory distress (30%), hydrops fetalis (28%), edema (24%), "visceral" effusions (20%), cyanosis (22%), cardiomegaly (17%), and ascites (13%).
• In late-onset GACI, the most common presenting findings were respiratory distress (66%), cyanosis (43%), refusal to feed (34%), heart failure (29%), vomiting (24%), irritability (21%), failure to thrive (17%), fever (16%), hypertension (12%), and edema (7%).
• Males and females were affected with similar frequency: 43% of those with early-onset GACI and 48% of late-onset GACI were female.
## Presentation
A review of published information on 161 individuals with GACI [
A bimodal age of presentation. 48% had early onset (i.e., in utero or within the first week of life) and 52% had late onset (median age three months).
In early-onset GACI, the most common initial findings were fetal distress (46%), heart failure (44%), polyhydramnios (38%), hypertension (33%), respiratory distress (30%), hydrops fetalis (28%), edema (24%), "visceral" effusions (20%), cyanosis (22%), cardiomegaly (17%), and ascites (13%).
In late-onset GACI, the most common presenting findings were respiratory distress (66%), cyanosis (43%), refusal to feed (34%), heart failure (29%), vomiting (24%), irritability (21%), failure to thrive (17%), fever (16%), hypertension (12%), and edema (7%).
Males and females were affected with similar frequency: 43% of those with early-onset GACI and 48% of late-onset GACI were female.
For individuals with fetal involvement, arterial calcifications are commonly detected at the time of prenatal ultrasound (most commonly in the third trimester, but imaging diagnosis in the second trimester is also possible). For infants with postnatal late-onset GACI, the presenting findings (respiratory distress, cyanosis, refusal to feed, heart failure) lead to imaging studies such as echocardiography and/or CT, and the detection of arterial calcification suggests the diagnosis.
• A bimodal age of presentation. 48% had early onset (i.e., in utero or within the first week of life) and 52% had late onset (median age three months).
• In early-onset GACI, the most common initial findings were fetal distress (46%), heart failure (44%), polyhydramnios (38%), hypertension (33%), respiratory distress (30%), hydrops fetalis (28%), edema (24%), "visceral" effusions (20%), cyanosis (22%), cardiomegaly (17%), and ascites (13%).
• In late-onset GACI, the most common presenting findings were respiratory distress (66%), cyanosis (43%), refusal to feed (34%), heart failure (29%), vomiting (24%), irritability (21%), failure to thrive (17%), fever (16%), hypertension (12%), and edema (7%).
• Males and females were affected with similar frequency: 43% of those with early-onset GACI and 48% of late-onset GACI were female.
## Arterial Calcification
Autopsy studies (reviewed by
In a cohort of long-term survivors of GACI, the most common sites of arterial calcification were the aorta (14/16), and renal (11/16), mesenteric (11/16), coronary (10/16), iliac (10/16), and pulmonary (10/16) arteries [
Although generally spared, the cerebral arteries have been involved in several reported individuals [
Peripheral arterial calcifications can present with decreased peripheral pulses; in exceptional cases, gangrene has occurred in the distal extremities [
Pulmonary hypertension refractory to medical therapy is possible [
Spontaneous resolution of calcification has been reported in several individuals [
Arterial calcifications or intimal proliferation may also explain the high frequency of recurrent pregnancy loss (≥4 miscarriages per family in 25% vs in 1%-2% in the general population) and hematochezia (15% vs 2% in the general population) [
## Extravascular Calcifications
Periarticular calcifications have been noted in eight of 16 surviving individuals with GACI [
Other sites of extravascular calcification include the ear lobes [
## Pseudoxanthoma Elasticum (PXE) Findings
Individuals with GACI can manifest PXE-like changes; these were seen in four of 20 survivors, with onset between ages two and 43 years [
It has been speculated that children with GACI and findings of PXE were not reported until recently because most died before they developed typical signs of PXE, and many features of PXE (e.g., angioid streaks and skin lesions) are frequently overlooked in the clinical examination of individuals with GACI [
## Hypophosphatemic Rickets / Osteomalacia
Individuals with GACI caused by pathogenic variants in
The average age for the development of hypophosphatemia was 1.6 years [
There are no reports of hypophosphatemia in individuals with GACI caused by pathogenic variants of
## Nephrocalcinosis
Bilateral medullary nephrocalcinosis was seen in five of ten individuals with ENPP1 deficiency who received standard treatment for hypophosphatemic rickets/osteomalacia, while it was not detected in any of seven individuals who were naïve to treatment. Cortical nephrocalcinosis can be seen in the absence of treatment. While medullary nephrocalcinosis is likely a complication from treatment of rickets/osteomalacia (and thus seen only in ENPP1 deficiency), cortical nephrocalcinosis likely represents a consequence of ischemia (and can be seen either with ENPP1 or ABCC6 deficiency) [
## Cervical Spine Fusion
Fusion of the posterior elements of the cervical spine (posterior vertebral bodies, articular processes, laminae) was seen in four of 16 individuals with ENPP1 deficiency [
## Hearing Loss
In GACI, hearing loss can be conductive, sensorineural, or mixed, and can present as early as in the neonatal period [
Sensorineural hearing loss is presumably due to calcifications of the arteries supplying the inner ear [
## Development
Although cognitive development has not been formally assessed in a cohort of individuals with GACI, the majority appear to have normal development. However, the authors are aware of a few individuals with severe global developmental delay in the setting of prior strokes or encephalomalacia. In individuals with periarticular calcifications, motor milestones can be delayed due to pain around the affected joints [Authors, personal observation].
## Variability
In one family in which the father and son were homozygous for the same
## Prognosis
In a series of 55 children, the mortality rate at age six months was 30 of 55 (55%) despite intensive therapy [
Long-term survivors, with several in their 20s, include twins age 21 years [
Bisphosphonate treatment was associated with survival beyond infancy in 11 of 17 individuals, while 18 of 26 individuals not treated with bisphosphonates died in infancy [
## Genotype-Phenotype Correlations
Marked phenotypic heterogeneity, even among surviving sibs with identical genotypes, argues against a genotype-phenotype correlation in GACI [
## Nomenclature
In the past, generalized arterial calcification of infancy (GACI) has been variously referred to as idiopathic obliterative arteriopathy, infantile calcifying arteriopathy, occlusive infantile arteriopathy, medial coronary sclerosis of infancy, diffuse arterial calcifying elastopathy of infancy, and arteriopathia calcificans infantum.
## Prevalence
GACI shows no ethnic or racial predilection, and has been described throughout the world.
The disease frequency is estimated at one in 200,000 pregnancies, and the carrier frequency at one in 223 individuals [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
Short stature, dental caries, & bone deformities
Hypophosphatemia, hyperphosphaturia, & ↑ plasma alkaline phosphatase
Distinctive hypopigmented macules; punctate keratosis on areas of cornification (specifically the palms & soles)
Rare cutaneous calcifications (incl calcinosis cutis & calcific tendinopathy) have been noted.
Systemic disorder affecting elastic tissue of the skin, eye, & CV & GI systems
Commonly presents w/papules in the skin &/or w/angioid streaks of the retina found on routine eye exam or assoc w/retinal hemorrhage
Rarely, may present w/vascular signs & symptoms, (e.g., GI bleeding, angina, or intermittent claudication)
↓ vision (from macular hemorrhage & disciform scarring of the macula) is most frequent cause of morbidity & disability.
Normal life span in most persons
AD = autosomal dominant; AR = autosomal recessive; CV = cardiovascular; dx = diagnosis; GACI = generalized arterial calcification of infancy; GI = gastrointestinal; MOI = mode of inheritance
Of note, fibroblast growth factor 23 (
That is, no vascular or periarticular calcifications on imaging studies.
• Short stature, dental caries, & bone deformities
• Hypophosphatemia, hyperphosphaturia, & ↑ plasma alkaline phosphatase
• Distinctive hypopigmented macules; punctate keratosis on areas of cornification (specifically the palms & soles)
• Rare cutaneous calcifications (incl calcinosis cutis & calcific tendinopathy) have been noted.
• Systemic disorder affecting elastic tissue of the skin, eye, & CV & GI systems
• Commonly presents w/papules in the skin &/or w/angioid streaks of the retina found on routine eye exam or assoc w/retinal hemorrhage
• Rarely, may present w/vascular signs & symptoms, (e.g., GI bleeding, angina, or intermittent claudication)
• ↓ vision (from macular hemorrhage & disciform scarring of the macula) is most frequent cause of morbidity & disability.
• Normal life span in most persons
## Differential Diagnosis
Severe aortic calcification, dental anomalies (delayed eruption and early loss of permanent teeth, alveolar bone erosion), osteopenia, and acroosteolysis are salient features of the disease [
Unlike generalized arterial calcification of infancy (GACI), aortic calcification in Singleton-Merten syndrome starts later in life (age range at diagnosis: 6-39 years).
Diffuse arterial calcification tends to affect the media of the vessels, and extensive extravascular calcification involves the renal tubules, bronchial walls, and basal mucosa and muscularis mucosae of the stomach.
Compared with GACI, metastatic calcification exhibits a different distribution of extravascular calcification, and the microscopic vascular changes occur in the media with little intimal proliferation.
Increased echogenicity due to calcification has been described in the wall of the pulmonary trunk, proximal branch pulmonary arteries [
Histologically, calcium is deposited primarily in the media [
• Severe aortic calcification, dental anomalies (delayed eruption and early loss of permanent teeth, alveolar bone erosion), osteopenia, and acroosteolysis are salient features of the disease [
• Unlike generalized arterial calcification of infancy (GACI), aortic calcification in Singleton-Merten syndrome starts later in life (age range at diagnosis: 6-39 years).
• Diffuse arterial calcification tends to affect the media of the vessels, and extensive extravascular calcification involves the renal tubules, bronchial walls, and basal mucosa and muscularis mucosae of the stomach.
• Compared with GACI, metastatic calcification exhibits a different distribution of extravascular calcification, and the microscopic vascular changes occur in the media with little intimal proliferation.
• Increased echogenicity due to calcification has been described in the wall of the pulmonary trunk, proximal branch pulmonary arteries [
• Histologically, calcium is deposited primarily in the media [
## Disorders with Vascular Calcification
Severe aortic calcification, dental anomalies (delayed eruption and early loss of permanent teeth, alveolar bone erosion), osteopenia, and acroosteolysis are salient features of the disease [
Unlike generalized arterial calcification of infancy (GACI), aortic calcification in Singleton-Merten syndrome starts later in life (age range at diagnosis: 6-39 years).
Diffuse arterial calcification tends to affect the media of the vessels, and extensive extravascular calcification involves the renal tubules, bronchial walls, and basal mucosa and muscularis mucosae of the stomach.
Compared with GACI, metastatic calcification exhibits a different distribution of extravascular calcification, and the microscopic vascular changes occur in the media with little intimal proliferation.
Increased echogenicity due to calcification has been described in the wall of the pulmonary trunk, proximal branch pulmonary arteries [
Histologically, calcium is deposited primarily in the media [
• Severe aortic calcification, dental anomalies (delayed eruption and early loss of permanent teeth, alveolar bone erosion), osteopenia, and acroosteolysis are salient features of the disease [
• Unlike generalized arterial calcification of infancy (GACI), aortic calcification in Singleton-Merten syndrome starts later in life (age range at diagnosis: 6-39 years).
• Diffuse arterial calcification tends to affect the media of the vessels, and extensive extravascular calcification involves the renal tubules, bronchial walls, and basal mucosa and muscularis mucosae of the stomach.
• Compared with GACI, metastatic calcification exhibits a different distribution of extravascular calcification, and the microscopic vascular changes occur in the media with little intimal proliferation.
• Increased echogenicity due to calcification has been described in the wall of the pulmonary trunk, proximal branch pulmonary arteries [
• Histologically, calcium is deposited primarily in the media [
## Disorders with Occlusive Arteriopathy
## Management
No clinical practice guidelines for GACI have been published.
To establish the extent of disease and needs in an individual diagnosed with generalized arterial calcification of infancy (GACI), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with GACI
EKG & echocardiogram
Assessment of blood pressure
Serum creatinine
Serum phosphorus
Urine phosphorus
Urine creatinine
Alkaline phosphatase
Serum calcium
Serum PTH
Tubular reabsorption of phosphate
Ratio of renal tubular maximum reabsorption rate of phosphate to GFR
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
GFR = glomerular filtration rate; MOI = mode of inheritance; PTH = parathyroid hormone
Referral to a pediatric nephrologist is indicated in the setting of refractory hypertension
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with GACI
Etidronate (20 mg/kg/d PO)
Pamidronate (0.25 mg/kg on day 1, then 0.5 mg/kg/d on days 2 & 3 for 1st cycle, then 0.5 mg/kg/d x3 days IV per cycle; cycles rptd every 2 mos)
Risedronate (1mg/kg/wk PO)
After initiation of therapy, vascular calcifications have been reported to disappear as early as 2.5 wks (as assessed by radiographs) and as late as 2 yrs [
Vascular calcifications do not reappear after discontinuation of treatment even after 10 yrs [
Prolonged etidronate use in persons w/GACI has been assoc w/severe skeletal toxicity, incl radiographic findings resembling hypophosphatasia
ACE = angiotensin-converting enzyme; PTH = parathyroid hormone; VEGF = vascular endothelial growth factor
It remains unclear whether bisphosphonates (etidronate in particular) are associated with improved survival.
Radiographic findings resembling hypophosphatasia include pan craniosynostosis, bowing of long bones, metaphyseal cupping and fraying, and radiolucent tongues.
Radiographic findings resembling osteopetrosis include osteosclerosis and femoral Erlenmeyer flask deformity.
No specific guidelines address the issue of surveillance. The appropriate intervals for monitoring depend on clinical findings and need to be more frequent in those with a more severe presentation.
Recommended Surveillance for Individuals with GACI
Echocardiography
Troponin
PTH = parathyroid hormone
Although no clinical studies have been conducted, it seems prudent to avoid the use of warfarin if possible. The matrix Gla protein (MGP), a potent anti-mineralization factor, needs to be activated by a vitamin K-dependent enzyme, and warfarin interferes with the vitamin K cycle. Warfarin has also been shown to accelerate ectopic mineralization in
One question is whether burosumab, an anti-FGF23 monoclonal antibody approved by the FDA for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, could also treat the hypophosphatemic rickets of ENPP1 deficiency. This approach, however, remains controversial due to theoretic concerns that it could worsen ectopic calcification by lowering pyrophosphate concentrations. However, one individual with ENPP1-related rickets, who was initially thought to have X-linked hypophosphatemia, received burosumab for months without developing any vascular calcification [
It is appropriate to evaluate the younger sibs of a proband with GACI in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. Evaluations can include:
Molecular genetic testing if the GACI-causing pathogenic variants in the family are known;
Imaging studies if the pathogenic variants in the family are not known.
See
One infant who did not initially respond to etidronate administration eventually showed improvement with a combination of etidronate, magnesium, and calcium carbonate [
Search
• EKG & echocardiogram
• Assessment of blood pressure
• Serum creatinine
• Serum phosphorus
• Urine phosphorus
• Urine creatinine
• Alkaline phosphatase
• Serum calcium
• Serum PTH
• Tubular reabsorption of phosphate
• Ratio of renal tubular maximum reabsorption rate of phosphate to GFR
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• Etidronate (20 mg/kg/d PO)
• Pamidronate (0.25 mg/kg on day 1, then 0.5 mg/kg/d on days 2 & 3 for 1st cycle, then 0.5 mg/kg/d x3 days IV per cycle; cycles rptd every 2 mos)
• Risedronate (1mg/kg/wk PO)
• After initiation of therapy, vascular calcifications have been reported to disappear as early as 2.5 wks (as assessed by radiographs) and as late as 2 yrs [
• Vascular calcifications do not reappear after discontinuation of treatment even after 10 yrs [
• Prolonged etidronate use in persons w/GACI has been assoc w/severe skeletal toxicity, incl radiographic findings resembling hypophosphatasia
• Echocardiography
• Troponin
• Molecular genetic testing if the GACI-causing pathogenic variants in the family are known;
• Imaging studies if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with generalized arterial calcification of infancy (GACI), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with GACI
EKG & echocardiogram
Assessment of blood pressure
Serum creatinine
Serum phosphorus
Urine phosphorus
Urine creatinine
Alkaline phosphatase
Serum calcium
Serum PTH
Tubular reabsorption of phosphate
Ratio of renal tubular maximum reabsorption rate of phosphate to GFR
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
GFR = glomerular filtration rate; MOI = mode of inheritance; PTH = parathyroid hormone
Referral to a pediatric nephrologist is indicated in the setting of refractory hypertension
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• EKG & echocardiogram
• Assessment of blood pressure
• Serum creatinine
• Serum phosphorus
• Urine phosphorus
• Urine creatinine
• Alkaline phosphatase
• Serum calcium
• Serum PTH
• Tubular reabsorption of phosphate
• Ratio of renal tubular maximum reabsorption rate of phosphate to GFR
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with GACI
Etidronate (20 mg/kg/d PO)
Pamidronate (0.25 mg/kg on day 1, then 0.5 mg/kg/d on days 2 & 3 for 1st cycle, then 0.5 mg/kg/d x3 days IV per cycle; cycles rptd every 2 mos)
Risedronate (1mg/kg/wk PO)
After initiation of therapy, vascular calcifications have been reported to disappear as early as 2.5 wks (as assessed by radiographs) and as late as 2 yrs [
Vascular calcifications do not reappear after discontinuation of treatment even after 10 yrs [
Prolonged etidronate use in persons w/GACI has been assoc w/severe skeletal toxicity, incl radiographic findings resembling hypophosphatasia
ACE = angiotensin-converting enzyme; PTH = parathyroid hormone; VEGF = vascular endothelial growth factor
It remains unclear whether bisphosphonates (etidronate in particular) are associated with improved survival.
Radiographic findings resembling hypophosphatasia include pan craniosynostosis, bowing of long bones, metaphyseal cupping and fraying, and radiolucent tongues.
Radiographic findings resembling osteopetrosis include osteosclerosis and femoral Erlenmeyer flask deformity.
• Etidronate (20 mg/kg/d PO)
• Pamidronate (0.25 mg/kg on day 1, then 0.5 mg/kg/d on days 2 & 3 for 1st cycle, then 0.5 mg/kg/d x3 days IV per cycle; cycles rptd every 2 mos)
• Risedronate (1mg/kg/wk PO)
• After initiation of therapy, vascular calcifications have been reported to disappear as early as 2.5 wks (as assessed by radiographs) and as late as 2 yrs [
• Vascular calcifications do not reappear after discontinuation of treatment even after 10 yrs [
• Prolonged etidronate use in persons w/GACI has been assoc w/severe skeletal toxicity, incl radiographic findings resembling hypophosphatasia
## Surveillance
No specific guidelines address the issue of surveillance. The appropriate intervals for monitoring depend on clinical findings and need to be more frequent in those with a more severe presentation.
Recommended Surveillance for Individuals with GACI
Echocardiography
Troponin
PTH = parathyroid hormone
• Echocardiography
• Troponin
## Agents/Circumstances to Avoid
Although no clinical studies have been conducted, it seems prudent to avoid the use of warfarin if possible. The matrix Gla protein (MGP), a potent anti-mineralization factor, needs to be activated by a vitamin K-dependent enzyme, and warfarin interferes with the vitamin K cycle. Warfarin has also been shown to accelerate ectopic mineralization in
One question is whether burosumab, an anti-FGF23 monoclonal antibody approved by the FDA for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, could also treat the hypophosphatemic rickets of ENPP1 deficiency. This approach, however, remains controversial due to theoretic concerns that it could worsen ectopic calcification by lowering pyrophosphate concentrations. However, one individual with ENPP1-related rickets, who was initially thought to have X-linked hypophosphatemia, received burosumab for months without developing any vascular calcification [
## Evaluation of Relatives at Risk
It is appropriate to evaluate the younger sibs of a proband with GACI in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. Evaluations can include:
Molecular genetic testing if the GACI-causing pathogenic variants in the family are known;
Imaging studies if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the GACI-causing pathogenic variants in the family are known;
• Imaging studies if the pathogenic variants in the family are not known.
## Therapies Under Investigation
One infant who did not initially respond to etidronate administration eventually showed improvement with a combination of etidronate, magnesium, and calcium carbonate [
Search
## Genetic Counseling
Generalized arterial calcification of infancy (GACI) is inherited in an autosomal recessive manner.
The parents of an affected child are typically heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a GACI-causing pathogenic variant and to allow reliable recurrence risk assessment.
In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either: (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred
Note: In a consanguineous family, both the father and the proband were homozygous for the same
Most heterozygotes are asymptomatic and are not at risk of developing the disorder. However, adult individuals with heterozygous
If both parents are known to be heterozygous for a GACI-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither pathogenic variant.
A sib who inherits biallelic pathogenic variants may have a clinical course markedly different from that of the proband (see Clinical Description,
Most heterozygotes are asymptomatic and are not at risk of developing the disorder, although it is possible that certain heterozygous pathogenic variants in
Because mortality in infancy is high, no individuals with GACI have been reported to have children to date.
It is entirely possible that affected individuals who survive into adulthood will be able to conceive. For these individuals, offspring will be obligate heterozygotes for a pathogenic variant in
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
The detection of an echogenic intracardiac focus as early as 20 weeks' gestation has been proposed as an early marker of the disease in individuals with a family history of GACI [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are typically heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a GACI-causing pathogenic variant and to allow reliable recurrence risk assessment.
• In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either: (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred
• Note: In a consanguineous family, both the father and the proband were homozygous for the same
• In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either: (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred
• Note: In a consanguineous family, both the father and the proband were homozygous for the same
• Most heterozygotes are asymptomatic and are not at risk of developing the disorder. However, adult individuals with heterozygous
• In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either: (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred
• Note: In a consanguineous family, both the father and the proband were homozygous for the same
• If both parents are known to be heterozygous for a GACI-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither pathogenic variant.
• A sib who inherits biallelic pathogenic variants may have a clinical course markedly different from that of the proband (see Clinical Description,
• Most heterozygotes are asymptomatic and are not at risk of developing the disorder, although it is possible that certain heterozygous pathogenic variants in
• Because mortality in infancy is high, no individuals with GACI have been reported to have children to date.
• It is entirely possible that affected individuals who survive into adulthood will be able to conceive. For these individuals, offspring will be obligate heterozygotes for a pathogenic variant in
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Generalized arterial calcification of infancy (GACI) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are typically heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a GACI-causing pathogenic variant and to allow reliable recurrence risk assessment.
In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either: (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred
Note: In a consanguineous family, both the father and the proband were homozygous for the same
Most heterozygotes are asymptomatic and are not at risk of developing the disorder. However, adult individuals with heterozygous
If both parents are known to be heterozygous for a GACI-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither pathogenic variant.
A sib who inherits biallelic pathogenic variants may have a clinical course markedly different from that of the proband (see Clinical Description,
Most heterozygotes are asymptomatic and are not at risk of developing the disorder, although it is possible that certain heterozygous pathogenic variants in
Because mortality in infancy is high, no individuals with GACI have been reported to have children to date.
It is entirely possible that affected individuals who survive into adulthood will be able to conceive. For these individuals, offspring will be obligate heterozygotes for a pathogenic variant in
• The parents of an affected child are typically heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a GACI-causing pathogenic variant and to allow reliable recurrence risk assessment.
• In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either: (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred
• Note: In a consanguineous family, both the father and the proband were homozygous for the same
• In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either: (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred
• Note: In a consanguineous family, both the father and the proband were homozygous for the same
• Most heterozygotes are asymptomatic and are not at risk of developing the disorder. However, adult individuals with heterozygous
• In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either: (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred
• Note: In a consanguineous family, both the father and the proband were homozygous for the same
• If both parents are known to be heterozygous for a GACI-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither pathogenic variant.
• A sib who inherits biallelic pathogenic variants may have a clinical course markedly different from that of the proband (see Clinical Description,
• Most heterozygotes are asymptomatic and are not at risk of developing the disorder, although it is possible that certain heterozygous pathogenic variants in
• Because mortality in infancy is high, no individuals with GACI have been reported to have children to date.
• It is entirely possible that affected individuals who survive into adulthood will be able to conceive. For these individuals, offspring will be obligate heterozygotes for a pathogenic variant in
## Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
The detection of an echogenic intracardiac focus as early as 20 weeks' gestation has been proposed as an early marker of the disease in individuals with a family history of GACI [
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 123
Argyle TX 76226
•
• PO Box 123
• Argyle TX 76226
•
## Molecular Genetics
Generalized Arterial Calcification of Infancy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Generalized Arterial Calcification of Infancy (
ENPP1 breaks the phosphodiester bonds of extracellular nucleotides. Its most important substrate is ATP, cleaved into AMP and inorganic pyrophosphate. A deficiency of ENPP1 activity thus leads to a deficiency of both AMP and inorganic pyrophosphate. Pyrophosphate is the main inhibitor of hydroxyapatite deposition, so its deficiency leads to ectopic calcification, while the deficiency of AMP (or downstream adenosine) leads to intimal proliferation and consequently arterial narrowing.
## Molecular Pathogenesis
ENPP1 breaks the phosphodiester bonds of extracellular nucleotides. Its most important substrate is ATP, cleaved into AMP and inorganic pyrophosphate. A deficiency of ENPP1 activity thus leads to a deficiency of both AMP and inorganic pyrophosphate. Pyrophosphate is the main inhibitor of hydroxyapatite deposition, so its deficiency leads to ectopic calcification, while the deficiency of AMP (or downstream adenosine) leads to intimal proliferation and consequently arterial narrowing.
## Chapter Notes
This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute.
30 December 2020 (ha) Comprehensive update posted live
13 November 2014 (me) Review posted live
25 June 2014 (cf) Original submission
• 30 December 2020 (ha) Comprehensive update posted live
• 13 November 2014 (me) Review posted live
• 25 June 2014 (cf) Original submission
## Acknowledgments
This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute.
## Revision History
30 December 2020 (ha) Comprehensive update posted live
13 November 2014 (me) Review posted live
25 June 2014 (cf) Original submission
• 30 December 2020 (ha) Comprehensive update posted live
• 13 November 2014 (me) Review posted live
• 25 June 2014 (cf) Original submission
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] |
13/11/2014
|
30/12/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
galactosemia
|
galactosemia
|
[
"Galactose-1-Phosphate Uridylyltransferase Deficiency",
"GALT Deficiency",
"GALT Deficiency",
"Galactose-1-Phosphate Uridylyltransferase Deficiency",
"Classic Galactosemia",
"Clinical Variant Galactosemia",
"Galactose-1-phosphate uridylyltransferase",
"GALT",
"Classic Galactosemia and Clinical Variant Galactosemia"
] |
Classic Galactosemia and Clinical Variant Galactosemia
|
Gerard T Berry
|
Summary The term "galactosemia" refers to disorders of galactose metabolism that include classic galactosemia, clinical variant galactosemia, and biochemical variant galactosemia (not covered in this chapter). This The diagnosis of classic galactosemia and clinical variant galactosemia is established by detection of elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity, and/or biallelic pathogenic variants in In classic galactosemia, erythrocyte galactose-1-phosphate is usually >10 mg/dL and erythrocyte GALT enzyme activity is absent or barely detectable. In clinical variant galactosemia, erythrocyte GALT enzyme activity is close to or above 1% of control values but probably never >10%-15%. However, in African Americans with clinical variant galactosemia, the erythrocyte GALT enzyme activity may be absent or barely detectable but is often much higher in liver and in intestinal tissue (e.g., 10% of control values). Virtually 100% of infants with classic galactosemia or clinical variant galactosemia can be detected in newborn screening programs that include testing for galactosemia in their panel. However, infants with clinical variant galactosemia may be missed if the program only measures blood total galactose level and not erythrocyte GALT enzyme activity. Perform prenatal diagnosis when the If prenatal testing has not been performed, test the newborn for either the family-specific Classic galactosemia and clinical variant galactosemia are inherited in an autosomal recessive manner. Couples who have had one affected child have a 25% chance of having an affected child in each subsequent pregnancy. Molecular genetic carrier testing for at-risk sibs and prenatal testing for pregnancies at increased risk are an option if the
|
Classic galactosemia
Clinical variant galactosemia
For synonyms and outdated names see
The biochemical variant form of galactosemia is exemplified by
• Classic galactosemia
• Clinical variant galactosemia
## Diagnosis
An international clinical guideline addressing management has been published [
NBS for classic galactosemia and clinical variant galactosemia is primarily based on quantification of the following analytes and/or enzymatic testing, depending on the state:
Total content of erythrocyte galactose-1-phosphate and blood galactose concentration; and/or
Erythrocyte GALT enzyme activity
Total erythrocyte galactose-1-phosphate and blood galactose concentration values above the cutoff reported by the screening laboratory are considered positive and require follow-up testing in a biochemical genetics laboratory.
In
Erythrocyte galactose-1-phosphate may be as high as 120 mg/dL, but is usually >10 mg/dL in the newborn period. When the affected individual is on a lactose-free diet, the level is ≥1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
Galactose-1-phosphate uridylyltransferase (GALT) enzyme activity is absent or barely detectable.
In
Erythrocyte galactose-1-phosphate is usually >10 mg/dL. When the affected individual is on a lactose-free diet, the level is usually <1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
Erythrocyte GALT enzyme activity is close to or above 1% of control values but probably never >10%-15%.
Note: In African Americans with clinical variant galactosemia, the erythrocyte GALT enzyme activity may be absent or barely detectable but is often much higher in liver and in intestinal tissue (e.g., 10% of control values).
In certain populations (e.g., African Americans with hypomorphic alleles including p.Ser135Leu/Ser135Leu), erythrocyte GALT enzyme activity may be absent or barely detectable.
Dietary intervention – including replacing all milk products with lactose-free formulas (e.g., Isomil
A symptomatic individual who has either atypical findings, untreated infantile-onset classic galactosemia, or clinical variant galactosemia may present as a result of any of the following: NBS not performed; false negative NBS result; caregivers not adherent to recommended treatment following a positive NBS result.
Untreated infant:
Feeding problems
Failure to thrive
Liver failure
Bleeding
Untreated older person:
Developmental delay
Speech problems
Abnormalities of motor function, including extrapyramidal findings with ataxia
Cataracts
Liver failure/cirrhosis
Premature ovarian failure in females
The diagnosis of classic galactosemia or clinical variant galactosemia
Molecular genetic testing approaches include
Molecular Genetic Testing Used in Classic Galactosemia and Clinical Variant Galactosemia
See
See
Common pathogenic variants include those associated with classic galactosemia –
The 5.2-kb deletion is common in the Ashkenazim (see
Pathogenic variants included in targeted variant panels may vary by laboratory; detection rates will vary accordingly.
In individuals with biochemically confirmed classic galactosemia and clinical variant galactosemia [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Total content of erythrocyte galactose-1-phosphate and blood galactose concentration; and/or
• Erythrocyte GALT enzyme activity
• Erythrocyte galactose-1-phosphate may be as high as 120 mg/dL, but is usually >10 mg/dL in the newborn period. When the affected individual is on a lactose-free diet, the level is ≥1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
• Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
• Galactose-1-phosphate uridylyltransferase (GALT) enzyme activity is absent or barely detectable.
• Erythrocyte galactose-1-phosphate is usually >10 mg/dL. When the affected individual is on a lactose-free diet, the level is usually <1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
• Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
• Erythrocyte GALT enzyme activity is close to or above 1% of control values but probably never >10%-15%.
• Note: In African Americans with clinical variant galactosemia, the erythrocyte GALT enzyme activity may be absent or barely detectable but is often much higher in liver and in intestinal tissue (e.g., 10% of control values).
• In certain populations (e.g., African Americans with hypomorphic alleles including p.Ser135Leu/Ser135Leu), erythrocyte GALT enzyme activity may be absent or barely detectable.
• Untreated infant:
• Feeding problems
• Failure to thrive
• Liver failure
• Bleeding
• Feeding problems
• Failure to thrive
• Liver failure
• Bleeding
• Untreated older person:
• Developmental delay
• Speech problems
• Abnormalities of motor function, including extrapyramidal findings with ataxia
• Cataracts
• Liver failure/cirrhosis
• Premature ovarian failure in females
• Developmental delay
• Speech problems
• Abnormalities of motor function, including extrapyramidal findings with ataxia
• Cataracts
• Liver failure/cirrhosis
• Premature ovarian failure in females
• Feeding problems
• Failure to thrive
• Liver failure
• Bleeding
• Developmental delay
• Speech problems
• Abnormalities of motor function, including extrapyramidal findings with ataxia
• Cataracts
• Liver failure/cirrhosis
• Premature ovarian failure in females
## Scenarios
NBS for classic galactosemia and clinical variant galactosemia is primarily based on quantification of the following analytes and/or enzymatic testing, depending on the state:
Total content of erythrocyte galactose-1-phosphate and blood galactose concentration; and/or
Erythrocyte GALT enzyme activity
Total erythrocyte galactose-1-phosphate and blood galactose concentration values above the cutoff reported by the screening laboratory are considered positive and require follow-up testing in a biochemical genetics laboratory.
In
Erythrocyte galactose-1-phosphate may be as high as 120 mg/dL, but is usually >10 mg/dL in the newborn period. When the affected individual is on a lactose-free diet, the level is ≥1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
Galactose-1-phosphate uridylyltransferase (GALT) enzyme activity is absent or barely detectable.
In
Erythrocyte galactose-1-phosphate is usually >10 mg/dL. When the affected individual is on a lactose-free diet, the level is usually <1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
Erythrocyte GALT enzyme activity is close to or above 1% of control values but probably never >10%-15%.
Note: In African Americans with clinical variant galactosemia, the erythrocyte GALT enzyme activity may be absent or barely detectable but is often much higher in liver and in intestinal tissue (e.g., 10% of control values).
In certain populations (e.g., African Americans with hypomorphic alleles including p.Ser135Leu/Ser135Leu), erythrocyte GALT enzyme activity may be absent or barely detectable.
Dietary intervention – including replacing all milk products with lactose-free formulas (e.g., Isomil
A symptomatic individual who has either atypical findings, untreated infantile-onset classic galactosemia, or clinical variant galactosemia may present as a result of any of the following: NBS not performed; false negative NBS result; caregivers not adherent to recommended treatment following a positive NBS result.
Untreated infant:
Feeding problems
Failure to thrive
Liver failure
Bleeding
Untreated older person:
Developmental delay
Speech problems
Abnormalities of motor function, including extrapyramidal findings with ataxia
Cataracts
Liver failure/cirrhosis
Premature ovarian failure in females
• Total content of erythrocyte galactose-1-phosphate and blood galactose concentration; and/or
• Erythrocyte GALT enzyme activity
• Erythrocyte galactose-1-phosphate may be as high as 120 mg/dL, but is usually >10 mg/dL in the newborn period. When the affected individual is on a lactose-free diet, the level is ≥1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
• Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
• Galactose-1-phosphate uridylyltransferase (GALT) enzyme activity is absent or barely detectable.
• Erythrocyte galactose-1-phosphate is usually >10 mg/dL. When the affected individual is on a lactose-free diet, the level is usually <1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
• Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
• Erythrocyte GALT enzyme activity is close to or above 1% of control values but probably never >10%-15%.
• Note: In African Americans with clinical variant galactosemia, the erythrocyte GALT enzyme activity may be absent or barely detectable but is often much higher in liver and in intestinal tissue (e.g., 10% of control values).
• In certain populations (e.g., African Americans with hypomorphic alleles including p.Ser135Leu/Ser135Leu), erythrocyte GALT enzyme activity may be absent or barely detectable.
• Untreated infant:
• Feeding problems
• Failure to thrive
• Liver failure
• Bleeding
• Feeding problems
• Failure to thrive
• Liver failure
• Bleeding
• Untreated older person:
• Developmental delay
• Speech problems
• Abnormalities of motor function, including extrapyramidal findings with ataxia
• Cataracts
• Liver failure/cirrhosis
• Premature ovarian failure in females
• Developmental delay
• Speech problems
• Abnormalities of motor function, including extrapyramidal findings with ataxia
• Cataracts
• Liver failure/cirrhosis
• Premature ovarian failure in females
• Feeding problems
• Failure to thrive
• Liver failure
• Bleeding
• Developmental delay
• Speech problems
• Abnormalities of motor function, including extrapyramidal findings with ataxia
• Cataracts
• Liver failure/cirrhosis
• Premature ovarian failure in females
## Scenario 1 – Abnormal Newborn Screening (NBS) Result
NBS for classic galactosemia and clinical variant galactosemia is primarily based on quantification of the following analytes and/or enzymatic testing, depending on the state:
Total content of erythrocyte galactose-1-phosphate and blood galactose concentration; and/or
Erythrocyte GALT enzyme activity
Total erythrocyte galactose-1-phosphate and blood galactose concentration values above the cutoff reported by the screening laboratory are considered positive and require follow-up testing in a biochemical genetics laboratory.
In
Erythrocyte galactose-1-phosphate may be as high as 120 mg/dL, but is usually >10 mg/dL in the newborn period. When the affected individual is on a lactose-free diet, the level is ≥1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
Galactose-1-phosphate uridylyltransferase (GALT) enzyme activity is absent or barely detectable.
In
Erythrocyte galactose-1-phosphate is usually >10 mg/dL. When the affected individual is on a lactose-free diet, the level is usually <1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
Erythrocyte GALT enzyme activity is close to or above 1% of control values but probably never >10%-15%.
Note: In African Americans with clinical variant galactosemia, the erythrocyte GALT enzyme activity may be absent or barely detectable but is often much higher in liver and in intestinal tissue (e.g., 10% of control values).
In certain populations (e.g., African Americans with hypomorphic alleles including p.Ser135Leu/Ser135Leu), erythrocyte GALT enzyme activity may be absent or barely detectable.
Dietary intervention – including replacing all milk products with lactose-free formulas (e.g., Isomil
• Total content of erythrocyte galactose-1-phosphate and blood galactose concentration; and/or
• Erythrocyte GALT enzyme activity
• Erythrocyte galactose-1-phosphate may be as high as 120 mg/dL, but is usually >10 mg/dL in the newborn period. When the affected individual is on a lactose-free diet, the level is ≥1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
• Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
• Galactose-1-phosphate uridylyltransferase (GALT) enzyme activity is absent or barely detectable.
• Erythrocyte galactose-1-phosphate is usually >10 mg/dL. When the affected individual is on a lactose-free diet, the level is usually <1.0 mg/dL. Normal level of erythrocyte galactose-1-phosphate is <1 mg/dL.
• Plasma free galactose is usually >10 mg/dL, but may be as high as 90-360 mg/dL (5-20 mmol/L).
• Erythrocyte GALT enzyme activity is close to or above 1% of control values but probably never >10%-15%.
• Note: In African Americans with clinical variant galactosemia, the erythrocyte GALT enzyme activity may be absent or barely detectable but is often much higher in liver and in intestinal tissue (e.g., 10% of control values).
• In certain populations (e.g., African Americans with hypomorphic alleles including p.Ser135Leu/Ser135Leu), erythrocyte GALT enzyme activity may be absent or barely detectable.
## Scenario 2 – Symptomatic Individual
A symptomatic individual who has either atypical findings, untreated infantile-onset classic galactosemia, or clinical variant galactosemia may present as a result of any of the following: NBS not performed; false negative NBS result; caregivers not adherent to recommended treatment following a positive NBS result.
Untreated infant:
Feeding problems
Failure to thrive
Liver failure
Bleeding
Untreated older person:
Developmental delay
Speech problems
Abnormalities of motor function, including extrapyramidal findings with ataxia
Cataracts
Liver failure/cirrhosis
Premature ovarian failure in females
• Untreated infant:
• Feeding problems
• Failure to thrive
• Liver failure
• Bleeding
• Feeding problems
• Failure to thrive
• Liver failure
• Bleeding
• Untreated older person:
• Developmental delay
• Speech problems
• Abnormalities of motor function, including extrapyramidal findings with ataxia
• Cataracts
• Liver failure/cirrhosis
• Premature ovarian failure in females
• Developmental delay
• Speech problems
• Abnormalities of motor function, including extrapyramidal findings with ataxia
• Cataracts
• Liver failure/cirrhosis
• Premature ovarian failure in females
• Feeding problems
• Failure to thrive
• Liver failure
• Bleeding
• Developmental delay
• Speech problems
• Abnormalities of motor function, including extrapyramidal findings with ataxia
• Cataracts
• Liver failure/cirrhosis
• Premature ovarian failure in females
## Establishing the Diagnosis
The diagnosis of classic galactosemia or clinical variant galactosemia
Molecular genetic testing approaches include
Molecular Genetic Testing Used in Classic Galactosemia and Clinical Variant Galactosemia
See
See
Common pathogenic variants include those associated with classic galactosemia –
The 5.2-kb deletion is common in the Ashkenazim (see
Pathogenic variants included in targeted variant panels may vary by laboratory; detection rates will vary accordingly.
In individuals with biochemically confirmed classic galactosemia and clinical variant galactosemia [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
Galactosemia caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT) may be divided into three clinical/biochemical phenotypes: (1) classic galactosemia, (2) clinical variant galactosemia, and (3) biochemical variant galactosemia (not covered in this
Within days of ingesting breast milk or lactose-containing formulas, infants with classic galactosemia develop life-threatening complications including feeding problems, failure to thrive, hypoglycemia, hepatocellular damage, bleeding diathesis, and jaundice (see
If a lactose-free diet is provided during the first three to ten days of life, the signs of classic galactosemia resolve quickly and prognosis for prevention of liver failure,
Classic galactosemia is associated with extreme variability in chronic complications and/or long-term outcome. Even individuals who have not been sick in the newborn period and who were begun on a lactose-free diet from birth (e.g., those with a prior affected sib in the family) may manifest language delay, speech defects, learning disabilities, cognitive impairment, and in females, POI. These problems may manifest as early as age one to two years, and in almost all instances, no findings that would have predicted eventual brain and ovarian dysfunction were present in early infancy. A minority of individuals may exhibit documented neurologic abnormalities including tremor (postural or intentional), cerebellar ataxia, and dystonia. No findings early in the disease course are good predictors of these long-term complications. Overall, the quality of life is reduced in adults with classic galactosemia, and more so when compared to individuals with
If classic galactosemia is not treated, sepsis with
Frequency of Specific Findings in Symptomatic Neonates with Classic Galactosemia
From a survey reporting findings in 270 symptomatic neonates [
If the diagnosis of classic galactosemia is not established, the infant who is partially treated with intravenous antibiotics and self-restricted lactose intake demonstrates relapsing and episodic jaundice and bleeding from altered hemostasis concomitant with the introduction of lactose. If treatment is delayed, complications such as growth restriction and progressive liver disease are likely. Rare affected individuals may develop vitreous hemorrhages that may produce blindness [
The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
Severe ataxia was observed in two teenagers.
Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
The mean age at menarche was 14 years with a range from ten to 18 years.
Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
The individual is homozygous for
The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
The recovery of
Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
Restriction of milk in the mother's diet during pregnancy was reported for 21 of the 38 infants who were treated from birth. The long-term outcome of these 21 was no better than that of the 17 individuals whose intake of mother's milk was not restricted during the pregnancy.
No significant differences could be observed in the rate of complications between the individuals with residual enzyme activity and those with no measurable enzyme activity, except that individuals with some enzyme activity tended to be taller for age.
Individuals with variant forms of galactosemia may have some aspects of classic galactosemia, including early cataracts, liver disease, mild intellectual disability with ataxia, and growth restriction [
Clinical variant galactosemia is exemplified by the disease that occurs in African Americans and native Africans in South Africa with a
If a lactose-restricted diet is provided during the first ten days of life, the severe acute neonatal complications usually do not occur.
To the best of current knowledge, African Americans with clinical variant galactosemia and adequate early treatment do not develop long-term complications, including POI.
Significant genotype-phenotype correlations have been noted [
Use of the galactosemia classification system in
The original identification of the p.Ser135Leu pathogenic variant was exclusively in African Americans; however, it is present on occasion in infants without known African American ancestry.
Known as "
See
In the homozygous state, the pathogenic variant interferes with the catalytic reaction. It is associated with increased risks for POI and childhood apraxia of speech [
In one cross-sectional retrospective study correlating genotype with outcome in individuals with classic galactosemia, a greater proportion of individuals with a poor outcome were homozygous for the p.Gln188Arg pathogenic variant, and a greater proportion with a good outcome were not homozygous for the p.Gln188Arg pathogenic variant. However, one adult female and one adult male homozygous for the p.Gln188Arg pathogenic variant who had begun normal lactose intake at age three years exhibited no worsening of the underlying classic galactosemia phenotype [
If therapy is initiated in the neonatal period, African Americans with galactosemia who have this allele in the homozygous state have a good prognosis. Generally, these individuals are not prone to
Data are limited on outcome in persons who are compound heterozygous (p.[Ser135Leu];[Gln188Arg]); however, they appear to have fewer complications than individuals with the genotype p.[Gln188Arg]+[p.Gln188Arg], associated with classic galactosemia.
In the homozygous state D
Compound heterozygotes with D
However, compound heterozygosity for D
Other compound heterozygotes (e.g., p.[Gln188Arg]+[Arg333Gly]) have a good long-term outcome [
A clear genotype-phenotype correlation is seen when classic galactosemia with genotypes such as p.[Gln188Arg]+[Gln188Arg] is compared with clinical variant galactosemia caused by the p.[Ser135Leu]+[Ser135Leu] genotype. For example, almost all females with the p.[Gln188Arg]+[Gln188Arg] genotype manifest POI, whereas POI is almost unheard of in African American women with the p.[Ser135Leu]+[Ser135Leu] genotype. A critical unanswered question is how much residual GALT enzyme activity in target tissues there must be to eliminate chronic diet-independent complications. To illustrate, cryptic residual GALT enzyme activity may be a potential modifier of scholastic outcome in school-age children [
While on a lactose-restricted diet, persons with classic galactosemia display erythrocyte galactose-1-phosphate levels between 1 and 5 mg/dL and urine galactitol levels between 100 and 400 μmol/mmol creatinine, whereas persons with a p.[Ser135Leu]+[Ser135Leu] genotype usually have an erythrocyte galactose-1-phosphate level below 1 mg/dL, and urine galactitol that is below 100 μmol/mmol creatinine and often in the normal range [
Persons with biochemical variant galactosemia – for example, compound heterozygotes for c.563A>G (p.Gln188Arg) and D
Note: Many of the more than 300
The Genetic Hypergalactosemias
Based on the results of newborn screening programs, the prevalence of classic galactosemia is 1:48,000 [
The frequency of classic galactosemia in Ireland is 1:16,476 [
While it is not possible to provide prevalence data for clinical variant galactosemia, the estimated prevalence of the
• The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
• Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
• The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
• Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
• More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
• A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
• Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
• The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
• More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
• A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
• Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
• The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
• Severe ataxia was observed in two teenagers.
• Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
• Severe ataxia was observed in two teenagers.
• Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
• The mean age at menarche was 14 years with a range from ten to 18 years.
• Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
• Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
• Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The mean age at menarche was 14 years with a range from ten to 18 years.
• Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
• Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
• Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
•
• Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
• There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
• Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
• There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
• Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
• Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
• Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
• Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
• The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
• Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
• More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
• A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
• Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
• The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
• Severe ataxia was observed in two teenagers.
• Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
• The mean age at menarche was 14 years with a range from ten to 18 years.
• Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
• Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
• Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
• There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
• Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
• Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
• Restriction of milk in the mother's diet during pregnancy was reported for 21 of the 38 infants who were treated from birth. The long-term outcome of these 21 was no better than that of the 17 individuals whose intake of mother's milk was not restricted during the pregnancy.
• No significant differences could be observed in the rate of complications between the individuals with residual enzyme activity and those with no measurable enzyme activity, except that individuals with some enzyme activity tended to be taller for age.
• In the homozygous state, the pathogenic variant interferes with the catalytic reaction. It is associated with increased risks for POI and childhood apraxia of speech [
• In one cross-sectional retrospective study correlating genotype with outcome in individuals with classic galactosemia, a greater proportion of individuals with a poor outcome were homozygous for the p.Gln188Arg pathogenic variant, and a greater proportion with a good outcome were not homozygous for the p.Gln188Arg pathogenic variant. However, one adult female and one adult male homozygous for the p.Gln188Arg pathogenic variant who had begun normal lactose intake at age three years exhibited no worsening of the underlying classic galactosemia phenotype [
• If therapy is initiated in the neonatal period, African Americans with galactosemia who have this allele in the homozygous state have a good prognosis. Generally, these individuals are not prone to
• Data are limited on outcome in persons who are compound heterozygous (p.[Ser135Leu];[Gln188Arg]); however, they appear to have fewer complications than individuals with the genotype p.[Gln188Arg]+[p.Gln188Arg], associated with classic galactosemia.
• In the homozygous state D
• Compound heterozygotes with D
• However, compound heterozygosity for D
• A clear genotype-phenotype correlation is seen when classic galactosemia with genotypes such as p.[Gln188Arg]+[Gln188Arg] is compared with clinical variant galactosemia caused by the p.[Ser135Leu]+[Ser135Leu] genotype. For example, almost all females with the p.[Gln188Arg]+[Gln188Arg] genotype manifest POI, whereas POI is almost unheard of in African American women with the p.[Ser135Leu]+[Ser135Leu] genotype. A critical unanswered question is how much residual GALT enzyme activity in target tissues there must be to eliminate chronic diet-independent complications. To illustrate, cryptic residual GALT enzyme activity may be a potential modifier of scholastic outcome in school-age children [
• While on a lactose-restricted diet, persons with classic galactosemia display erythrocyte galactose-1-phosphate levels between 1 and 5 mg/dL and urine galactitol levels between 100 and 400 μmol/mmol creatinine, whereas persons with a p.[Ser135Leu]+[Ser135Leu] genotype usually have an erythrocyte galactose-1-phosphate level below 1 mg/dL, and urine galactitol that is below 100 μmol/mmol creatinine and often in the normal range [
• Persons with biochemical variant galactosemia – for example, compound heterozygotes for c.563A>G (p.Gln188Arg) and D
## Clinical Description
Galactosemia caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT) may be divided into three clinical/biochemical phenotypes: (1) classic galactosemia, (2) clinical variant galactosemia, and (3) biochemical variant galactosemia (not covered in this
Within days of ingesting breast milk or lactose-containing formulas, infants with classic galactosemia develop life-threatening complications including feeding problems, failure to thrive, hypoglycemia, hepatocellular damage, bleeding diathesis, and jaundice (see
If a lactose-free diet is provided during the first three to ten days of life, the signs of classic galactosemia resolve quickly and prognosis for prevention of liver failure,
Classic galactosemia is associated with extreme variability in chronic complications and/or long-term outcome. Even individuals who have not been sick in the newborn period and who were begun on a lactose-free diet from birth (e.g., those with a prior affected sib in the family) may manifest language delay, speech defects, learning disabilities, cognitive impairment, and in females, POI. These problems may manifest as early as age one to two years, and in almost all instances, no findings that would have predicted eventual brain and ovarian dysfunction were present in early infancy. A minority of individuals may exhibit documented neurologic abnormalities including tremor (postural or intentional), cerebellar ataxia, and dystonia. No findings early in the disease course are good predictors of these long-term complications. Overall, the quality of life is reduced in adults with classic galactosemia, and more so when compared to individuals with
If classic galactosemia is not treated, sepsis with
Frequency of Specific Findings in Symptomatic Neonates with Classic Galactosemia
From a survey reporting findings in 270 symptomatic neonates [
If the diagnosis of classic galactosemia is not established, the infant who is partially treated with intravenous antibiotics and self-restricted lactose intake demonstrates relapsing and episodic jaundice and bleeding from altered hemostasis concomitant with the introduction of lactose. If treatment is delayed, complications such as growth restriction and progressive liver disease are likely. Rare affected individuals may develop vitreous hemorrhages that may produce blindness [
The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
Severe ataxia was observed in two teenagers.
Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
The mean age at menarche was 14 years with a range from ten to 18 years.
Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
The individual is homozygous for
The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
The recovery of
Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
Restriction of milk in the mother's diet during pregnancy was reported for 21 of the 38 infants who were treated from birth. The long-term outcome of these 21 was no better than that of the 17 individuals whose intake of mother's milk was not restricted during the pregnancy.
No significant differences could be observed in the rate of complications between the individuals with residual enzyme activity and those with no measurable enzyme activity, except that individuals with some enzyme activity tended to be taller for age.
Individuals with variant forms of galactosemia may have some aspects of classic galactosemia, including early cataracts, liver disease, mild intellectual disability with ataxia, and growth restriction [
Clinical variant galactosemia is exemplified by the disease that occurs in African Americans and native Africans in South Africa with a
If a lactose-restricted diet is provided during the first ten days of life, the severe acute neonatal complications usually do not occur.
To the best of current knowledge, African Americans with clinical variant galactosemia and adequate early treatment do not develop long-term complications, including POI.
• The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
• Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
• The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
• Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
• More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
• A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
• Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
• The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
• More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
• A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
• Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
• The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
• Severe ataxia was observed in two teenagers.
• Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
• Severe ataxia was observed in two teenagers.
• Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
• The mean age at menarche was 14 years with a range from ten to 18 years.
• Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
• Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
• Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The mean age at menarche was 14 years with a range from ten to 18 years.
• Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
• Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
• Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
•
• Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
• There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
• Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
• There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
• Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
• Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
• Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
• Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
• The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
• Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
• More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
• A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
• Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
• The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
• Severe ataxia was observed in two teenagers.
• Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
• The mean age at menarche was 14 years with a range from ten to 18 years.
• Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
• Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
• Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
• There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
• Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
• Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
• Restriction of milk in the mother's diet during pregnancy was reported for 21 of the 38 infants who were treated from birth. The long-term outcome of these 21 was no better than that of the 17 individuals whose intake of mother's milk was not restricted during the pregnancy.
• No significant differences could be observed in the rate of complications between the individuals with residual enzyme activity and those with no measurable enzyme activity, except that individuals with some enzyme activity tended to be taller for age.
## Classic Galactosemia
Within days of ingesting breast milk or lactose-containing formulas, infants with classic galactosemia develop life-threatening complications including feeding problems, failure to thrive, hypoglycemia, hepatocellular damage, bleeding diathesis, and jaundice (see
If a lactose-free diet is provided during the first three to ten days of life, the signs of classic galactosemia resolve quickly and prognosis for prevention of liver failure,
Classic galactosemia is associated with extreme variability in chronic complications and/or long-term outcome. Even individuals who have not been sick in the newborn period and who were begun on a lactose-free diet from birth (e.g., those with a prior affected sib in the family) may manifest language delay, speech defects, learning disabilities, cognitive impairment, and in females, POI. These problems may manifest as early as age one to two years, and in almost all instances, no findings that would have predicted eventual brain and ovarian dysfunction were present in early infancy. A minority of individuals may exhibit documented neurologic abnormalities including tremor (postural or intentional), cerebellar ataxia, and dystonia. No findings early in the disease course are good predictors of these long-term complications. Overall, the quality of life is reduced in adults with classic galactosemia, and more so when compared to individuals with
If classic galactosemia is not treated, sepsis with
Frequency of Specific Findings in Symptomatic Neonates with Classic Galactosemia
From a survey reporting findings in 270 symptomatic neonates [
If the diagnosis of classic galactosemia is not established, the infant who is partially treated with intravenous antibiotics and self-restricted lactose intake demonstrates relapsing and episodic jaundice and bleeding from altered hemostasis concomitant with the introduction of lactose. If treatment is delayed, complications such as growth restriction and progressive liver disease are likely. Rare affected individuals may develop vitreous hemorrhages that may produce blindness [
The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
Severe ataxia was observed in two teenagers.
Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
The mean age at menarche was 14 years with a range from ten to 18 years.
Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
The individual is homozygous for
The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
The recovery of
Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
Restriction of milk in the mother's diet during pregnancy was reported for 21 of the 38 infants who were treated from birth. The long-term outcome of these 21 was no better than that of the 17 individuals whose intake of mother's milk was not restricted during the pregnancy.
No significant differences could be observed in the rate of complications between the individuals with residual enzyme activity and those with no measurable enzyme activity, except that individuals with some enzyme activity tended to be taller for age.
• The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
• Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
• The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
• Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
• More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
• A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
• Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
• The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
• More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
• A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
• Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
• The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
• Severe ataxia was observed in two teenagers.
• Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
• Severe ataxia was observed in two teenagers.
• Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
• The mean age at menarche was 14 years with a range from ten to 18 years.
• Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
• Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
• Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The mean age at menarche was 14 years with a range from ten to 18 years.
• Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
• Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
• Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
•
• Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
• There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
• Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
• There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
• Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
• Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
• Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
• Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
• The mean IQ scores of the individuals as a group declined slightly (4-7 points) with increasing age.
• Studies of Dutch individuals at various ages using a quality-of-life questionnaire indicated subnormal cognitive outcomes [
• More than 90% of individuals with speech problems were described as having delayed vocabulary and articulation problems. The speech problems resolved in only 24%.
• A more formal analysis found speech problems in 44% of individuals; 38% had a specific diagnosis including childhood apraxia of speech [
• Speech defects are heterogeneous (involving both central defects and motor abnormalities) and evolve with time [
• The developmental quotients and IQ scores observed in individuals with speech disorders as a group were significantly lower than those of individuals with normal speech, although some individuals with speech problems tested in the average range.
• Severe ataxia was observed in two teenagers.
• Adults manifested tremors, dysarthria, cerebellar ataxia, and dystonia [
• The mean age at menarche was 14 years with a range from ten to 18 years.
• Eight of 34 women older than age 17 years (including 2 with "streak gonads") had primary amenorrhea.
• Most women developed oligomenorrhea and secondary amenorrhea within a few years of menarche.
• Only five of 17 women older than age 22 years had normal menstruation. Two, who gave birth at ages 18 and 26 years, had never experienced normal menstrual periods.
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• The individual is homozygous for
• The mean erythrocyte galactose-1-phosphate concentration is >3.5 mg/dL during therapy.
• The recovery of
• Normal serum concentrations of testosterone and/or follicle-stimulating hormone and luteinizing hormone were reported for males. However, the literature has few reports of males with classic galactosemia who have fathered a child [
• There have been no data to support structural abnormalities in the male reproductive tract that would lead to infertility; preliminary data suggest an increased prevalence of cryptorchidism and low semen volume [
• Nearly half the cataracts were described as "mild," "transient," or "neonatal" and resolved with dietary treatment; only eight were treated surgically.
• Dietary treatment had begun at a mean age of 77 days for those with cataracts compared to 20 days for those without cataracts. However, one of the eight individuals who required cataract surgery was an infant who had been treated from birth.
• Restriction of milk in the mother's diet during pregnancy was reported for 21 of the 38 infants who were treated from birth. The long-term outcome of these 21 was no better than that of the 17 individuals whose intake of mother's milk was not restricted during the pregnancy.
• No significant differences could be observed in the rate of complications between the individuals with residual enzyme activity and those with no measurable enzyme activity, except that individuals with some enzyme activity tended to be taller for age.
## Clinical Variant Galactosemia
Individuals with variant forms of galactosemia may have some aspects of classic galactosemia, including early cataracts, liver disease, mild intellectual disability with ataxia, and growth restriction [
Clinical variant galactosemia is exemplified by the disease that occurs in African Americans and native Africans in South Africa with a
If a lactose-restricted diet is provided during the first ten days of life, the severe acute neonatal complications usually do not occur.
To the best of current knowledge, African Americans with clinical variant galactosemia and adequate early treatment do not develop long-term complications, including POI.
## Genotype-Phenotype Correlations
Significant genotype-phenotype correlations have been noted [
Use of the galactosemia classification system in
The original identification of the p.Ser135Leu pathogenic variant was exclusively in African Americans; however, it is present on occasion in infants without known African American ancestry.
Known as "
See
In the homozygous state, the pathogenic variant interferes with the catalytic reaction. It is associated with increased risks for POI and childhood apraxia of speech [
In one cross-sectional retrospective study correlating genotype with outcome in individuals with classic galactosemia, a greater proportion of individuals with a poor outcome were homozygous for the p.Gln188Arg pathogenic variant, and a greater proportion with a good outcome were not homozygous for the p.Gln188Arg pathogenic variant. However, one adult female and one adult male homozygous for the p.Gln188Arg pathogenic variant who had begun normal lactose intake at age three years exhibited no worsening of the underlying classic galactosemia phenotype [
If therapy is initiated in the neonatal period, African Americans with galactosemia who have this allele in the homozygous state have a good prognosis. Generally, these individuals are not prone to
Data are limited on outcome in persons who are compound heterozygous (p.[Ser135Leu];[Gln188Arg]); however, they appear to have fewer complications than individuals with the genotype p.[Gln188Arg]+[p.Gln188Arg], associated with classic galactosemia.
In the homozygous state D
Compound heterozygotes with D
However, compound heterozygosity for D
Other compound heterozygotes (e.g., p.[Gln188Arg]+[Arg333Gly]) have a good long-term outcome [
A clear genotype-phenotype correlation is seen when classic galactosemia with genotypes such as p.[Gln188Arg]+[Gln188Arg] is compared with clinical variant galactosemia caused by the p.[Ser135Leu]+[Ser135Leu] genotype. For example, almost all females with the p.[Gln188Arg]+[Gln188Arg] genotype manifest POI, whereas POI is almost unheard of in African American women with the p.[Ser135Leu]+[Ser135Leu] genotype. A critical unanswered question is how much residual GALT enzyme activity in target tissues there must be to eliminate chronic diet-independent complications. To illustrate, cryptic residual GALT enzyme activity may be a potential modifier of scholastic outcome in school-age children [
While on a lactose-restricted diet, persons with classic galactosemia display erythrocyte galactose-1-phosphate levels between 1 and 5 mg/dL and urine galactitol levels between 100 and 400 μmol/mmol creatinine, whereas persons with a p.[Ser135Leu]+[Ser135Leu] genotype usually have an erythrocyte galactose-1-phosphate level below 1 mg/dL, and urine galactitol that is below 100 μmol/mmol creatinine and often in the normal range [
Persons with biochemical variant galactosemia – for example, compound heterozygotes for c.563A>G (p.Gln188Arg) and D
Note: Many of the more than 300
• In the homozygous state, the pathogenic variant interferes with the catalytic reaction. It is associated with increased risks for POI and childhood apraxia of speech [
• In one cross-sectional retrospective study correlating genotype with outcome in individuals with classic galactosemia, a greater proportion of individuals with a poor outcome were homozygous for the p.Gln188Arg pathogenic variant, and a greater proportion with a good outcome were not homozygous for the p.Gln188Arg pathogenic variant. However, one adult female and one adult male homozygous for the p.Gln188Arg pathogenic variant who had begun normal lactose intake at age three years exhibited no worsening of the underlying classic galactosemia phenotype [
• If therapy is initiated in the neonatal period, African Americans with galactosemia who have this allele in the homozygous state have a good prognosis. Generally, these individuals are not prone to
• Data are limited on outcome in persons who are compound heterozygous (p.[Ser135Leu];[Gln188Arg]); however, they appear to have fewer complications than individuals with the genotype p.[Gln188Arg]+[p.Gln188Arg], associated with classic galactosemia.
• In the homozygous state D
• Compound heterozygotes with D
• However, compound heterozygosity for D
• A clear genotype-phenotype correlation is seen when classic galactosemia with genotypes such as p.[Gln188Arg]+[Gln188Arg] is compared with clinical variant galactosemia caused by the p.[Ser135Leu]+[Ser135Leu] genotype. For example, almost all females with the p.[Gln188Arg]+[Gln188Arg] genotype manifest POI, whereas POI is almost unheard of in African American women with the p.[Ser135Leu]+[Ser135Leu] genotype. A critical unanswered question is how much residual GALT enzyme activity in target tissues there must be to eliminate chronic diet-independent complications. To illustrate, cryptic residual GALT enzyme activity may be a potential modifier of scholastic outcome in school-age children [
• While on a lactose-restricted diet, persons with classic galactosemia display erythrocyte galactose-1-phosphate levels between 1 and 5 mg/dL and urine galactitol levels between 100 and 400 μmol/mmol creatinine, whereas persons with a p.[Ser135Leu]+[Ser135Leu] genotype usually have an erythrocyte galactose-1-phosphate level below 1 mg/dL, and urine galactitol that is below 100 μmol/mmol creatinine and often in the normal range [
• Persons with biochemical variant galactosemia – for example, compound heterozygotes for c.563A>G (p.Gln188Arg) and D
## Nomenclature
The Genetic Hypergalactosemias
## Prevalence
Based on the results of newborn screening programs, the prevalence of classic galactosemia is 1:48,000 [
The frequency of classic galactosemia in Ireland is 1:16,476 [
While it is not possible to provide prevalence data for clinical variant galactosemia, the estimated prevalence of the
## Genetically Related (Allelic) Disorders
The Duarte variant (D
Note: The Los Angeles (LA) variant (D
In biochemical variant galactosemia:
Erythrocyte galactose-1-phosphate is usually >1 mg/dL, but may be as high as 35 mg/dL. When the individual is on a lactose-free diet, the level is <1 mg/dL.
Residual erythrocyte GALT enzyme activity is usually >15% and, on average, is 25% of control values.
• Erythrocyte galactose-1-phosphate is usually >1 mg/dL, but may be as high as 35 mg/dL. When the individual is on a lactose-free diet, the level is <1 mg/dL.
• Residual erythrocyte GALT enzyme activity is usually >15% and, on average, is 25% of control values.
## Differential Diagnosis
The differential diagnosis for neonatal hepatotoxicity includes infectious diseases, obstructive biliary disease, and metabolic diseases; see
Note: Establishing the diagnosis of sepsis does not exclude the possibility of galactosemia, as sepsis (particularly
Genes of Interest in the Differential Diagnosis of Neonatal Hepatotoxicity
AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorders of glycosylation; MOI = mode of inheritance
Genes of Interest in the Differential Diagnosis of Hypergalactosemias
FTT = failure to thrive; NBS = newborn screening
The cataracts are caused by accumulation of galactose in lens fibers and its reduction to galactitol, an impermeant alcohol that results in increased intracellular osmolality and water imbibition.
## Management
When classic galactosemia or clinical variant galactosemia is suspected during the diagnostic evaluation (i.e., due to a positive newborn screen or based on clinical features), dietary intervention should be initiated immediately. An international clinical guideline addressing management has been published [
To establish the extent of disease and needs in an individual diagnosed with classic galactosemia or clinical variant galactosemia, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Classic Galactosemia and Clinical Variant Galactosemia
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)
Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis).
Measurement of erythrocyte galactose-1-phoshate concentration & urinary galactitol as baseline for monitoring of treatment (See
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider EEG if seizures are a concern.
Consider brain MRI, as needed.
MOI = mode of inheritance
After a new diagnosis of classic galactosemia or clinical variant galactosemia in a child, the closest hospital and local pediatrician should also be informed.
Assess liver function tests and coagulation factors; obtain liver ultrasound.
Consultation with a neurologist and obtaining a brain MRI is very important in establishing the nature of any neurologic deficits and the corresponding brain lesions.
Measurement of follicle-stimulating hormone and luteinizing hormone during minipuberty (between 2 weeks and 3 months of life) may provide indications of future gonadal health. While controversial, preservation of ovarian tissue has been proposed as a treatment option for POI [
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
An international clinical guideline addressing management has been published [
Treatment in Individuals with Classic Galactosemia and Clinical Variant Galactosemia
Elemental formulas that contain small amounts of galactose such as Alimentum,
A formula (Neocate
Mgmt of diet is less important after infancy & early childhood, when milk & dairy products are no longer primary source of energy.
It is debated how stringent diet should be after infancy, as endogenous galactose production is an order of magnitude higher than that ingested from foods other than milk.
DD = developmental delay; ID = intellectual disability; FSH = follicle-stimulating hormone; NBS = newborn screening; OB/GYN = obstetrician/gynecologist; POI = premature ovarian insufficiency
Because 90% of the newborn's carbohydrate source is lactose and human milk contains 6%-8% lactose, cow's milk 3%-4% lactose, and most proprietary infant formulas 7% lactose, all of these milk products must be replaced immediately by a formula that is free of lactose (e.g., Isomil
Soy formulas typically contain sucrose, fructose, and galactose-containing oligosaccharides that cannot be hydrolyzed in the small intestine.
Until more prospective evidence-based medicine studies have been performed with a large number of subjects, parents should be educated about the lifelong need for dietary restriction of cow's milk and dairy products.
There is controversy as to whether females should be given estrogen and progesterone early in adolescence to retard "oocyte wastage" and whether more aggressive treatment plans (similar to those used in oncology) should be employed. In this regard, the autonomy of the affected female must be respected and, in the case of a pre-adolescent individual, her capacity for making an informed decision taken into consideration. Hospital ethics boards should be involved in any decision making and each case treated individually [
The consideration of ovarian biopsy with oocyte preservation for future use in females with classic galactosemia and premature ovarian insufficiency (POI) is controversial. If this type of procedure (which is becoming more common for females undergoing cancer chemotherapy) is being considered, consultation with the hospital ethics committee is recommended.
One female with POI conceived following follicle-stimulating hormone therapy, and subsequently delivered a normal child [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
See
Because bone mineral density in children and adults with classic galactosemia and clinical variant galactosemia may be diminished, supplements of vitamin D in excess of 1,000 IU/day and vitamin K have been recommended [
For calcium and vitamin D intake recommendations, see the NIH Osteoporosis and Related Bone Diseases
If routine follow-up visits with a dietitian knowledgeable about metabolic disorders have verified that calcium and vitamin D intake are adequate for age and if plasma 25-hydroxyvitamin D is within the normal range but bone mineral density is decreased, consultation with a pediatric and/or adult endocrinologist may be warranted.
Some affected individuals may develop gastrointestinal dysfunction such as chronic constipation. For those with severe symptoms, evaluation by a gastroenterologist may be considered [
See also the management guidelines published by
Every three months for the first year of life or as needed depending on the nature of potential acute complications
Every six months during the second year of life
Yearly thereafter
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations in
Recommended Surveillance for Individuals with Classic Galactosemia and Clinical Variant Galactosemia
DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; POI = premature ovarian insufficiency; PT = physical therapy
Concentrations <5 mg/dL are considered within the therapeutic range.
If sudden increases in either erythrocyte galactose-1-phosphate or urinary galactitol are detected, dietary sources of excess galactose should be sought or evaluation for other causes initiated.
Erythrocyte galactose-1-phosphate and urine galactitol may provide comparable information regarding adherence to a lactose-restricted diet.
Urinary galactitol is often not affected by acute dietary ingestion of galactose.
Measurement of urinary galactitol is not necessary for long-term monitoring. Urinary galactitol analysis is especially valuable in affected individuals who have been given red blood cell transfusions; values >78 mmol/mol creatinine are abnormal.
If the initial evaluation does not reveal a diagnosis of a speech or language disorder, reevaluation every three to 12 months during infancy and early childhood depending on the assessments performed by the developmental specialists and physicians
It is very unusual for a person with classic galactosemia to present after early infancy with cataracts, as cataract development probably requires significant intake of cow's milk and dairy products.
Routine metabolic dietetic visits should verify that calcium and vitamin D intake is adequate for age and that plasma 25-hydroxyvitamin D is within the normal range. Even so, bone mineral density may be decreased in certain affected individuals for reasons that are not understood. Under these circumstances, consultation with a pediatric and/or adult endocrinologist may be warranted.
The following should be avoided:
Breast milk, proprietary infant formulas containing lactose, cow's milk, dairy products, and casein- or whey-containing foods
Lactose- or galactose-containing drug preparations
Medicines that contain lactose (tablets, capsules, sweetened elixirs), especially during infancy
See
Research suggests that despite exogenous galactose restriction, endogenous galactose production may approach 1-2 g/day [
Approaches to lowering endogenous production of galactose-1-phosphate are under investigation using small inhibitors of the GALK enzyme [
Search
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)
• Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis).
• Measurement of erythrocyte galactose-1-phoshate concentration & urinary galactitol as baseline for monitoring of treatment (See
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider EEG if seizures are a concern.
• Consider brain MRI, as needed.
• Elemental formulas that contain small amounts of galactose such as Alimentum,
• A formula (Neocate
• Mgmt of diet is less important after infancy & early childhood, when milk & dairy products are no longer primary source of energy.
• It is debated how stringent diet should be after infancy, as endogenous galactose production is an order of magnitude higher than that ingested from foods other than milk.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• For calcium and vitamin D intake recommendations, see the NIH Osteoporosis and Related Bone Diseases
• If routine follow-up visits with a dietitian knowledgeable about metabolic disorders have verified that calcium and vitamin D intake are adequate for age and if plasma 25-hydroxyvitamin D is within the normal range but bone mineral density is decreased, consultation with a pediatric and/or adult endocrinologist may be warranted.
• Every three months for the first year of life or as needed depending on the nature of potential acute complications
• Every six months during the second year of life
• Yearly thereafter
• Breast milk, proprietary infant formulas containing lactose, cow's milk, dairy products, and casein- or whey-containing foods
• Lactose- or galactose-containing drug preparations
• Medicines that contain lactose (tablets, capsules, sweetened elixirs), especially during infancy
## Evaluations Following Initial Diagnosis in the Newborn Period
To establish the extent of disease and needs in an individual diagnosed with classic galactosemia or clinical variant galactosemia, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of Classic Galactosemia and Clinical Variant Galactosemia
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)
Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis).
Measurement of erythrocyte galactose-1-phoshate concentration & urinary galactitol as baseline for monitoring of treatment (See
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider EEG if seizures are a concern.
Consider brain MRI, as needed.
MOI = mode of inheritance
After a new diagnosis of classic galactosemia or clinical variant galactosemia in a child, the closest hospital and local pediatrician should also be informed.
Assess liver function tests and coagulation factors; obtain liver ultrasound.
Consultation with a neurologist and obtaining a brain MRI is very important in establishing the nature of any neurologic deficits and the corresponding brain lesions.
Measurement of follicle-stimulating hormone and luteinizing hormone during minipuberty (between 2 weeks and 3 months of life) may provide indications of future gonadal health. While controversial, preservation of ovarian tissue has been proposed as a treatment option for POI [
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)
• Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis).
• Measurement of erythrocyte galactose-1-phoshate concentration & urinary galactitol as baseline for monitoring of treatment (See
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider EEG if seizures are a concern.
• Consider brain MRI, as needed.
## Treatment of Manifestations and Complications
An international clinical guideline addressing management has been published [
Treatment in Individuals with Classic Galactosemia and Clinical Variant Galactosemia
Elemental formulas that contain small amounts of galactose such as Alimentum,
A formula (Neocate
Mgmt of diet is less important after infancy & early childhood, when milk & dairy products are no longer primary source of energy.
It is debated how stringent diet should be after infancy, as endogenous galactose production is an order of magnitude higher than that ingested from foods other than milk.
DD = developmental delay; ID = intellectual disability; FSH = follicle-stimulating hormone; NBS = newborn screening; OB/GYN = obstetrician/gynecologist; POI = premature ovarian insufficiency
Because 90% of the newborn's carbohydrate source is lactose and human milk contains 6%-8% lactose, cow's milk 3%-4% lactose, and most proprietary infant formulas 7% lactose, all of these milk products must be replaced immediately by a formula that is free of lactose (e.g., Isomil
Soy formulas typically contain sucrose, fructose, and galactose-containing oligosaccharides that cannot be hydrolyzed in the small intestine.
Until more prospective evidence-based medicine studies have been performed with a large number of subjects, parents should be educated about the lifelong need for dietary restriction of cow's milk and dairy products.
There is controversy as to whether females should be given estrogen and progesterone early in adolescence to retard "oocyte wastage" and whether more aggressive treatment plans (similar to those used in oncology) should be employed. In this regard, the autonomy of the affected female must be respected and, in the case of a pre-adolescent individual, her capacity for making an informed decision taken into consideration. Hospital ethics boards should be involved in any decision making and each case treated individually [
The consideration of ovarian biopsy with oocyte preservation for future use in females with classic galactosemia and premature ovarian insufficiency (POI) is controversial. If this type of procedure (which is becoming more common for females undergoing cancer chemotherapy) is being considered, consultation with the hospital ethics committee is recommended.
One female with POI conceived following follicle-stimulating hormone therapy, and subsequently delivered a normal child [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Elemental formulas that contain small amounts of galactose such as Alimentum,
• A formula (Neocate
• Mgmt of diet is less important after infancy & early childhood, when milk & dairy products are no longer primary source of energy.
• It is debated how stringent diet should be after infancy, as endogenous galactose production is an order of magnitude higher than that ingested from foods other than milk.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech therapy services will be provided within the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
## Prevention of Primary Manifestations
See
## Prevention of Secondary Complications
Because bone mineral density in children and adults with classic galactosemia and clinical variant galactosemia may be diminished, supplements of vitamin D in excess of 1,000 IU/day and vitamin K have been recommended [
For calcium and vitamin D intake recommendations, see the NIH Osteoporosis and Related Bone Diseases
If routine follow-up visits with a dietitian knowledgeable about metabolic disorders have verified that calcium and vitamin D intake are adequate for age and if plasma 25-hydroxyvitamin D is within the normal range but bone mineral density is decreased, consultation with a pediatric and/or adult endocrinologist may be warranted.
Some affected individuals may develop gastrointestinal dysfunction such as chronic constipation. For those with severe symptoms, evaluation by a gastroenterologist may be considered [
• For calcium and vitamin D intake recommendations, see the NIH Osteoporosis and Related Bone Diseases
• If routine follow-up visits with a dietitian knowledgeable about metabolic disorders have verified that calcium and vitamin D intake are adequate for age and if plasma 25-hydroxyvitamin D is within the normal range but bone mineral density is decreased, consultation with a pediatric and/or adult endocrinologist may be warranted.
## Surveillance
See also the management guidelines published by
Every three months for the first year of life or as needed depending on the nature of potential acute complications
Every six months during the second year of life
Yearly thereafter
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations in
Recommended Surveillance for Individuals with Classic Galactosemia and Clinical Variant Galactosemia
DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; POI = premature ovarian insufficiency; PT = physical therapy
Concentrations <5 mg/dL are considered within the therapeutic range.
If sudden increases in either erythrocyte galactose-1-phosphate or urinary galactitol are detected, dietary sources of excess galactose should be sought or evaluation for other causes initiated.
Erythrocyte galactose-1-phosphate and urine galactitol may provide comparable information regarding adherence to a lactose-restricted diet.
Urinary galactitol is often not affected by acute dietary ingestion of galactose.
Measurement of urinary galactitol is not necessary for long-term monitoring. Urinary galactitol analysis is especially valuable in affected individuals who have been given red blood cell transfusions; values >78 mmol/mol creatinine are abnormal.
If the initial evaluation does not reveal a diagnosis of a speech or language disorder, reevaluation every three to 12 months during infancy and early childhood depending on the assessments performed by the developmental specialists and physicians
It is very unusual for a person with classic galactosemia to present after early infancy with cataracts, as cataract development probably requires significant intake of cow's milk and dairy products.
Routine metabolic dietetic visits should verify that calcium and vitamin D intake is adequate for age and that plasma 25-hydroxyvitamin D is within the normal range. Even so, bone mineral density may be decreased in certain affected individuals for reasons that are not understood. Under these circumstances, consultation with a pediatric and/or adult endocrinologist may be warranted.
• Every three months for the first year of life or as needed depending on the nature of potential acute complications
• Every six months during the second year of life
• Yearly thereafter
## Schedule for Individuals with Classic or Clinical Variant Galactosemia
Every three months for the first year of life or as needed depending on the nature of potential acute complications
Every six months during the second year of life
Yearly thereafter
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations in
Recommended Surveillance for Individuals with Classic Galactosemia and Clinical Variant Galactosemia
DXA = dual-energy x-ray absorptiometry; FSH = follicle-stimulating hormone; POI = premature ovarian insufficiency; PT = physical therapy
Concentrations <5 mg/dL are considered within the therapeutic range.
If sudden increases in either erythrocyte galactose-1-phosphate or urinary galactitol are detected, dietary sources of excess galactose should be sought or evaluation for other causes initiated.
Erythrocyte galactose-1-phosphate and urine galactitol may provide comparable information regarding adherence to a lactose-restricted diet.
Urinary galactitol is often not affected by acute dietary ingestion of galactose.
Measurement of urinary galactitol is not necessary for long-term monitoring. Urinary galactitol analysis is especially valuable in affected individuals who have been given red blood cell transfusions; values >78 mmol/mol creatinine are abnormal.
If the initial evaluation does not reveal a diagnosis of a speech or language disorder, reevaluation every three to 12 months during infancy and early childhood depending on the assessments performed by the developmental specialists and physicians
It is very unusual for a person with classic galactosemia to present after early infancy with cataracts, as cataract development probably requires significant intake of cow's milk and dairy products.
Routine metabolic dietetic visits should verify that calcium and vitamin D intake is adequate for age and that plasma 25-hydroxyvitamin D is within the normal range. Even so, bone mineral density may be decreased in certain affected individuals for reasons that are not understood. Under these circumstances, consultation with a pediatric and/or adult endocrinologist may be warranted.
• Every three months for the first year of life or as needed depending on the nature of potential acute complications
• Every six months during the second year of life
• Yearly thereafter
## Agents/Circumstances to Avoid
The following should be avoided:
Breast milk, proprietary infant formulas containing lactose, cow's milk, dairy products, and casein- or whey-containing foods
Lactose- or galactose-containing drug preparations
Medicines that contain lactose (tablets, capsules, sweetened elixirs), especially during infancy
• Breast milk, proprietary infant formulas containing lactose, cow's milk, dairy products, and casein- or whey-containing foods
• Lactose- or galactose-containing drug preparations
• Medicines that contain lactose (tablets, capsules, sweetened elixirs), especially during infancy
## Evaluation of Relatives at Risk
See
## Pregnancy Management
## Therapies Under Investigation
Research suggests that despite exogenous galactose restriction, endogenous galactose production may approach 1-2 g/day [
Approaches to lowering endogenous production of galactose-1-phosphate are under investigation using small inhibitors of the GALK enzyme [
Search
## Genetic Counseling
Classic galactosemia and clinical variant galactosemia are inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.
The offspring of an individual with classic galactosemia or clinical variant galactosemia are obligate heterozygotes (carriers) for a pathogenic variant in
If one parent has classic galactosemia or clinical variant galactosemia and the other parent is a carrier, each child has a 50% chance of being a heterozygote and a 50% chance of having classic galactosemia or clinical variant galactosemia.
~50% of control values in carriers of classic galactosemia;
~50% of control values in carriers of
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Prenatal testing (or preimplantation genetic testing) using molecular genetic testing is preferred over enzyme analysis.
Note: When a fetus has classic galactosemia or clinical variant galactosemia, amniotic fluid concentration of galactitol is elevated in the late third trimester and has been used in the past for prenatal testing.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.
• The offspring of an individual with classic galactosemia or clinical variant galactosemia are obligate heterozygotes (carriers) for a pathogenic variant in
• If one parent has classic galactosemia or clinical variant galactosemia and the other parent is a carrier, each child has a 50% chance of being a heterozygote and a 50% chance of having classic galactosemia or clinical variant galactosemia.
• ~50% of control values in carriers of classic galactosemia;
• ~50% of control values in carriers of
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Classic galactosemia and clinical variant galactosemia are inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.
The offspring of an individual with classic galactosemia or clinical variant galactosemia are obligate heterozygotes (carriers) for a pathogenic variant in
If one parent has classic galactosemia or clinical variant galactosemia and the other parent is a carrier, each child has a 50% chance of being a heterozygote and a 50% chance of having classic galactosemia or clinical variant galactosemia.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and do not develop galactosemia.
• The offspring of an individual with classic galactosemia or clinical variant galactosemia are obligate heterozygotes (carriers) for a pathogenic variant in
• If one parent has classic galactosemia or clinical variant galactosemia and the other parent is a carrier, each child has a 50% chance of being a heterozygote and a 50% chance of having classic galactosemia or clinical variant galactosemia.
## Carrier Detection
~50% of control values in carriers of classic galactosemia;
~50% of control values in carriers of
• ~50% of control values in carriers of classic galactosemia;
• ~50% of control values in carriers of
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Prenatal testing (or preimplantation genetic testing) using molecular genetic testing is preferred over enzyme analysis.
Note: When a fetus has classic galactosemia or clinical variant galactosemia, amniotic fluid concentration of galactitol is elevated in the late third trimester and has been used in the past for prenatal testing.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
TEMPLE (Tools Enabling Metabolic Parents LEarning)
United Kingdom
31 Cotysmore Road
Sutton Coldfield West Midlands B75 6BJ
United Kingdom
350 Northern Boulevard
Suite 324 - 1079
Albany NY 12204-1000
United Kingdom
Health Resources & Services Administration
For information about the GalNet Registry, see
•
• TEMPLE (Tools Enabling Metabolic Parents LEarning)
• United Kingdom
•
•
• 31 Cotysmore Road
• Sutton Coldfield West Midlands B75 6BJ
• United Kingdom
•
•
•
•
• 350 Northern Boulevard
• Suite 324 - 1079
• Albany NY 12204-1000
•
•
•
•
• United Kingdom
•
•
• Health Resources & Services Administration
•
## Molecular Genetics
Classic Galactosemia and Clinical Variant Galactosemia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Classic Galactosemia and Clinical Variant Galactosemia (
The GALT enzyme catalyzes the conversion of galactose-1-phosphate and UDPglucose to UDPgalactose and Glu-1-P in a two-step process termed a ping-pong or bi-bi molecular reaction (
UDPglucose binds to the active site and glucose-1-phosphate is released, leaving UMP covalently linked to the enzyme.
Galactose-1-phosphate then lands at the active site, engages the bound UMP, and following cleavage of the phosphonium bond, UDP galactose is released.
When GALT enzyme activity is deficient, galactose-1-phosphate, galactose, and galactitol accumulate (
Since individuals with classic galactosemia who are prospectively treated may manifest all of the so-called chronic diet-independent complications, and since the amniotic fluid of affected fetuses contains high levels of galactitol and the cord blood of affected newborns contains elevated levels of erythrocyte galactose-1-phosphate, one must consider whether the long-term complications of GALT enzyme deficiency are due to prenatal toxicity [
Notable
Variants listed in the table have been provided by the author.
The Duarte D
A complex deletion that involves a 3,163-bp deletion of the
Seen in persons of Ashkenazi Jewish ethnicity
• UDPglucose binds to the active site and glucose-1-phosphate is released, leaving UMP covalently linked to the enzyme.
• Galactose-1-phosphate then lands at the active site, engages the bound UMP, and following cleavage of the phosphonium bond, UDP galactose is released.
## Molecular Pathogenesis
The GALT enzyme catalyzes the conversion of galactose-1-phosphate and UDPglucose to UDPgalactose and Glu-1-P in a two-step process termed a ping-pong or bi-bi molecular reaction (
UDPglucose binds to the active site and glucose-1-phosphate is released, leaving UMP covalently linked to the enzyme.
Galactose-1-phosphate then lands at the active site, engages the bound UMP, and following cleavage of the phosphonium bond, UDP galactose is released.
When GALT enzyme activity is deficient, galactose-1-phosphate, galactose, and galactitol accumulate (
Since individuals with classic galactosemia who are prospectively treated may manifest all of the so-called chronic diet-independent complications, and since the amniotic fluid of affected fetuses contains high levels of galactitol and the cord blood of affected newborns contains elevated levels of erythrocyte galactose-1-phosphate, one must consider whether the long-term complications of GALT enzyme deficiency are due to prenatal toxicity [
Notable
Variants listed in the table have been provided by the author.
The Duarte D
A complex deletion that involves a 3,163-bp deletion of the
Seen in persons of Ashkenazi Jewish ethnicity
• UDPglucose binds to the active site and glucose-1-phosphate is released, leaving UMP covalently linked to the enzyme.
• Galactose-1-phosphate then lands at the active site, engages the bound UMP, and following cleavage of the phosphonium bond, UDP galactose is released.
## Chapter Notes
The GalNet Registry is maintained as a research tool by a steering committee composed of investigators from the USA and Europe. It is not currently open to the public.
Gerard T Berry is the Harvey Levy Chair in Metabolism at the Boston Children's Hospital and Professor of Pediatrics at the Harvard Medical School. He is the Director of Metabolism Program at Boston Children's Hospital and the Director of the Harvard Medical School Biochemical Genetics Training Program. He is a member of the Broad Institute of Harvard and MIT. He was the recipient of the 2004 Emmanuel Shapiro Society for Inherited Metabolic Disorders (SIMD) Award. As a member of the SIMD Board of Directors, Dr Berry is the SIMD President Elect. He is the co-chair of the Undiagnosed Disease Network (UDN) metabolomics working group. Dr Berry has established an international center for galactosemia at Boston Children's Hospital. His research has been in both the clinical and basic science spheres. The Berry laboratory has been heavily involved in stable isotope breath testing and whole-body galactose modeling in patients with galactosemia. He created new accurate methods to quantify GALT, GALK, and GALE enzyme activities using LC-MS/MS methodology. More recently his laboratory has turned to studying human induced pluripotent stem (IPS) cells generated from blood and fibroblasts of individuals with galactosemia. He is using synthetic cortical neurons derived from IPS cells, as well as human organoids, to study the mechanisms of central nervous system dysfunction and cell death in galactosemia.
I thank the Galactosemia Foundation for their many years of support of this work, all of my colleagues and co-investigators, and the patients and families who have contributed so much and participated in the various research studies.
Gerard T Berry, MD, FFACMG (2014-present)Louis J Elsas II, MD, FFACMG; University of Miami (1999-2014)
11 March 2021 (ma) Comprehensive update posted live
9 March 2017 (ma) Comprehensive update posted live
3 April 2014 (me) Comprehensive update posted live
26 October 2010 (me) Comprehensive update posted live
27 September 2007 (me) Comprehensive update posted live
2 May 2005 (me) Comprehensive update posted live
27 March 2003 (me) Comprehensive update posted live
4 February 2000 (me) Review posted live
31 August 1999 (le) Original submission
• 11 March 2021 (ma) Comprehensive update posted live
• 9 March 2017 (ma) Comprehensive update posted live
• 3 April 2014 (me) Comprehensive update posted live
• 26 October 2010 (me) Comprehensive update posted live
• 27 September 2007 (me) Comprehensive update posted live
• 2 May 2005 (me) Comprehensive update posted live
• 27 March 2003 (me) Comprehensive update posted live
• 4 February 2000 (me) Review posted live
• 31 August 1999 (le) Original submission
## Author Notes
Gerard T Berry is the Harvey Levy Chair in Metabolism at the Boston Children's Hospital and Professor of Pediatrics at the Harvard Medical School. He is the Director of Metabolism Program at Boston Children's Hospital and the Director of the Harvard Medical School Biochemical Genetics Training Program. He is a member of the Broad Institute of Harvard and MIT. He was the recipient of the 2004 Emmanuel Shapiro Society for Inherited Metabolic Disorders (SIMD) Award. As a member of the SIMD Board of Directors, Dr Berry is the SIMD President Elect. He is the co-chair of the Undiagnosed Disease Network (UDN) metabolomics working group. Dr Berry has established an international center for galactosemia at Boston Children's Hospital. His research has been in both the clinical and basic science spheres. The Berry laboratory has been heavily involved in stable isotope breath testing and whole-body galactose modeling in patients with galactosemia. He created new accurate methods to quantify GALT, GALK, and GALE enzyme activities using LC-MS/MS methodology. More recently his laboratory has turned to studying human induced pluripotent stem (IPS) cells generated from blood and fibroblasts of individuals with galactosemia. He is using synthetic cortical neurons derived from IPS cells, as well as human organoids, to study the mechanisms of central nervous system dysfunction and cell death in galactosemia.
## Acknowledgments
I thank the Galactosemia Foundation for their many years of support of this work, all of my colleagues and co-investigators, and the patients and families who have contributed so much and participated in the various research studies.
## Author History
Gerard T Berry, MD, FFACMG (2014-present)Louis J Elsas II, MD, FFACMG; University of Miami (1999-2014)
## Revision History
11 March 2021 (ma) Comprehensive update posted live
9 March 2017 (ma) Comprehensive update posted live
3 April 2014 (me) Comprehensive update posted live
26 October 2010 (me) Comprehensive update posted live
27 September 2007 (me) Comprehensive update posted live
2 May 2005 (me) Comprehensive update posted live
27 March 2003 (me) Comprehensive update posted live
4 February 2000 (me) Review posted live
31 August 1999 (le) Original submission
• 11 March 2021 (ma) Comprehensive update posted live
• 9 March 2017 (ma) Comprehensive update posted live
• 3 April 2014 (me) Comprehensive update posted live
• 26 October 2010 (me) Comprehensive update posted live
• 27 September 2007 (me) Comprehensive update posted live
• 2 May 2005 (me) Comprehensive update posted live
• 27 March 2003 (me) Comprehensive update posted live
• 4 February 2000 (me) Review posted live
• 31 August 1999 (le) Original submission
## References
Welling L, Bernstein LE, Berry GT, Burlina AB, Eyskens F, Gautschi M, Grünewald S, Gubbels CS, Knerr I, Labrune P, van der Lee JH, MacDonald A, Murphy E, Portnoi PA, Õunap K, Potter NL, Rubio-Gozalbo ME, Spencer JB, Timmers I, Treacy EP, Van Calcar SC, Waisbren SE, Bosch AM; Galactosemia Network (GalNet). International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. Available
• Welling L, Bernstein LE, Berry GT, Burlina AB, Eyskens F, Gautschi M, Grünewald S, Gubbels CS, Knerr I, Labrune P, van der Lee JH, MacDonald A, Murphy E, Portnoi PA, Õunap K, Potter NL, Rubio-Gozalbo ME, Spencer JB, Timmers I, Treacy EP, Van Calcar SC, Waisbren SE, Bosch AM; Galactosemia Network (GalNet). International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. Available
## Published Guidelines / Consensus Statements
Welling L, Bernstein LE, Berry GT, Burlina AB, Eyskens F, Gautschi M, Grünewald S, Gubbels CS, Knerr I, Labrune P, van der Lee JH, MacDonald A, Murphy E, Portnoi PA, Õunap K, Potter NL, Rubio-Gozalbo ME, Spencer JB, Timmers I, Treacy EP, Van Calcar SC, Waisbren SE, Bosch AM; Galactosemia Network (GalNet). International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. Available
• Welling L, Bernstein LE, Berry GT, Burlina AB, Eyskens F, Gautschi M, Grünewald S, Gubbels CS, Knerr I, Labrune P, van der Lee JH, MacDonald A, Murphy E, Portnoi PA, Õunap K, Potter NL, Rubio-Gozalbo ME, Spencer JB, Timmers I, Treacy EP, Van Calcar SC, Waisbren SE, Bosch AM; Galactosemia Network (GalNet). International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. Available
## Literature Cited
Galactose metabolism, the Leloir pathway
Galactose metabolism, GALT deficiency
|
[] |
4/2/2000
|
11/3/2021
|
2/7/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
gale-def
|
gale-def
|
[
"Galactosemia Type III",
"GALE Deficiency",
"UDP-Galactose-4'-Epimerase Deficiency",
"GALE Deficiency",
"Galactosemia Type III",
"UDP-Galactose-4'-Epimerase Deficiency",
"UDP-glucose 4-epimerase",
"GALE",
"Epimerase Deficiency Galactosemia"
] |
Epimerase Deficiency Galactosemia
|
Judith Fridovich-Keil, Lora Bean, Miao He, Richard Schroer
|
Summary Epimerase deficiency galactosemia (GALE deficiency galactosemia) is generally considered a continuum comprising several forms: Infants with generalized epimerase deficiency galactosemia develop clinical findings on a regular milk diet (which contains lactose, a disaccharide of galactose and glucose); manifestations include hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose/lactose from their diet resolves or prevents these acute symptoms. Longer-term features that may be seen in those with generalized epimerase deficiency include short stature, developmental delay, sensorineural hearing loss, and skeletal anomalies. In contrast, neonates with the peripheral or intermediate form generally remain clinically well even on a regular milk diet and are usually only identified by biochemical testing, often in newborn screening programs. The diagnosis of epimerase deficiency galactosemia is established in a proband with impaired GALE activity in RBC or other cells and/or biallelic pathogenic variants in Epimerase deficiency galactosemia is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Epimerase deficiency galactosemia (GALE deficiency galactosemia) is a continuum comprising three forms:
Epimerase deficiency galactosemia
In states in which the newborn screening program includes measurements of both total galactose (gal+gal-1P) and GALT enzyme activity (see
Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and
GALT enzyme activity is normal.
In states in which total galactose is only measured if GALT enzyme activity is low, an infant with GALE deficiency will have a normal newborn screening result for galactosemia.
Hypotonia
Poor feeding
Vomiting
Weight loss
Jaundice
Hepatomegaly
Liver dysfunction
Cataracts
No clinical findings (peripheral and intermediate forms of GALE deficiency)
Elevated RBC hemolysate gal-1P concentration (normal: 0-1.0 mg/100 mL RBC):
As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency
>30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency
Urinary galactose concentrations as high as 116 mmol/L (2.09 g/100 mL, control <30 mg/100 mL)
Non-glucose reducing substance in the urine (which represents urinary galactose)
Elevated urinary galactitol concentrations (normal: 6 years)
Generalized aminoaciduria
Normal GALT, GALK, and GALM enzyme activities
Note: If epimerase deficiency galactosemia is suspected, assessment of enzymatic activity for GALT, GALK, and GALM is
A diagnosis of epimerase deficiency galactosemia
0.0-8.0 μmol/hr/g hemoglobin (Hb) GALE enzyme activity in red blood cells (RBC) (normal 17.1-40.1 μmol/hr/g Hb) as determined by the traditional spectrophotometric assay
<0.5 μmol/hr/g Hb GALE enzyme activity in RBC using liquid chromatography/tandem mass spectrometry (normal 2.3-12.7 μmol/hr/g Hb) [
Identification of biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Epimerase Deficiency Galactosemia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Whole-gene sequencing has revealed ostensibly causal
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
At the time of this writing, no deletions or duplications involving
GALE enzyme activity can be measured in fibroblasts or lymphoblasts to help distinguish between the generalized, peripheral, and intermediate forms of epimerase deficiency galactosemia; however, to the authors' knowledge this testing is not currently offered on a clinical basis.
• In states in which the newborn screening program includes measurements of both total galactose (gal+gal-1P) and GALT enzyme activity (see
• Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and
• GALT enzyme activity is normal.
• Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and
• GALT enzyme activity is normal.
• In states in which total galactose is only measured if GALT enzyme activity is low, an infant with GALE deficiency will have a normal newborn screening result for galactosemia.
• Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and
• GALT enzyme activity is normal.
• Hypotonia
• Poor feeding
• Vomiting
• Weight loss
• Jaundice
• Hepatomegaly
• Liver dysfunction
• Cataracts
• No clinical findings (peripheral and intermediate forms of GALE deficiency)
• Elevated RBC hemolysate gal-1P concentration (normal: 0-1.0 mg/100 mL RBC):
• As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency
• >30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency
• As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency
• >30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency
• Urinary galactose concentrations as high as 116 mmol/L (2.09 g/100 mL, control <30 mg/100 mL)
• Non-glucose reducing substance in the urine (which represents urinary galactose)
• Elevated urinary galactitol concentrations (normal: 6 years)
• Generalized aminoaciduria
• Normal GALT, GALK, and GALM enzyme activities
• Note: If epimerase deficiency galactosemia is suspected, assessment of enzymatic activity for GALT, GALK, and GALM is
• As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency
• >30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency
• 0.0-8.0 μmol/hr/g hemoglobin (Hb) GALE enzyme activity in red blood cells (RBC) (normal 17.1-40.1 μmol/hr/g Hb) as determined by the traditional spectrophotometric assay
• <0.5 μmol/hr/g Hb GALE enzyme activity in RBC using liquid chromatography/tandem mass spectrometry (normal 2.3-12.7 μmol/hr/g Hb) [
• Identification of biallelic pathogenic (or likely pathogenic) variants in
• For an introduction to multigene panels click
## Suggestive Findings
Epimerase deficiency galactosemia
In states in which the newborn screening program includes measurements of both total galactose (gal+gal-1P) and GALT enzyme activity (see
Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and
GALT enzyme activity is normal.
In states in which total galactose is only measured if GALT enzyme activity is low, an infant with GALE deficiency will have a normal newborn screening result for galactosemia.
Hypotonia
Poor feeding
Vomiting
Weight loss
Jaundice
Hepatomegaly
Liver dysfunction
Cataracts
No clinical findings (peripheral and intermediate forms of GALE deficiency)
Elevated RBC hemolysate gal-1P concentration (normal: 0-1.0 mg/100 mL RBC):
As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency
>30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency
Urinary galactose concentrations as high as 116 mmol/L (2.09 g/100 mL, control <30 mg/100 mL)
Non-glucose reducing substance in the urine (which represents urinary galactose)
Elevated urinary galactitol concentrations (normal: 6 years)
Generalized aminoaciduria
Normal GALT, GALK, and GALM enzyme activities
Note: If epimerase deficiency galactosemia is suspected, assessment of enzymatic activity for GALT, GALK, and GALM is
• In states in which the newborn screening program includes measurements of both total galactose (gal+gal-1P) and GALT enzyme activity (see
• Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and
• GALT enzyme activity is normal.
• Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and
• GALT enzyme activity is normal.
• In states in which total galactose is only measured if GALT enzyme activity is low, an infant with GALE deficiency will have a normal newborn screening result for galactosemia.
• Total galactose (sum of galactose and galactose-1-phosphate) is elevated; and
• GALT enzyme activity is normal.
• Hypotonia
• Poor feeding
• Vomiting
• Weight loss
• Jaundice
• Hepatomegaly
• Liver dysfunction
• Cataracts
• No clinical findings (peripheral and intermediate forms of GALE deficiency)
• Elevated RBC hemolysate gal-1P concentration (normal: 0-1.0 mg/100 mL RBC):
• As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency
• >30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency
• As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency
• >30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency
• Urinary galactose concentrations as high as 116 mmol/L (2.09 g/100 mL, control <30 mg/100 mL)
• Non-glucose reducing substance in the urine (which represents urinary galactose)
• Elevated urinary galactitol concentrations (normal: 6 years)
• Generalized aminoaciduria
• Normal GALT, GALK, and GALM enzyme activities
• Note: If epimerase deficiency galactosemia is suspected, assessment of enzymatic activity for GALT, GALK, and GALM is
• As high as 170 mg/100 mL packed RBC in those with generalized epimerase deficiency
• >30 mg/100 mL packed RBC in those with intermediate or peripheral epimerase deficiency
## Establishing the Diagnosis
A diagnosis of epimerase deficiency galactosemia
0.0-8.0 μmol/hr/g hemoglobin (Hb) GALE enzyme activity in red blood cells (RBC) (normal 17.1-40.1 μmol/hr/g Hb) as determined by the traditional spectrophotometric assay
<0.5 μmol/hr/g Hb GALE enzyme activity in RBC using liquid chromatography/tandem mass spectrometry (normal 2.3-12.7 μmol/hr/g Hb) [
Identification of biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Epimerase Deficiency Galactosemia
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Whole-gene sequencing has revealed ostensibly causal
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
At the time of this writing, no deletions or duplications involving
GALE enzyme activity can be measured in fibroblasts or lymphoblasts to help distinguish between the generalized, peripheral, and intermediate forms of epimerase deficiency galactosemia; however, to the authors' knowledge this testing is not currently offered on a clinical basis.
• 0.0-8.0 μmol/hr/g hemoglobin (Hb) GALE enzyme activity in red blood cells (RBC) (normal 17.1-40.1 μmol/hr/g Hb) as determined by the traditional spectrophotometric assay
• <0.5 μmol/hr/g Hb GALE enzyme activity in RBC using liquid chromatography/tandem mass spectrometry (normal 2.3-12.7 μmol/hr/g Hb) [
• Identification of biallelic pathogenic (or likely pathogenic) variants in
• For an introduction to multigene panels click
## Additional Testing
GALE enzyme activity can be measured in fibroblasts or lymphoblasts to help distinguish between the generalized, peripheral, and intermediate forms of epimerase deficiency galactosemia; however, to the authors' knowledge this testing is not currently offered on a clinical basis.
## Clinical Characteristics
The clinical severity of epimerase deficiency galactosemia caused by reduced activity of the enzyme GALE [
Epimerase deficiency galactosemia can be divided by apparent enzyme activity level in specific cell types into the following three forms: generalized, peripheral, and intermediate (see
A key difference between generalized epimerase deficiency galactosemia and intermediate or peripheral epimerase deficiency galactosemia is that individuals with generalized epimerase deficiency galactosemia develop clinical findings on a normal milk diet, while infants with peripheral or intermediate epimerase deficiency galactosemia remain clinically well, at least in the neonatal period.
Generalized epimerase deficiency galactosemia is rare, with only nine individuals from five families described in the literature [
Generalized Epimerase Deficiency Galactosemia: Frequency of Select Features
Not all affected individuals were assessed for each feature listed.
See
Infants with generalized epimerase deficiency galactosemia who are on a diet containing galactose/lactose typically present with symptoms reminiscent of
Long-term outcome information for persons with generalized epimerase deficiency galactosemia is limited due to the small number of known affected individuals. Some have demonstrated long-term complications that became evident by early childhood (including sensorineural hearing impairment and physical and cognitive developmental delay and/or learning difficulties) while others have not. Confounding factors include the fact that a majority, but not all, of the individuals reported were born to known consanguineous parents, raising the concern that homozygosity for other autosomal recessive alleles – other than
Positional talipes equinovarus [
Normal puberty with no apparent evidence of premature ovarian insufficiency [
Dilated cardiomyopathy that responded to standard treatment in one affected sib [
Neonates with the peripheral form are usually asymptomatic even on a regular milk diet; these infants are only identified following biochemical detection of elevated total galactose on newborn screening.
Children with peripheral epimerase deficiency galactosemia appear to remain asymptomatic even if maintained on a normal milk diet.
Neonates with the intermediate form are also usually asymptomatic even on a regular milk diet and are only identified through newborn screening. The long-term outcome remains unclear. One affected individual, who was not treated with dietary restriction of galactose/lactose as an infant, experienced delays in both motor and cognitive development that became evident in early childhood [
Because the numbers of individuals reported with molecularly confirmed epimerase deficiency galactosemia are currently limited, it is difficult to make strong genotype-phenotype correlations. However, some
Individuals who are homozygous for
Individuals who have biallelic
Some authors refer to the different forms of galactosemia as type I, type II, type III, and type IV galactosemia, in which:
Type I galactosemia refers to
Type II galactosemia refers to GALK deficiency;
Type III galactosemia refers to GALE deficiency (epimerase deficiency galactosemia);
Type IV galactosemia refers to GALM deficiency (galactose mutarotase deficiency) [
True prevalence figures are unavailable at this time. Generalized epimerase deficiency galactosemia is very rare; however, epimerase deficiency galactosemia detected by newborn screening may be as frequent as about 1:6,700 among African American infants and about 1:70,000 among US infants of European ancestry [
• Positional talipes equinovarus [
• Normal puberty with no apparent evidence of premature ovarian insufficiency [
• Dilated cardiomyopathy that responded to standard treatment in one affected sib [
• Individuals who are homozygous for
• Individuals who have biallelic
• Type I galactosemia refers to
• Type II galactosemia refers to GALK deficiency;
• Type III galactosemia refers to GALE deficiency (epimerase deficiency galactosemia);
• Type IV galactosemia refers to GALM deficiency (galactose mutarotase deficiency) [
## Clinical Description
The clinical severity of epimerase deficiency galactosemia caused by reduced activity of the enzyme GALE [
Epimerase deficiency galactosemia can be divided by apparent enzyme activity level in specific cell types into the following three forms: generalized, peripheral, and intermediate (see
A key difference between generalized epimerase deficiency galactosemia and intermediate or peripheral epimerase deficiency galactosemia is that individuals with generalized epimerase deficiency galactosemia develop clinical findings on a normal milk diet, while infants with peripheral or intermediate epimerase deficiency galactosemia remain clinically well, at least in the neonatal period.
Generalized epimerase deficiency galactosemia is rare, with only nine individuals from five families described in the literature [
Generalized Epimerase Deficiency Galactosemia: Frequency of Select Features
Not all affected individuals were assessed for each feature listed.
See
Infants with generalized epimerase deficiency galactosemia who are on a diet containing galactose/lactose typically present with symptoms reminiscent of
Long-term outcome information for persons with generalized epimerase deficiency galactosemia is limited due to the small number of known affected individuals. Some have demonstrated long-term complications that became evident by early childhood (including sensorineural hearing impairment and physical and cognitive developmental delay and/or learning difficulties) while others have not. Confounding factors include the fact that a majority, but not all, of the individuals reported were born to known consanguineous parents, raising the concern that homozygosity for other autosomal recessive alleles – other than
Positional talipes equinovarus [
Normal puberty with no apparent evidence of premature ovarian insufficiency [
Dilated cardiomyopathy that responded to standard treatment in one affected sib [
Neonates with the peripheral form are usually asymptomatic even on a regular milk diet; these infants are only identified following biochemical detection of elevated total galactose on newborn screening.
Children with peripheral epimerase deficiency galactosemia appear to remain asymptomatic even if maintained on a normal milk diet.
Neonates with the intermediate form are also usually asymptomatic even on a regular milk diet and are only identified through newborn screening. The long-term outcome remains unclear. One affected individual, who was not treated with dietary restriction of galactose/lactose as an infant, experienced delays in both motor and cognitive development that became evident in early childhood [
• Positional talipes equinovarus [
• Normal puberty with no apparent evidence of premature ovarian insufficiency [
• Dilated cardiomyopathy that responded to standard treatment in one affected sib [
## Generalized Epimerase Deficiency Galactosemia
Generalized epimerase deficiency galactosemia is rare, with only nine individuals from five families described in the literature [
Generalized Epimerase Deficiency Galactosemia: Frequency of Select Features
Not all affected individuals were assessed for each feature listed.
See
Infants with generalized epimerase deficiency galactosemia who are on a diet containing galactose/lactose typically present with symptoms reminiscent of
Long-term outcome information for persons with generalized epimerase deficiency galactosemia is limited due to the small number of known affected individuals. Some have demonstrated long-term complications that became evident by early childhood (including sensorineural hearing impairment and physical and cognitive developmental delay and/or learning difficulties) while others have not. Confounding factors include the fact that a majority, but not all, of the individuals reported were born to known consanguineous parents, raising the concern that homozygosity for other autosomal recessive alleles – other than
Positional talipes equinovarus [
Normal puberty with no apparent evidence of premature ovarian insufficiency [
Dilated cardiomyopathy that responded to standard treatment in one affected sib [
• Positional talipes equinovarus [
• Normal puberty with no apparent evidence of premature ovarian insufficiency [
• Dilated cardiomyopathy that responded to standard treatment in one affected sib [
## Peripheral Epimerase Deficiency Galactosemia
Neonates with the peripheral form are usually asymptomatic even on a regular milk diet; these infants are only identified following biochemical detection of elevated total galactose on newborn screening.
Children with peripheral epimerase deficiency galactosemia appear to remain asymptomatic even if maintained on a normal milk diet.
## Intermediate Epimerase Deficiency Galactosemia
Neonates with the intermediate form are also usually asymptomatic even on a regular milk diet and are only identified through newborn screening. The long-term outcome remains unclear. One affected individual, who was not treated with dietary restriction of galactose/lactose as an infant, experienced delays in both motor and cognitive development that became evident in early childhood [
## Genotype-Phenotype Correlations
Because the numbers of individuals reported with molecularly confirmed epimerase deficiency galactosemia are currently limited, it is difficult to make strong genotype-phenotype correlations. However, some
Individuals who are homozygous for
Individuals who have biallelic
• Individuals who are homozygous for
• Individuals who have biallelic
## Nomenclature
Some authors refer to the different forms of galactosemia as type I, type II, type III, and type IV galactosemia, in which:
Type I galactosemia refers to
Type II galactosemia refers to GALK deficiency;
Type III galactosemia refers to GALE deficiency (epimerase deficiency galactosemia);
Type IV galactosemia refers to GALM deficiency (galactose mutarotase deficiency) [
• Type I galactosemia refers to
• Type II galactosemia refers to GALK deficiency;
• Type III galactosemia refers to GALE deficiency (epimerase deficiency galactosemia);
• Type IV galactosemia refers to GALM deficiency (galactose mutarotase deficiency) [
## Prevalence
True prevalence figures are unavailable at this time. Generalized epimerase deficiency galactosemia is very rare; however, epimerase deficiency galactosemia detected by newborn screening may be as frequent as about 1:6,700 among African American infants and about 1:70,000 among US infants of European ancestry [
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Note: Studies in a mouse model confirmed that the cataracts seen in GALK-deficiency, and presumably also in other forms of galactosemia, are caused by accumulation of the galactose metabolite, galactitol, in the lens. Galactitol is an impermeant alcohol which results in increased intracellular osmolality and swelling with loss of plasma membrane redox potential and consequent cell death.
Liver dysfunction / liver failure
Portosystemic venous shunting
Hepatic arteriovenous malformations
Fanconi-Bickel syndrome (OMIM
Congenital disorder of glycosylation type 1T (PGM1-CDG, see
• Liver dysfunction / liver failure
• Portosystemic venous shunting
• Hepatic arteriovenous malformations
• Fanconi-Bickel syndrome (OMIM
• Congenital disorder of glycosylation type 1T (PGM1-CDG, see
## Management
When epimerase deficiency galactosemia is suspected during the diagnostic evaluation (for example, if total galactose is elevated on newborn screening results), initiation of a galactose/lactose-restricted diet should begin immediately (see
To the authors' knowledge, no clinical practice guidelines for epimerase deficiency galactosemia have been published.
To establish the extent of disease and needs in an individual diagnosed with epimerase deficiency galactosemia that is not clearly peripheral, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Epimerase Deficiency Galactosemia
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures & clubfoot
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Incl for non-glucose reducing substances
Consider renal imaging, such as renal ultrasound, if renal abnormalities are suspected.
Community or
Social work involvement for parental support.
OT = occupational therapy; MOI= mode of inheritance; PT = physical therapy
To include serum AST, ALT, albumin, total protein, total and conjugated bilirubin, prothrombin time, and partial thromboplastin time
One affected person who died in the neonatal period was reported to have large kidneys with intratubular renal calcifications [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Generalized or Intermediate Epimerase Deficiency Galactosemia
Elemental formula (which is prescribed for infants w/classic galactosemia) should NOT be used.
The galactose intake needed for optimal outcome remains unknown.
Restriction of dietary galactose/lactose appears to correct or prevent the common acute signs and symptoms of the disorder: hepatic dysfunction, renal dysfunction, and mild cataracts. However, it may not correct tissue damage that occurred due to prolonged galactose exposure (e.g., hepatic cirrhosis or mature cataracts) (see
Elemental formula should not be prescribed for infants with generalized epimerase deficiency galactosemia because the GALE enzyme is required for the endogenous biosynthesis of UDP-galactose; that is, persons with epimerase deficiency galactosemia may require trace environmental sources of galactose.
Historically, some healthcare providers recommended that individuals with classic galactosemia also abstain from non-dairy foods that contain more than trace levels of galactose/lactose; however, most non-dairy foods have been deemed acceptable for individuals with classic galactosemia [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
The challenge in treating an asymptomatic newborn with epimerase deficiency galactosemia is that it may take months to obtain the results of tests used to distinguish peripheral epimerase deficiency galactosemia from intermediate epimerase deficiency galactosemia (see Establishing the Diagnosis,
In generalized epimerase deficiency galactosemia restriction of dietary galactose/lactose appears to correct or prevent the common acute signs and symptoms of the disorder: hepatic dysfunction, renal dysfunction, and mild cataracts. Presumably, as in classic galactosemia, dietary treatment would not correct profound tissue damage resulting from prolonged galactose exposure (e.g., hepatic cirrhosis or mature cataracts) or structural defects that likely originated in utero (e.g., cardiomyopathy).
In generalized epimerase deficiency galactosemia dietary restriction of galactose/lactose also prevents early feeding issues, vomiting, poor weight gain, hepatic dysfunction, and cataracts.
Recommended Surveillance for Individuals with Generalized or Intermediate Epimerase Deficiency Galactosemia
OT = occupational therapy; PT = physical therapy
Especially if the diet is to be normalized
Acceptable levels of gal-1P in GALE deficiency are not known but are estimated from experience with classic galactosemia to be <3.5 mg/100 mL in red blood cells.
Persons with generalized epimerase deficiency galactosemia should be on a galactose/lactose-restricted diet, certainly as infants and perhaps for life.
Persons with intermediate epimerase deficiency galactosemia may be placed on a galactose/lactose-restricted diet, either transiently or long term. Assessment of hemolysate gal-1P and/or urinary galactitol following a galactose challenge (e.g., 2 weeks on a normal diet) may help determine if an individual should remain on a galactose/lactose-restricted diet for longer periods of time.
If prenatal testing has not been performed (see
Molecular genetic testing if the pathogenic variants in the family are known
Measurement of GALE enzyme activity in red blood cells if the pathogenic variants in the family are not known
Note: If there are concerns about the reliability of the prenatal testing, soy-based formula may be given while the diagnostic testing is being performed.
See
Search
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures & clubfoot
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Incl for non-glucose reducing substances
• Consider renal imaging, such as renal ultrasound, if renal abnormalities are suspected.
• Community or
• Social work involvement for parental support.
• Elemental formula (which is prescribed for infants w/classic galactosemia) should NOT be used.
• The galactose intake needed for optimal outcome remains unknown.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Molecular genetic testing if the pathogenic variants in the family are known
• Measurement of GALE enzyme activity in red blood cells if the pathogenic variants in the family are not known
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with epimerase deficiency galactosemia that is not clearly peripheral, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Epimerase Deficiency Galactosemia
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures & clubfoot
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Incl for non-glucose reducing substances
Consider renal imaging, such as renal ultrasound, if renal abnormalities are suspected.
Community or
Social work involvement for parental support.
OT = occupational therapy; MOI= mode of inheritance; PT = physical therapy
To include serum AST, ALT, albumin, total protein, total and conjugated bilirubin, prothrombin time, and partial thromboplastin time
One affected person who died in the neonatal period was reported to have large kidneys with intratubular renal calcifications [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures & clubfoot
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Incl for non-glucose reducing substances
• Consider renal imaging, such as renal ultrasound, if renal abnormalities are suspected.
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Generalized or Intermediate Epimerase Deficiency Galactosemia
Elemental formula (which is prescribed for infants w/classic galactosemia) should NOT be used.
The galactose intake needed for optimal outcome remains unknown.
Restriction of dietary galactose/lactose appears to correct or prevent the common acute signs and symptoms of the disorder: hepatic dysfunction, renal dysfunction, and mild cataracts. However, it may not correct tissue damage that occurred due to prolonged galactose exposure (e.g., hepatic cirrhosis or mature cataracts) (see
Elemental formula should not be prescribed for infants with generalized epimerase deficiency galactosemia because the GALE enzyme is required for the endogenous biosynthesis of UDP-galactose; that is, persons with epimerase deficiency galactosemia may require trace environmental sources of galactose.
Historically, some healthcare providers recommended that individuals with classic galactosemia also abstain from non-dairy foods that contain more than trace levels of galactose/lactose; however, most non-dairy foods have been deemed acceptable for individuals with classic galactosemia [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Elemental formula (which is prescribed for infants w/classic galactosemia) should NOT be used.
• The galactose intake needed for optimal outcome remains unknown.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
## Prevention of Primary Manifestations
The challenge in treating an asymptomatic newborn with epimerase deficiency galactosemia is that it may take months to obtain the results of tests used to distinguish peripheral epimerase deficiency galactosemia from intermediate epimerase deficiency galactosemia (see Establishing the Diagnosis,
In generalized epimerase deficiency galactosemia restriction of dietary galactose/lactose appears to correct or prevent the common acute signs and symptoms of the disorder: hepatic dysfunction, renal dysfunction, and mild cataracts. Presumably, as in classic galactosemia, dietary treatment would not correct profound tissue damage resulting from prolonged galactose exposure (e.g., hepatic cirrhosis or mature cataracts) or structural defects that likely originated in utero (e.g., cardiomyopathy).
In generalized epimerase deficiency galactosemia dietary restriction of galactose/lactose also prevents early feeding issues, vomiting, poor weight gain, hepatic dysfunction, and cataracts.
## Surveillance
Recommended Surveillance for Individuals with Generalized or Intermediate Epimerase Deficiency Galactosemia
OT = occupational therapy; PT = physical therapy
Especially if the diet is to be normalized
Acceptable levels of gal-1P in GALE deficiency are not known but are estimated from experience with classic galactosemia to be <3.5 mg/100 mL in red blood cells.
## Agents/Circumstances to Avoid
Persons with generalized epimerase deficiency galactosemia should be on a galactose/lactose-restricted diet, certainly as infants and perhaps for life.
Persons with intermediate epimerase deficiency galactosemia may be placed on a galactose/lactose-restricted diet, either transiently or long term. Assessment of hemolysate gal-1P and/or urinary galactitol following a galactose challenge (e.g., 2 weeks on a normal diet) may help determine if an individual should remain on a galactose/lactose-restricted diet for longer periods of time.
## Evaluation of Relatives at Risk
If prenatal testing has not been performed (see
Molecular genetic testing if the pathogenic variants in the family are known
Measurement of GALE enzyme activity in red blood cells if the pathogenic variants in the family are not known
Note: If there are concerns about the reliability of the prenatal testing, soy-based formula may be given while the diagnostic testing is being performed.
See
• Molecular genetic testing if the pathogenic variants in the family are known
• Measurement of GALE enzyme activity in red blood cells if the pathogenic variants in the family are not known
## Therapies Under Investigation
Search
## Genetic Counseling
Epimerase deficiency galactosemia is inherited in an autosomal recessive manner.
The parents of an affected child are typically heterozygotes (i.e., carriers of a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy could not explain a proband who is compound heterozygous for two different pathogenic variants in
Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.
If both parents are known to be heterozygous for a
Data [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.
Note: Although biochemical testing to detect carriers is also a possibility, the ranges for control and carrier GALE enzyme activity overlap, thus making molecular genetic testing the preferred method for carrier detection.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at increased risk of being carriers.
Note: Theoretically, prenatal testing could be accomplished by enzymatic studies of amniocytes or CVS tissue; however, due to lack of a GALE reference range for the relevant sample type and appropriate controls, this testing is not typically offered on a clinical basis.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are typically heterozygotes (i.e., carriers of a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy could not explain a proband who is compound heterozygous for two different pathogenic variants in
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy could not explain a proband who is compound heterozygous for two different pathogenic variants in
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy could not explain a proband who is compound heterozygous for two different pathogenic variants in
• If both parents are known to be heterozygous for a
• Data [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at increased risk of being carriers.
## Mode of Inheritance
Epimerase deficiency galactosemia is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are typically heterozygotes (i.e., carriers of a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy could not explain a proband who is compound heterozygous for two different pathogenic variants in
Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.
If both parents are known to be heterozygous for a
Data [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.
• The parents of an affected child are typically heterozygotes (i.e., carriers of a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy could not explain a proband who is compound heterozygous for two different pathogenic variants in
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy could not explain a proband who is compound heterozygous for two different pathogenic variants in
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Uniparental isodisomy could not explain a proband who is compound heterozygous for two different pathogenic variants in
• If both parents are known to be heterozygous for a
• Data [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing symptoms of generalized epimerase deficiency galactosemia.
## Carrier Detection
Note: Although biochemical testing to detect carriers is also a possibility, the ranges for control and carrier GALE enzyme activity overlap, thus making molecular genetic testing the preferred method for carrier detection.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at increased risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at increased risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Theoretically, prenatal testing could be accomplished by enzymatic studies of amniocytes or CVS tissue; however, due to lack of a GALE reference range for the relevant sample type and appropriate controls, this testing is not typically offered on a clinical basis.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
TEMPLE (Tools Enabling Metabolic Parents LEarning)
United Kingdom
350 Northern Boulevard
Suite 324 - 1079
Albany NY 12204-1000
United Kingdom
Health Resources & Services Administration
•
• TEMPLE (Tools Enabling Metabolic Parents LEarning)
• United Kingdom
•
•
• 350 Northern Boulevard
• Suite 324 - 1079
• Albany NY 12204-1000
•
•
• United Kingdom
•
•
• Health Resources & Services Administration
•
## Molecular Genetics
Epimerase Deficiency Galactosemia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Epimerase Deficiency Galactosemia (
Galactose is metabolized in humans and other species by the three-enzyme Leloir pathway comprising the enzymes galactokinase (GALK, EC 2.7.1.6), galactose 1-P uridylyltransferase (GALT, EC 2.7.7.12), and UDP-galactose 4'-epimerase (GALE, EC 5.1.3.2). A fourth enzyme, galactose mutarotase (GALM, EC 5.1.3.3), catalyzes the epimerization of β-D-galactose, released from lactose, to α-D-galactose, which is a substrate for GALK. As illustrated in
As in
Persons with epimerase deficiency galactosemia who are exposed to galactose demonstrate abnormal accumulation of UDP-galactose (UDP-gal). However, because GALE is required in humans for the endogenous biosynthesis of UDP-gal and also UDP-N-acetylgalactosamine (UDP-galNAc), at least part of the pathophysiology of epimerase deficiency galactosemia may result from inadequate production of these compounds, especially in utero, ostensibly leading to deficient or aberrant production of glycoproteins and glycolipids including cerebrosides.
No individuals with complete loss of GALE enzyme activity in non-peripheral cells have been reported [
The c.280G>A (p.Val94Met) pathogenic variant, which is associated with a severe presentation, leaves approximately 5% residual enzyme activity with regard to UDP-gal metabolism and close to 25% residual enzyme activity with regard to UDP-galNAc metabolism [
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Galactose is metabolized in humans and other species by the three-enzyme Leloir pathway comprising the enzymes galactokinase (GALK, EC 2.7.1.6), galactose 1-P uridylyltransferase (GALT, EC 2.7.7.12), and UDP-galactose 4'-epimerase (GALE, EC 5.1.3.2). A fourth enzyme, galactose mutarotase (GALM, EC 5.1.3.3), catalyzes the epimerization of β-D-galactose, released from lactose, to α-D-galactose, which is a substrate for GALK. As illustrated in
As in
Persons with epimerase deficiency galactosemia who are exposed to galactose demonstrate abnormal accumulation of UDP-galactose (UDP-gal). However, because GALE is required in humans for the endogenous biosynthesis of UDP-gal and also UDP-N-acetylgalactosamine (UDP-galNAc), at least part of the pathophysiology of epimerase deficiency galactosemia may result from inadequate production of these compounds, especially in utero, ostensibly leading to deficient or aberrant production of glycoproteins and glycolipids including cerebrosides.
No individuals with complete loss of GALE enzyme activity in non-peripheral cells have been reported [
The c.280G>A (p.Val94Met) pathogenic variant, which is associated with a severe presentation, leaves approximately 5% residual enzyme activity with regard to UDP-gal metabolism and close to 25% residual enzyme activity with regard to UDP-galNAc metabolism [
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
The authors gratefully acknowledge the time and efforts of the many patients, families, health care professionals, and scientists who have brought our knowledge of epimerase deficiency galactosemia to its current state. JLFK also gratefully acknowledges funding from the National Institutes of Health and the Galactosemia Foundation.
4 March 2021 (ma) Comprehensive update posted live
16 June 2016 (ma) Comprehensive update posted live
24 October 2013 (me) Comprehensive update posted live
25 January 2011 (me) Review posted live
31 August 2010 (jfk) Original submission
• 4 March 2021 (ma) Comprehensive update posted live
• 16 June 2016 (ma) Comprehensive update posted live
• 24 October 2013 (me) Comprehensive update posted live
• 25 January 2011 (me) Review posted live
• 31 August 2010 (jfk) Original submission
## Acknowledgments
The authors gratefully acknowledge the time and efforts of the many patients, families, health care professionals, and scientists who have brought our knowledge of epimerase deficiency galactosemia to its current state. JLFK also gratefully acknowledges funding from the National Institutes of Health and the Galactosemia Foundation.
## Revision History
4 March 2021 (ma) Comprehensive update posted live
16 June 2016 (ma) Comprehensive update posted live
24 October 2013 (me) Comprehensive update posted live
25 January 2011 (me) Review posted live
31 August 2010 (jfk) Original submission
• 4 March 2021 (ma) Comprehensive update posted live
• 16 June 2016 (ma) Comprehensive update posted live
• 24 October 2013 (me) Comprehensive update posted live
• 25 January 2011 (me) Review posted live
• 31 August 2010 (jfk) Original submission
## References
## Literature Cited
Leloir pathway
|
[
"A Alano, S Almashanu, JM Chinsky, P Costeas, MG Blitzer, EA Wulfsberg, TM Cowan. Molecular characterization of a unique patient with epimerase-deficiency galactosaemia.. J Inherit Metab Dis. 1998;21:341-50",
"A Alano, S Almashanu, P Maceratesi, J Reichardt, S Panny, TM Cowan. UDP-galactose-4-epimerase deficiency among African-Americans: evidence for multiple alleles.. J Invest Med. 1997;45:191A",
"AM Brokate-Llanos, JM Monje, S Murdoch Pdel, MJ Muñoz. Developmental defects in a Caenorhabditis elegans model for type III galactosemia.. Genetics. 2014;198:1559-69",
"J Chen, GA Meyers, MJ Bennett. An interference-free two-step enzyme assay with UPLC-tandem mass spectrometric product measurement for the clinical diagnosis of uridine diphosphate galactose-4-epimerase deficiency.. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;959:5-9",
"JM Daenzer, RD Sanders, D Hang, JL Fridovich-Keil. UDP-galactose 4'-epimerase activities toward UDP-Gal and UDP-GalNAc play different roles in the development of Drosophila melanogaster.. PLoS Genet. 2012;8",
"F Dias Costa, S Ferdinandusse, C Pinto, A Dias, L Keldermans, D Quelhas, G Matthijs, PA Mooijer, L Diogo, J Jaeken, P Garcia. Galactose epimerase deficiency: expanding the phenotype.. JIMD Rep. 2017;37:19-25",
"LR Garibaldi, S Canini, A Superti-Furga, G Lamedica, M Filocamo, N Marchese, C Borrone. Galactosemia caused by generalized uridine diphosphate galactose-4-epimerase deficiency.. J Pediatr. 1983;103:927-30",
"R. Gitzelmann. Deficiency of uridine diphosphate galactose 4-epimerase in blood cells of an apparently healthy infant. Preliminary communication.. Helv Paediatr Acta. 1972;27:125-30",
"MJ Henderson, JB Holton, R MacFaul. Further observations in a case of uridine diphosphate galactose-4-epimerase deficiency with a severe clinical presentation.. J Inherit Metab Dis. 1983;6:17-20",
"JB Hennermann, P Schadewaldt, B Vetter, YS Shin, E Mönch, J Klein. Features and outcome of galactokinase deficiency in children diagnosed by newborn screening.. J Inherit Metab Dis. 2011;34:399-407",
"JB Holton, MG Gillett, R MacFaul, R Young. Galactosaemia: a new severe variant due to uridine diphosphate galactose-4-epimerase deficiency.. Arch Dis Child. 1981;56:885-7",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"S Iwasawa, A Kikuchi, Y Wada, N Arai-Ichinoi, O Sakamoto, G Tamiya, S. Kure. The prevalence of GALM mutations that cause galactosemia: A database of functionally evaluated variants.. Mol Genet Metab. 2019;126:362-7",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"HM Kalckar. Galactose metabolism and cell \"sociology\".. Science. 1965;150:305-13",
"KK Openo, JM Schulz, CA Vargas, CS Orton, MP Epstein, RE Schnur, F Scaglia, GT Berry, GS Gottesman, C Ficicioglu, AE Slonim, RJ Schroer, C Yu, VE Rangel, J Keenan, K Lamance, JL Fridovich-Keil. Epimerase-deficiency galactosemia is not a binary condition.. Am J Hum Genet. 2006;78:89-102",
"HD Park, KU Park, JQ Kim, CH Shin, SW Yang, DH Lee, YH Song, J Song. The molecular basis of UDP-galactose-4-epimerase (GALE) deficiency galactosemia in Korean patients.. Genet Med. 2005;7:646-9",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"ME Rubio-Gozalbo, B Derks, AM Das, U Meyer, D Möslinger, ML Couce, A Empain, C Ficicioglu, N Juliá Palacios, MM De Los Santos De Pelegrin, IA Rivera, S Scholl-Bürgi, AM Bosch, D Cassiman, D Demirbas, M Gautschi, I Knerr, P Labrune, A Skouma, P Verloo, SB Wortmann, EP Treacy, DJ Timson, GT Berry. Galactokinase deficiency: lessons from the GalNet registry.. Genet Med. 2021;23:202-10",
"RD Sanders, JM Sefton, KH Moberg, JL Fridovich-Keil. UDP-galactose 4' epimerase (GALE) is essential for development of Drosophila melanogaster.. Dis Model Mech. 2010;3:628-38",
"IB Sardharwalla, JE Wraith, C Bridge, B Fowler, SA Roberts. A patient with severe type of epimerase deficiency galactosaemia.. J Inherit Metab Dis. 1988;11:249-51",
"M Sarkar, SS Bose, G Mondal, S Chatterjee. Generalized epimerase deficiency galactosemia.. Indian J Pediatr. 2010;77:909-10",
"A Seo, S Gulsuner, S Pierce, M Ben-Harosh, H Shalev, T Walsh, T Krasnov, O Dgany, S Doulatov, H Tamary, A Shimamura, MC King. Inherited thrombocytopenia associated with mutation of UDP-galactose-4-epimerase (GALE).. Hum Mol Genet. 2019;28:133-42",
"LC Tegtmeyer, S Rust, M van Scherpenzeel, BG Ng, ME Losfeld, S Timal, K Raymond, P He, M Ichikawa, J Veltman, K Huijben, YS Shin, V Sharma, M Adamowicz, M Lammens, J Reunert, A Witten, E Schrapers, G Matthijs, J Jaeken, D Rymen, T Stojkovic, P Laforêt, F Petit, O Aumaître, E Czarnowska, M Piraud, T Podskarbi, CA Stanley, R Matalon, P Burda, S Seyyedi, V Debus, P Socha, J Sykut-Cegielska, F van Spronsen, L de Meirleir, P Vajro, T DeClue, C Ficicioglu, Y Wada, RA Wevers, D Vanderschaeghe, N Callewaert, R Fingerhut, E van Schaftingen, HH Freeze, E Morava, DJ Lefeber, T Marquardt. Multiple phenotypes in phosphoglucomutase 1 deficiency.. N Engl J Med. 2014;370:533-42",
"DJ Timson. Type IV galactosemia.. Genet Med. 2019;21:1283-5",
"SC Van Calcar, LE Bernstein, FJ Rohr, CH Scaman, S Yannicelli, GT Berry. A re-evaluation of life-long severe galactose restriction for the nutrition management of classic galactosemia.. Mol Genet Metab. 2014;112:191-7",
"Y Wada, A Kikuchi, N Arai-Ichinoi, O Sakamoto, Y Takezawa, S Iwasawa, T Niihori, H Nyuzuki, Y Nakajima, E Ogawa, M Ishige, H Hirai, H Sasai, R Fujiki, M Shirota, R Funayama, M Yamamoto, T Ito, O Ohara, K Nakayama, Y Aoki, S Koshiba, T Fukao, S. Kure. Biallelic GALM pathogenic variants cause a novel type of galactosemia.. Genet Med. 2019;21:1286-94",
"JH Walter, RE Roberts, GT Besley, JE Wraith, MA Cleary, JB Holton, R MacFaul. Generalised uridine diphosphate galactose-4-epimerase deficiency.. Arch Dis Child. 1999;80:374-6",
"TM Wohlers, NC Christacos, MT Harreman, JL Fridovich-Keil. Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia.. Am J Hum Genet. 1999;64:462-70",
"TM Wohlers, JL Fridovich-Keil. Studies of the V94M-substituted human UDPgalactose-4-epimerase enzyme associated with generalized epimerase-deficiency galactosaemia.. J Inherit Metab Dis. 2000;23:713-29"
] |
25/1/2011
|
4/3/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
gan
|
gan
|
[
"Gigaxonin",
"GAN",
"GAN-Related Neurodegeneration"
] |
Puneet Opal
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Early-onset peripheral motor and sensory neuropathy (in all individuals)
Variable findings typically observed in classic giant axonal neuropathy:
Infantile- to early childhood-onset CNS involvement that may include developmental delay / intellectual disability, cerebellar signs (ataxia, oculomotor involvement, nystagmus, dysarthria), and/or pyramidal tract signs (i.e., spasticity)
Kinky hair. Tightly curled lackluster hair that differs markedly from that of the parents. In individuals with milder phenotypes the hair tends to be mildly curly rather than frizzled or kinky [
Nerve conduction studies often show normal to moderately reduced nerve conduction velocity but severely reduced compound motor action potentials and absent sensory nerve action potentials.
Auditory brain stem evoked responses, visual evoked responses, and somatosensory evoked responses are often abnormal
Brain MRI and magnetic resonance spectroscopy (MRS) reveal evidence of significant demyelination and glial proliferation in the white matter, but no neuroaxonal loss [
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Early-onset peripheral motor and sensory neuropathy (in all individuals)
• Variable findings typically observed in classic giant axonal neuropathy:
• Infantile- to early childhood-onset CNS involvement that may include developmental delay / intellectual disability, cerebellar signs (ataxia, oculomotor involvement, nystagmus, dysarthria), and/or pyramidal tract signs (i.e., spasticity)
• Kinky hair. Tightly curled lackluster hair that differs markedly from that of the parents. In individuals with milder phenotypes the hair tends to be mildly curly rather than frizzled or kinky [
• Infantile- to early childhood-onset CNS involvement that may include developmental delay / intellectual disability, cerebellar signs (ataxia, oculomotor involvement, nystagmus, dysarthria), and/or pyramidal tract signs (i.e., spasticity)
• Kinky hair. Tightly curled lackluster hair that differs markedly from that of the parents. In individuals with milder phenotypes the hair tends to be mildly curly rather than frizzled or kinky [
• Infantile- to early childhood-onset CNS involvement that may include developmental delay / intellectual disability, cerebellar signs (ataxia, oculomotor involvement, nystagmus, dysarthria), and/or pyramidal tract signs (i.e., spasticity)
• Kinky hair. Tightly curled lackluster hair that differs markedly from that of the parents. In individuals with milder phenotypes the hair tends to be mildly curly rather than frizzled or kinky [
• Nerve conduction studies often show normal to moderately reduced nerve conduction velocity but severely reduced compound motor action potentials and absent sensory nerve action potentials.
• Auditory brain stem evoked responses, visual evoked responses, and somatosensory evoked responses are often abnormal
• Brain MRI and magnetic resonance spectroscopy (MRS) reveal evidence of significant demyelination and glial proliferation in the white matter, but no neuroaxonal loss [
## Suggestive Findings
Early-onset peripheral motor and sensory neuropathy (in all individuals)
Variable findings typically observed in classic giant axonal neuropathy:
Infantile- to early childhood-onset CNS involvement that may include developmental delay / intellectual disability, cerebellar signs (ataxia, oculomotor involvement, nystagmus, dysarthria), and/or pyramidal tract signs (i.e., spasticity)
Kinky hair. Tightly curled lackluster hair that differs markedly from that of the parents. In individuals with milder phenotypes the hair tends to be mildly curly rather than frizzled or kinky [
Nerve conduction studies often show normal to moderately reduced nerve conduction velocity but severely reduced compound motor action potentials and absent sensory nerve action potentials.
Auditory brain stem evoked responses, visual evoked responses, and somatosensory evoked responses are often abnormal
Brain MRI and magnetic resonance spectroscopy (MRS) reveal evidence of significant demyelination and glial proliferation in the white matter, but no neuroaxonal loss [
• Early-onset peripheral motor and sensory neuropathy (in all individuals)
• Variable findings typically observed in classic giant axonal neuropathy:
• Infantile- to early childhood-onset CNS involvement that may include developmental delay / intellectual disability, cerebellar signs (ataxia, oculomotor involvement, nystagmus, dysarthria), and/or pyramidal tract signs (i.e., spasticity)
• Kinky hair. Tightly curled lackluster hair that differs markedly from that of the parents. In individuals with milder phenotypes the hair tends to be mildly curly rather than frizzled or kinky [
• Infantile- to early childhood-onset CNS involvement that may include developmental delay / intellectual disability, cerebellar signs (ataxia, oculomotor involvement, nystagmus, dysarthria), and/or pyramidal tract signs (i.e., spasticity)
• Kinky hair. Tightly curled lackluster hair that differs markedly from that of the parents. In individuals with milder phenotypes the hair tends to be mildly curly rather than frizzled or kinky [
• Infantile- to early childhood-onset CNS involvement that may include developmental delay / intellectual disability, cerebellar signs (ataxia, oculomotor involvement, nystagmus, dysarthria), and/or pyramidal tract signs (i.e., spasticity)
• Kinky hair. Tightly curled lackluster hair that differs markedly from that of the parents. In individuals with milder phenotypes the hair tends to be mildly curly rather than frizzled or kinky [
• Nerve conduction studies often show normal to moderately reduced nerve conduction velocity but severely reduced compound motor action potentials and absent sensory nerve action potentials.
• Auditory brain stem evoked responses, visual evoked responses, and somatosensory evoked responses are often abnormal
• Brain MRI and magnetic resonance spectroscopy (MRS) reveal evidence of significant demyelination and glial proliferation in the white matter, but no neuroaxonal loss [
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
To date, approximately 50 families have been identified with biallelic
Select Features of Severe
+++ = always present; ++ = often present; + = rare
The motor and sensory peripheral neuropathy may also involve the cranial nerves, resulting in facial weakness, optic atrophy, and ophthalmoplegia. Tendon reflexes are often absent; Babinski sign may be present as a result of CNS involvement.
The majority of affected individuals show signs of CNS involvement including intellectual disability, cerebellar signs (ataxia, nystagmus, and dysarthria), epileptic seizures, and pyramidal tract signs (i.e., spasticity). Early intellectual development is nearly normal in many affected children, enabling them to attend a normal school initially; however, significant intellectual impairment usually occurs before the second decade of life.
Most affected individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. In those with the most severe manifestations, death usually occurs in the third decade, typically the result of secondary complications such as respiratory failure.
Milder phenotypes have been reported with later age of onset, extended survival, or modest CNS deterioration with pathology reminiscent of Charcot-Marie-Tooth axonal disorders, sometimes referred to as axonal CMT (plus) syndrome [
No clinically relevant genotype-phenotype correlations have been reported for
The term "axonal CMT (plus) syndrome" may be used to refer to predominantly motor and sensory neuropathy phenotypes (with little to no CNS involvement) that overlap with axonal forms of
To date, about 50 families with
## Clinical Description
To date, approximately 50 families have been identified with biallelic
Select Features of Severe
+++ = always present; ++ = often present; + = rare
The motor and sensory peripheral neuropathy may also involve the cranial nerves, resulting in facial weakness, optic atrophy, and ophthalmoplegia. Tendon reflexes are often absent; Babinski sign may be present as a result of CNS involvement.
The majority of affected individuals show signs of CNS involvement including intellectual disability, cerebellar signs (ataxia, nystagmus, and dysarthria), epileptic seizures, and pyramidal tract signs (i.e., spasticity). Early intellectual development is nearly normal in many affected children, enabling them to attend a normal school initially; however, significant intellectual impairment usually occurs before the second decade of life.
Most affected individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. In those with the most severe manifestations, death usually occurs in the third decade, typically the result of secondary complications such as respiratory failure.
Milder phenotypes have been reported with later age of onset, extended survival, or modest CNS deterioration with pathology reminiscent of Charcot-Marie-Tooth axonal disorders, sometimes referred to as axonal CMT (plus) syndrome [
## Classic Giant Axonal Neuropathy
The motor and sensory peripheral neuropathy may also involve the cranial nerves, resulting in facial weakness, optic atrophy, and ophthalmoplegia. Tendon reflexes are often absent; Babinski sign may be present as a result of CNS involvement.
The majority of affected individuals show signs of CNS involvement including intellectual disability, cerebellar signs (ataxia, nystagmus, and dysarthria), epileptic seizures, and pyramidal tract signs (i.e., spasticity). Early intellectual development is nearly normal in many affected children, enabling them to attend a normal school initially; however, significant intellectual impairment usually occurs before the second decade of life.
Most affected individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. In those with the most severe manifestations, death usually occurs in the third decade, typically the result of secondary complications such as respiratory failure.
## Milder
Milder phenotypes have been reported with later age of onset, extended survival, or modest CNS deterioration with pathology reminiscent of Charcot-Marie-Tooth axonal disorders, sometimes referred to as axonal CMT (plus) syndrome [
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been reported for
## Nomenclature
The term "axonal CMT (plus) syndrome" may be used to refer to predominantly motor and sensory neuropathy phenotypes (with little to no CNS involvement) that overlap with axonal forms of
## Prevalence
To date, about 50 families with
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
At onset, classic giant axonal neuropathy (GAN) presents with features (e.g., neuropathic deficits, giant axons, and neurofilament aggregation) similar to those associated with several severe, early-onset hereditary motor and sensory neuropathies [
Genes of Interest in the Differential Diagnosis of Classic Giant Axonal Neuropathy
Late-infantile metachromatic leukodystrophy (MLD) (See
Classic Menkes disease (See
Severe early-onset HMSN
Severe early-onset HMSN
AD = autosomal dominant; AR = autosomal recessive; CMT = Charcot-Marie-Tooth (neuropathy); CNS = central nervous system; DiffDx = differential diagnosis; GAN = giant axonal neuropathy; HMSN = hereditary motor and sensory neuropathy; MOI = mode of inheritance; PNS = peripheral nervous system; XL = X-linked
Arylsulfatase A deficiency is a disorder of impaired breakdown of sulfatides that occur throughout the body but are found in greatest abundance in nervous tissue, kidneys, and testes.
In the past the term Dejerine-Sottas syndrome was used to designate severe childhood-onset genetic neuropathies of any inheritance; the term is no longer in general use.
Milder
## Hereditary Disorders in the Differential Diagnosis of Classic Giant Axonal Neuropathy
At onset, classic giant axonal neuropathy (GAN) presents with features (e.g., neuropathic deficits, giant axons, and neurofilament aggregation) similar to those associated with several severe, early-onset hereditary motor and sensory neuropathies [
Genes of Interest in the Differential Diagnosis of Classic Giant Axonal Neuropathy
Late-infantile metachromatic leukodystrophy (MLD) (See
Classic Menkes disease (See
Severe early-onset HMSN
Severe early-onset HMSN
AD = autosomal dominant; AR = autosomal recessive; CMT = Charcot-Marie-Tooth (neuropathy); CNS = central nervous system; DiffDx = differential diagnosis; GAN = giant axonal neuropathy; HMSN = hereditary motor and sensory neuropathy; MOI = mode of inheritance; PNS = peripheral nervous system; XL = X-linked
Arylsulfatase A deficiency is a disorder of impaired breakdown of sulfatides that occur throughout the body but are found in greatest abundance in nervous tissue, kidneys, and testes.
In the past the term Dejerine-Sottas syndrome was used to designate severe childhood-onset genetic neuropathies of any inheritance; the term is no longer in general use.
## Differential Diagnosis of Milder
Milder
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Assessment to incl cranial nerve dysfunction (See
Consider motor & sensory NCV to document a sensorimotor axonal pattern of neuropathy.
Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
To incl assessment of:
Gross motor & fine motor skills
Mobility, ADL & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To assess:
Extraocular movement (re cranial nerve involvement & strabismus)
For evidence of optic atrophy: best corrected visual acuity, color vision, visual fields, visual evoked potentials, OCT, fundus exam
Need for visual aids
Nystagmus (caused by cerebellar dysfunction)
Strabismus (caused by involvement of cranial nerves III, IV &/or VI)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; ID = intellectual disability; LMN = lower motor neuron; MOI = mode of inheritance; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron
SARA = Scale for the Assessment and Rating of Ataxia; ICARS = International Co-operative Ataxia Rating Scale; BARS = Brief Ataxia Rating Scale
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Supportive care is focused on managing the clinical findings of the individual, and often involves a team including (pediatric) neurologists, orthopedic surgeons, physiotherapists, occupational and physical therapists, psychologists, and speech-language pathologists. Major goals are to optimize intellectual and physical development.
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs), feeding (e.g., weighted eating utensils), dressing (e.g., dressing hooks).
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Surgery as required for foot deformities in those who are ambulatory
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Consider alternative communication methods as needed (e.g., writing pads & digital devices).
Evaluate for visual aids.
Community vision services through Early Intervention or School District
ADL = activities of daily living; ASM = anti-seizure medication; FTT = failure to thrive; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Surveillance is individualized and involves monitoring response to ongoing interventions and identifying new manifestations. Surveillance may involve some or all of the recommendations in
Recommended Surveillance at Each Visit for Individuals with
Monitor those w/seizures as clinically indicated.
Assess progression of peripheral neuropathy, ataxia, spasticity, & cranial nerve dysfunction.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
Evaluate effectiveness of low-vision aids.
OT = occupational therapist; PT = physical therapist
Frequent reassessment is needed because of the progressive nature of the disorder. Special education often becomes necessary between ages five and 12 years.
See
Search
• Assessment to incl cranial nerve dysfunction (See
• Consider motor & sensory NCV to document a sensorimotor axonal pattern of neuropathy.
• Gross motor & fine motor skills
• Mobility, ADL & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Extraocular movement (re cranial nerve involvement & strabismus)
• For evidence of optic atrophy: best corrected visual acuity, color vision, visual fields, visual evoked potentials, OCT, fundus exam
• Need for visual aids
• Nystagmus (caused by cerebellar dysfunction)
• Strabismus (caused by involvement of cranial nerves III, IV &/or VI)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs), feeding (e.g., weighted eating utensils), dressing (e.g., dressing hooks).
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Evaluate for visual aids.
• Community vision services through Early Intervention or School District
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Monitor those w/seizures as clinically indicated.
• Assess progression of peripheral neuropathy, ataxia, spasticity, & cranial nerve dysfunction.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
• Evaluate effectiveness of low-vision aids.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Assessment to incl cranial nerve dysfunction (See
Consider motor & sensory NCV to document a sensorimotor axonal pattern of neuropathy.
Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
To incl assessment of:
Gross motor & fine motor skills
Mobility, ADL & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To assess:
Extraocular movement (re cranial nerve involvement & strabismus)
For evidence of optic atrophy: best corrected visual acuity, color vision, visual fields, visual evoked potentials, OCT, fundus exam
Need for visual aids
Nystagmus (caused by cerebellar dysfunction)
Strabismus (caused by involvement of cranial nerves III, IV &/or VI)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; ID = intellectual disability; LMN = lower motor neuron; MOI = mode of inheritance; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron
SARA = Scale for the Assessment and Rating of Ataxia; ICARS = International Co-operative Ataxia Rating Scale; BARS = Brief Ataxia Rating Scale
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Assessment to incl cranial nerve dysfunction (See
• Consider motor & sensory NCV to document a sensorimotor axonal pattern of neuropathy.
• Gross motor & fine motor skills
• Mobility, ADL & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Extraocular movement (re cranial nerve involvement & strabismus)
• For evidence of optic atrophy: best corrected visual acuity, color vision, visual fields, visual evoked potentials, OCT, fundus exam
• Need for visual aids
• Nystagmus (caused by cerebellar dysfunction)
• Strabismus (caused by involvement of cranial nerves III, IV &/or VI)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Supportive care is focused on managing the clinical findings of the individual, and often involves a team including (pediatric) neurologists, orthopedic surgeons, physiotherapists, occupational and physical therapists, psychologists, and speech-language pathologists. Major goals are to optimize intellectual and physical development.
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs), feeding (e.g., weighted eating utensils), dressing (e.g., dressing hooks).
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Surgery as required for foot deformities in those who are ambulatory
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Consider alternative communication methods as needed (e.g., writing pads & digital devices).
Evaluate for visual aids.
Community vision services through Early Intervention or School District
ADL = activities of daily living; ASM = anti-seizure medication; FTT = failure to thrive; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs), feeding (e.g., weighted eating utensils), dressing (e.g., dressing hooks).
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Evaluate for visual aids.
• Community vision services through Early Intervention or School District
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• When relevant, vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
Surveillance is individualized and involves monitoring response to ongoing interventions and identifying new manifestations. Surveillance may involve some or all of the recommendations in
Recommended Surveillance at Each Visit for Individuals with
Monitor those w/seizures as clinically indicated.
Assess progression of peripheral neuropathy, ataxia, spasticity, & cranial nerve dysfunction.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
Evaluate effectiveness of low-vision aids.
OT = occupational therapist; PT = physical therapist
Frequent reassessment is needed because of the progressive nature of the disorder. Special education often becomes necessary between ages five and 12 years.
• Monitor those w/seizures as clinically indicated.
• Assess progression of peripheral neuropathy, ataxia, spasticity, & cranial nerve dysfunction.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
• Evaluate effectiveness of low-vision aids.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected individual are typically heterozygotes (i.e., carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
And the child has compound heterozygous
And the child appears to have homozygous
Heterozygotes are clinically asymptomatic but can display mild axonal neuropathy, as revealed by moderate reduction of nerve action potential amplitudes [
If both parents are known to be heterozygous for a
Significant intrafamilial clinical variability has been reported in
If the proband has
Individuals with classic giant axonal neuropathy are not known to reproduce.
The offspring of an individual with a milder
Carrier testing for at-risk relatives requires prior identification of the
Note: Some clinically asymptomatic heterozygotes can show mild axonal neuropathy, as revealed by moderate reduction of nerve action potential amplitudes [
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are typically heterozygotes (i.e., carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• Heterozygotes are clinically asymptomatic but can display mild axonal neuropathy, as revealed by moderate reduction of nerve action potential amplitudes [
• And the child has compound heterozygous
• And the child appears to have homozygous
• If both parents are known to be heterozygous for a
• Significant intrafamilial clinical variability has been reported in
• If the proband has
• Individuals with classic giant axonal neuropathy are not known to reproduce.
• The offspring of an individual with a milder
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected individual are typically heterozygotes (i.e., carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
And the child has compound heterozygous
And the child appears to have homozygous
Heterozygotes are clinically asymptomatic but can display mild axonal neuropathy, as revealed by moderate reduction of nerve action potential amplitudes [
If both parents are known to be heterozygous for a
Significant intrafamilial clinical variability has been reported in
If the proband has
Individuals with classic giant axonal neuropathy are not known to reproduce.
The offspring of an individual with a milder
• The parents of an affected individual are typically heterozygotes (i.e., carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• Heterozygotes are clinically asymptomatic but can display mild axonal neuropathy, as revealed by moderate reduction of nerve action potential amplitudes [
• And the child has compound heterozygous
• And the child appears to have homozygous
• If both parents are known to be heterozygous for a
• Significant intrafamilial clinical variability has been reported in
• If the proband has
• Individuals with classic giant axonal neuropathy are not known to reproduce.
• The offspring of an individual with a milder
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
Note: Some clinically asymptomatic heterozygotes can show mild axonal neuropathy, as revealed by moderate reduction of nerve action potential amplitudes [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
19 Blue Jay Way
Rexford NY 12148
France
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• 19 Blue Jay Way
• Rexford NY 12148
•
•
•
•
• France
•
•
•
•
•
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•
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## Molecular Genetics
GAN-Related Neurodegeneration: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GAN-Related Neurodegeneration (
## Molecular Pathogenesis
## Chapter Notes
An overview of current work in the lab and contact information can be found on our
We acknowledge the generous funding from the Hannah’s Hope Fund, the Muscular Dystrophy Association, and the NIH, which supports our ongoing research and understanding of
Pascale Bomont, PhD; Institute for Neurosciences of Montpellier (2012-2021)Gregor Kuhlenbäumer, MD, PhD; University of Kiel (2003-2021)Puneet Opal, MD, PhD (2021-present)Vincent Timmerman, PhD; University of Antwerp (2003-2021)
14 October 2021 (bp) Comprehensive update posted live
9 October 2014 (me) Comprehensive update posted live
21 June 2012 (me) Comprehensive update posted live
2 July 2007 (me) Comprehensive update posted live
28 February 2005 (me) Comprehensive update posted live
9 January 2003 (me) Review posted live
5 August 2002 (vt) Original submission
• 14 October 2021 (bp) Comprehensive update posted live
• 9 October 2014 (me) Comprehensive update posted live
• 21 June 2012 (me) Comprehensive update posted live
• 2 July 2007 (me) Comprehensive update posted live
• 28 February 2005 (me) Comprehensive update posted live
• 9 January 2003 (me) Review posted live
• 5 August 2002 (vt) Original submission
## Author Notes
An overview of current work in the lab and contact information can be found on our
## Acknowledgments
We acknowledge the generous funding from the Hannah’s Hope Fund, the Muscular Dystrophy Association, and the NIH, which supports our ongoing research and understanding of
## Author History
Pascale Bomont, PhD; Institute for Neurosciences of Montpellier (2012-2021)Gregor Kuhlenbäumer, MD, PhD; University of Kiel (2003-2021)Puneet Opal, MD, PhD (2021-present)Vincent Timmerman, PhD; University of Antwerp (2003-2021)
## Revision History
14 October 2021 (bp) Comprehensive update posted live
9 October 2014 (me) Comprehensive update posted live
21 June 2012 (me) Comprehensive update posted live
2 July 2007 (me) Comprehensive update posted live
28 February 2005 (me) Comprehensive update posted live
9 January 2003 (me) Review posted live
5 August 2002 (vt) Original submission
• 14 October 2021 (bp) Comprehensive update posted live
• 9 October 2014 (me) Comprehensive update posted live
• 21 June 2012 (me) Comprehensive update posted live
• 2 July 2007 (me) Comprehensive update posted live
• 28 February 2005 (me) Comprehensive update posted live
• 9 January 2003 (me) Review posted live
• 5 August 2002 (vt) Original submission
## References
## Literature Cited
|
[] |
9/1/2003
|
14/10/2021
|
11/8/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
gata1
|
gata1
|
[
"Erythroid transcription factor",
"GATA1",
"GATA1-Related Cytopenia"
] |
Kaoru Takasaki, Melissa A Kacena, Wendy H Raskind, Mitchell J Weiss, Stella T Chou
|
Summary The diagnosis of
|
## Diagnosis
Excessive bruising
Mucosal bleeding (e.g., gingival bleeding, epistaxis)
Petechiae
Hydrops fetalis in some infants
Complete blood count. Thrombocytopenia and/or mild-to-severe anemia; rarely neutropenia
Peripheral blood smear examination. Platelets may be larger and more spherical; variation in erythrocyte size and shape
Bone marrow aspirate and biopsy
Hyper- or hypocellularity
Evidence of ineffective hematopoiesis
Increased or decreased numbers of megakaryocytes
Small, dysplastic megakaryocytes with signs of incomplete maturation
Dyserythropoiesis
Hypocellularity of granulocytic lineages
Mild-to-moderate reticulin fibrosis [
Platelet aggregation studies. Normal to abnormal platelet aggregation in response to agonists (e.g., ristocetin, adenosine diphosphate, epinephrine, collagen) in some individuals [
Electron microscopy. Reduced number of platelet alpha granules in some individuals [
Note: (1) Hematologic findings in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by cytopenia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.
• Excessive bruising
• Mucosal bleeding (e.g., gingival bleeding, epistaxis)
• Petechiae
• Hydrops fetalis in some infants
• Complete blood count. Thrombocytopenia and/or mild-to-severe anemia; rarely neutropenia
• Peripheral blood smear examination. Platelets may be larger and more spherical; variation in erythrocyte size and shape
• Bone marrow aspirate and biopsy
• Hyper- or hypocellularity
• Evidence of ineffective hematopoiesis
• Increased or decreased numbers of megakaryocytes
• Small, dysplastic megakaryocytes with signs of incomplete maturation
• Dyserythropoiesis
• Hypocellularity of granulocytic lineages
• Mild-to-moderate reticulin fibrosis [
• Hyper- or hypocellularity
• Evidence of ineffective hematopoiesis
• Increased or decreased numbers of megakaryocytes
• Small, dysplastic megakaryocytes with signs of incomplete maturation
• Dyserythropoiesis
• Hypocellularity of granulocytic lineages
• Mild-to-moderate reticulin fibrosis [
• Platelet aggregation studies. Normal to abnormal platelet aggregation in response to agonists (e.g., ristocetin, adenosine diphosphate, epinephrine, collagen) in some individuals [
• Electron microscopy. Reduced number of platelet alpha granules in some individuals [
• Hyper- or hypocellularity
• Evidence of ineffective hematopoiesis
• Increased or decreased numbers of megakaryocytes
• Small, dysplastic megakaryocytes with signs of incomplete maturation
• Dyserythropoiesis
• Hypocellularity of granulocytic lineages
• Mild-to-moderate reticulin fibrosis [
## Suggestive Findings
Excessive bruising
Mucosal bleeding (e.g., gingival bleeding, epistaxis)
Petechiae
Hydrops fetalis in some infants
Complete blood count. Thrombocytopenia and/or mild-to-severe anemia; rarely neutropenia
Peripheral blood smear examination. Platelets may be larger and more spherical; variation in erythrocyte size and shape
Bone marrow aspirate and biopsy
Hyper- or hypocellularity
Evidence of ineffective hematopoiesis
Increased or decreased numbers of megakaryocytes
Small, dysplastic megakaryocytes with signs of incomplete maturation
Dyserythropoiesis
Hypocellularity of granulocytic lineages
Mild-to-moderate reticulin fibrosis [
Platelet aggregation studies. Normal to abnormal platelet aggregation in response to agonists (e.g., ristocetin, adenosine diphosphate, epinephrine, collagen) in some individuals [
Electron microscopy. Reduced number of platelet alpha granules in some individuals [
Note: (1) Hematologic findings in
• Excessive bruising
• Mucosal bleeding (e.g., gingival bleeding, epistaxis)
• Petechiae
• Hydrops fetalis in some infants
• Complete blood count. Thrombocytopenia and/or mild-to-severe anemia; rarely neutropenia
• Peripheral blood smear examination. Platelets may be larger and more spherical; variation in erythrocyte size and shape
• Bone marrow aspirate and biopsy
• Hyper- or hypocellularity
• Evidence of ineffective hematopoiesis
• Increased or decreased numbers of megakaryocytes
• Small, dysplastic megakaryocytes with signs of incomplete maturation
• Dyserythropoiesis
• Hypocellularity of granulocytic lineages
• Mild-to-moderate reticulin fibrosis [
• Hyper- or hypocellularity
• Evidence of ineffective hematopoiesis
• Increased or decreased numbers of megakaryocytes
• Small, dysplastic megakaryocytes with signs of incomplete maturation
• Dyserythropoiesis
• Hypocellularity of granulocytic lineages
• Mild-to-moderate reticulin fibrosis [
• Platelet aggregation studies. Normal to abnormal platelet aggregation in response to agonists (e.g., ristocetin, adenosine diphosphate, epinephrine, collagen) in some individuals [
• Electron microscopy. Reduced number of platelet alpha granules in some individuals [
• Hyper- or hypocellularity
• Evidence of ineffective hematopoiesis
• Increased or decreased numbers of megakaryocytes
• Small, dysplastic megakaryocytes with signs of incomplete maturation
• Dyserythropoiesis
• Hypocellularity of granulocytic lineages
• Mild-to-moderate reticulin fibrosis [
## Establishing the Diagnosis
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by cytopenia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.
## Option 1
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by cytopenia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.
## Clinical Characteristics
Individuals with
Platelet counts are usually low (10-100 x 10
The severity of anemia ranges from mild dyserythropoiesis to severe hydrops fetalis requiring in utero transfusions [
Rarely,
At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are lifelong. However, improvement in anemia with age, despite a severe presentation in utero and/or early infancy, has also been reported [
At the milder end, the risk for bleeding may spontaneously decrease with age, despite continued thrombocytopenia [
Some affected individuals are recognized through incidental findings of mild-to-moderate cytopenia on routine blood count analysis. These individuals have a good prognosis.
Females may have menorrhagia or easy bruising [
To date, only limited genotype-phenotype correlations have been identified. However, the authors have compiled a comprehensive table of
Until pathogenic variants in
"Familial dyserythropoietic anemia and thrombocytopenia" [
"X-linked macrothrombocytopenia" [
"X-linked anemia with or without neutropenia and/or platelet abnormality" (XLANP) [
The diagnosis of "
• At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are lifelong. However, improvement in anemia with age, despite a severe presentation in utero and/or early infancy, has also been reported [
• At the milder end, the risk for bleeding may spontaneously decrease with age, despite continued thrombocytopenia [
• Some affected individuals are recognized through incidental findings of mild-to-moderate cytopenia on routine blood count analysis. These individuals have a good prognosis.
• "Familial dyserythropoietic anemia and thrombocytopenia" [
• "X-linked macrothrombocytopenia" [
• "X-linked anemia with or without neutropenia and/or platelet abnormality" (XLANP) [
## Clinical Description
Individuals with
Platelet counts are usually low (10-100 x 10
The severity of anemia ranges from mild dyserythropoiesis to severe hydrops fetalis requiring in utero transfusions [
Rarely,
At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are lifelong. However, improvement in anemia with age, despite a severe presentation in utero and/or early infancy, has also been reported [
At the milder end, the risk for bleeding may spontaneously decrease with age, despite continued thrombocytopenia [
Some affected individuals are recognized through incidental findings of mild-to-moderate cytopenia on routine blood count analysis. These individuals have a good prognosis.
Females may have menorrhagia or easy bruising [
• At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are lifelong. However, improvement in anemia with age, despite a severe presentation in utero and/or early infancy, has also been reported [
• At the milder end, the risk for bleeding may spontaneously decrease with age, despite continued thrombocytopenia [
• Some affected individuals are recognized through incidental findings of mild-to-moderate cytopenia on routine blood count analysis. These individuals have a good prognosis.
## Affected Males
Platelet counts are usually low (10-100 x 10
The severity of anemia ranges from mild dyserythropoiesis to severe hydrops fetalis requiring in utero transfusions [
Rarely,
At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are lifelong. However, improvement in anemia with age, despite a severe presentation in utero and/or early infancy, has also been reported [
At the milder end, the risk for bleeding may spontaneously decrease with age, despite continued thrombocytopenia [
Some affected individuals are recognized through incidental findings of mild-to-moderate cytopenia on routine blood count analysis. These individuals have a good prognosis.
• At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are lifelong. However, improvement in anemia with age, despite a severe presentation in utero and/or early infancy, has also been reported [
• At the milder end, the risk for bleeding may spontaneously decrease with age, despite continued thrombocytopenia [
• Some affected individuals are recognized through incidental findings of mild-to-moderate cytopenia on routine blood count analysis. These individuals have a good prognosis.
## Heterozygous Females
Females may have menorrhagia or easy bruising [
## Genotype-Phenotype Correlations
To date, only limited genotype-phenotype correlations have been identified. However, the authors have compiled a comprehensive table of
## Nomenclature
Until pathogenic variants in
"Familial dyserythropoietic anemia and thrombocytopenia" [
"X-linked macrothrombocytopenia" [
"X-linked anemia with or without neutropenia and/or platelet abnormality" (XLANP) [
The diagnosis of "
• "Familial dyserythropoietic anemia and thrombocytopenia" [
• "X-linked macrothrombocytopenia" [
• "X-linked anemia with or without neutropenia and/or platelet abnormality" (XLANP) [
## Prevalence
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Of note:
Numerous congenital thrombocytopenias may be considered in the differential diagnosis [
Thrombocytopenia may be the initial manifestation of bone marrow failure in individuals with a telomere biology disorder (e.g.,
Cryptorchidism and/or hypospadias may suggest the involvement of
Congenital causes of anemia that could potentially be confused with
Selected Genes of Interest in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
One person with gray platelet syndrome (GPS) had a
GPS can be inherited in an autosomal recessive manner (
Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner (
Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in
Approximately 40%-45% of individuals with autosomal dominant Diamond-Blackfan anemia (DBA) inherited the pathogenic variant from a parent; approximately 55%-60% have a
DBA is most often inherited in an autosomal dominant manner;
Paris-Trousseau thrombocytopenia (OMIM
• Numerous congenital thrombocytopenias may be considered in the differential diagnosis [
• Thrombocytopenia may be the initial manifestation of bone marrow failure in individuals with a telomere biology disorder (e.g.,
• Cryptorchidism and/or hypospadias may suggest the involvement of
• Congenital causes of anemia that could potentially be confused with
• Paris-Trousseau thrombocytopenia (OMIM
## Management
To establish the extent of disease and needs in an individual diagnosed with
Complete blood count (CBC) and examination of the peripheral blood smear to assess the degree of cytopenia(s) and morphologic abnormalities
Detailed history of the disease course, including the age at which hematologic disease was detected and the associated symptoms
Documentation of abnormal/unexpected bleeding episodes and platelet counts obtained at the time of the episodes to help determine whether platelet function is abnormal and whether disease severity has changed over time
Note: Platelet aggregation studies may identify functional abnormalities that predict a greater risk of bleeding for any given platelet count, but studies can be difficult to interpret when platelet counts are lower than 100,000/μL.
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of
For those with severe disease, hematopoietic stem cell transplant (HSCT) can be curative [
HSCT should be considered in individuals with severe
While HSCT may offer a cure, clinical experience with HSCT treatment in those with
Supportive care to improve quality of life, maximize function, and reduce complications is recommended.
Individuals with moderate-to-severe epistaxis, severe gingival bleeding, or other clinically significant bleeding should receive platelet transfusions. Transfusion requirements vary, as bleeding can be related to quantitative and/or qualitative platelet defects.
For individuals with thrombocytopenia and/or platelet aggregation defects, DDAVP
Platelet transfusion prior to surgical or invasive dental procedures is recommended for individuals with a history of pathologic bleeding, thrombocytopenia, and/or platelet dysfunction.
Individuals who are only mildly symptomatic (easy bruisability without mucosal or more severe bleeding) do not require specific treatment.
There is no evidence that splenectomy is beneficial in people with
Red blood cell transfusions for clinical manifestations of anemia (e.g., fatigue, tachycardia)
Iron chelation therapy may be needed in those with iron overload secondary to chronic red blood cell transfusion therapy.
Extended pre-transfusion red blood cell phenotyping and consideration of Rh and K antigen matching for individuals receiving frequent transfusions can facilitate antibody detection if alloimmunization occurs.
Individuals with neutropenia should be counseled regarding their increased risk of infection.
Treatment with prophylactic antibiotics should be based on the history of infections and overall clinical picture.
Individuals with neutropenia who present with fever should be evaluated promptly with a physical examination, CBC, and blood culture.
Febrile individuals who are severely neutropenic (absolute neutrophil count <500/µL) are typically treated with empiric parenteral antibiotics to avoid the possibility of life-threatening sepsis.
The frequency of CBCs should be tailored to disease severity.
Individuals with mild cytopenias should have annual CBCs.
Individuals with severe cytopenias who require transfusions should have monthly CBCs or as indicated by clinical signs and symptoms.
Additional surveillance with bone marrow aspirate and biopsy may be indicated in those with a phenotype similar to
Individuals undergoing repeated erythrocyte transfusions should be monitored for iron overload.
Individuals with thrombocytopenia and/or platelet aggregation defects should avoid antiplatelet agents including aspirin and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen).
Individuals with thrombocytopenia and/or platelet aggregation defects should avoid contact sports or activities with a high risk of trauma.
Individuals with severe neutropenia should avoid close contact with persons who have a communicable disease to minimize risk of infection.
Individuals with significant splenomegaly should avoid contact sports, which increase the risk of traumatic splenic rupture.
Note: Evaluation of at-risk relatives can include a CBC to evaluate for thrombocytopenia, anemia, or neutropenia. However, platelet, erythrocyte, and neutrophil counts can vary significantly in individuals with
See
Correction of the
Search
Unlike immune-mediated platelet disorders such as immune thrombocytopenic purpura,
Supplemental erythropoietin therapy is unlikely to be effective because the anemia is secondary to ineffective erythropoiesis, not erythropoietin deficiency.
• Complete blood count (CBC) and examination of the peripheral blood smear to assess the degree of cytopenia(s) and morphologic abnormalities
• Detailed history of the disease course, including the age at which hematologic disease was detected and the associated symptoms
• Documentation of abnormal/unexpected bleeding episodes and platelet counts obtained at the time of the episodes to help determine whether platelet function is abnormal and whether disease severity has changed over time
• Note: Platelet aggregation studies may identify functional abnormalities that predict a greater risk of bleeding for any given platelet count, but studies can be difficult to interpret when platelet counts are lower than 100,000/μL.
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of
• HSCT should be considered in individuals with severe
• While HSCT may offer a cure, clinical experience with HSCT treatment in those with
• Individuals with moderate-to-severe epistaxis, severe gingival bleeding, or other clinically significant bleeding should receive platelet transfusions. Transfusion requirements vary, as bleeding can be related to quantitative and/or qualitative platelet defects.
• For individuals with thrombocytopenia and/or platelet aggregation defects, DDAVP
• Platelet transfusion prior to surgical or invasive dental procedures is recommended for individuals with a history of pathologic bleeding, thrombocytopenia, and/or platelet dysfunction.
• Individuals who are only mildly symptomatic (easy bruisability without mucosal or more severe bleeding) do not require specific treatment.
• There is no evidence that splenectomy is beneficial in people with
• Red blood cell transfusions for clinical manifestations of anemia (e.g., fatigue, tachycardia)
• Iron chelation therapy may be needed in those with iron overload secondary to chronic red blood cell transfusion therapy.
• Extended pre-transfusion red blood cell phenotyping and consideration of Rh and K antigen matching for individuals receiving frequent transfusions can facilitate antibody detection if alloimmunization occurs.
• Individuals with neutropenia should be counseled regarding their increased risk of infection.
• Treatment with prophylactic antibiotics should be based on the history of infections and overall clinical picture.
• Individuals with neutropenia who present with fever should be evaluated promptly with a physical examination, CBC, and blood culture.
• Febrile individuals who are severely neutropenic (absolute neutrophil count <500/µL) are typically treated with empiric parenteral antibiotics to avoid the possibility of life-threatening sepsis.
• Individuals with mild cytopenias should have annual CBCs.
• Individuals with severe cytopenias who require transfusions should have monthly CBCs or as indicated by clinical signs and symptoms.
• Additional surveillance with bone marrow aspirate and biopsy may be indicated in those with a phenotype similar to
• Individuals undergoing repeated erythrocyte transfusions should be monitored for iron overload.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Complete blood count (CBC) and examination of the peripheral blood smear to assess the degree of cytopenia(s) and morphologic abnormalities
Detailed history of the disease course, including the age at which hematologic disease was detected and the associated symptoms
Documentation of abnormal/unexpected bleeding episodes and platelet counts obtained at the time of the episodes to help determine whether platelet function is abnormal and whether disease severity has changed over time
Note: Platelet aggregation studies may identify functional abnormalities that predict a greater risk of bleeding for any given platelet count, but studies can be difficult to interpret when platelet counts are lower than 100,000/μL.
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of
• Complete blood count (CBC) and examination of the peripheral blood smear to assess the degree of cytopenia(s) and morphologic abnormalities
• Detailed history of the disease course, including the age at which hematologic disease was detected and the associated symptoms
• Documentation of abnormal/unexpected bleeding episodes and platelet counts obtained at the time of the episodes to help determine whether platelet function is abnormal and whether disease severity has changed over time
• Note: Platelet aggregation studies may identify functional abnormalities that predict a greater risk of bleeding for any given platelet count, but studies can be difficult to interpret when platelet counts are lower than 100,000/μL.
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of
## Treatment of Manifestations
For those with severe disease, hematopoietic stem cell transplant (HSCT) can be curative [
HSCT should be considered in individuals with severe
While HSCT may offer a cure, clinical experience with HSCT treatment in those with
Supportive care to improve quality of life, maximize function, and reduce complications is recommended.
Individuals with moderate-to-severe epistaxis, severe gingival bleeding, or other clinically significant bleeding should receive platelet transfusions. Transfusion requirements vary, as bleeding can be related to quantitative and/or qualitative platelet defects.
For individuals with thrombocytopenia and/or platelet aggregation defects, DDAVP
Platelet transfusion prior to surgical or invasive dental procedures is recommended for individuals with a history of pathologic bleeding, thrombocytopenia, and/or platelet dysfunction.
Individuals who are only mildly symptomatic (easy bruisability without mucosal or more severe bleeding) do not require specific treatment.
There is no evidence that splenectomy is beneficial in people with
Red blood cell transfusions for clinical manifestations of anemia (e.g., fatigue, tachycardia)
Iron chelation therapy may be needed in those with iron overload secondary to chronic red blood cell transfusion therapy.
Extended pre-transfusion red blood cell phenotyping and consideration of Rh and K antigen matching for individuals receiving frequent transfusions can facilitate antibody detection if alloimmunization occurs.
Individuals with neutropenia should be counseled regarding their increased risk of infection.
Treatment with prophylactic antibiotics should be based on the history of infections and overall clinical picture.
Individuals with neutropenia who present with fever should be evaluated promptly with a physical examination, CBC, and blood culture.
Febrile individuals who are severely neutropenic (absolute neutrophil count <500/µL) are typically treated with empiric parenteral antibiotics to avoid the possibility of life-threatening sepsis.
• HSCT should be considered in individuals with severe
• While HSCT may offer a cure, clinical experience with HSCT treatment in those with
• Individuals with moderate-to-severe epistaxis, severe gingival bleeding, or other clinically significant bleeding should receive platelet transfusions. Transfusion requirements vary, as bleeding can be related to quantitative and/or qualitative platelet defects.
• For individuals with thrombocytopenia and/or platelet aggregation defects, DDAVP
• Platelet transfusion prior to surgical or invasive dental procedures is recommended for individuals with a history of pathologic bleeding, thrombocytopenia, and/or platelet dysfunction.
• Individuals who are only mildly symptomatic (easy bruisability without mucosal or more severe bleeding) do not require specific treatment.
• There is no evidence that splenectomy is beneficial in people with
• Red blood cell transfusions for clinical manifestations of anemia (e.g., fatigue, tachycardia)
• Iron chelation therapy may be needed in those with iron overload secondary to chronic red blood cell transfusion therapy.
• Extended pre-transfusion red blood cell phenotyping and consideration of Rh and K antigen matching for individuals receiving frequent transfusions can facilitate antibody detection if alloimmunization occurs.
• Individuals with neutropenia should be counseled regarding their increased risk of infection.
• Treatment with prophylactic antibiotics should be based on the history of infections and overall clinical picture.
• Individuals with neutropenia who present with fever should be evaluated promptly with a physical examination, CBC, and blood culture.
• Febrile individuals who are severely neutropenic (absolute neutrophil count <500/µL) are typically treated with empiric parenteral antibiotics to avoid the possibility of life-threatening sepsis.
## Targeted Therapy
For those with severe disease, hematopoietic stem cell transplant (HSCT) can be curative [
HSCT should be considered in individuals with severe
While HSCT may offer a cure, clinical experience with HSCT treatment in those with
• HSCT should be considered in individuals with severe
• While HSCT may offer a cure, clinical experience with HSCT treatment in those with
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended.
Individuals with moderate-to-severe epistaxis, severe gingival bleeding, or other clinically significant bleeding should receive platelet transfusions. Transfusion requirements vary, as bleeding can be related to quantitative and/or qualitative platelet defects.
For individuals with thrombocytopenia and/or platelet aggregation defects, DDAVP
Platelet transfusion prior to surgical or invasive dental procedures is recommended for individuals with a history of pathologic bleeding, thrombocytopenia, and/or platelet dysfunction.
Individuals who are only mildly symptomatic (easy bruisability without mucosal or more severe bleeding) do not require specific treatment.
There is no evidence that splenectomy is beneficial in people with
Red blood cell transfusions for clinical manifestations of anemia (e.g., fatigue, tachycardia)
Iron chelation therapy may be needed in those with iron overload secondary to chronic red blood cell transfusion therapy.
Extended pre-transfusion red blood cell phenotyping and consideration of Rh and K antigen matching for individuals receiving frequent transfusions can facilitate antibody detection if alloimmunization occurs.
Individuals with neutropenia should be counseled regarding their increased risk of infection.
Treatment with prophylactic antibiotics should be based on the history of infections and overall clinical picture.
Individuals with neutropenia who present with fever should be evaluated promptly with a physical examination, CBC, and blood culture.
Febrile individuals who are severely neutropenic (absolute neutrophil count <500/µL) are typically treated with empiric parenteral antibiotics to avoid the possibility of life-threatening sepsis.
• Individuals with moderate-to-severe epistaxis, severe gingival bleeding, or other clinically significant bleeding should receive platelet transfusions. Transfusion requirements vary, as bleeding can be related to quantitative and/or qualitative platelet defects.
• For individuals with thrombocytopenia and/or platelet aggregation defects, DDAVP
• Platelet transfusion prior to surgical or invasive dental procedures is recommended for individuals with a history of pathologic bleeding, thrombocytopenia, and/or platelet dysfunction.
• Individuals who are only mildly symptomatic (easy bruisability without mucosal or more severe bleeding) do not require specific treatment.
• There is no evidence that splenectomy is beneficial in people with
• Red blood cell transfusions for clinical manifestations of anemia (e.g., fatigue, tachycardia)
• Iron chelation therapy may be needed in those with iron overload secondary to chronic red blood cell transfusion therapy.
• Extended pre-transfusion red blood cell phenotyping and consideration of Rh and K antigen matching for individuals receiving frequent transfusions can facilitate antibody detection if alloimmunization occurs.
• Individuals with neutropenia should be counseled regarding their increased risk of infection.
• Treatment with prophylactic antibiotics should be based on the history of infections and overall clinical picture.
• Individuals with neutropenia who present with fever should be evaluated promptly with a physical examination, CBC, and blood culture.
• Febrile individuals who are severely neutropenic (absolute neutrophil count <500/µL) are typically treated with empiric parenteral antibiotics to avoid the possibility of life-threatening sepsis.
## Surveillance
The frequency of CBCs should be tailored to disease severity.
Individuals with mild cytopenias should have annual CBCs.
Individuals with severe cytopenias who require transfusions should have monthly CBCs or as indicated by clinical signs and symptoms.
Additional surveillance with bone marrow aspirate and biopsy may be indicated in those with a phenotype similar to
Individuals undergoing repeated erythrocyte transfusions should be monitored for iron overload.
• Individuals with mild cytopenias should have annual CBCs.
• Individuals with severe cytopenias who require transfusions should have monthly CBCs or as indicated by clinical signs and symptoms.
• Additional surveillance with bone marrow aspirate and biopsy may be indicated in those with a phenotype similar to
• Individuals undergoing repeated erythrocyte transfusions should be monitored for iron overload.
## Agents/Circumstances to Avoid
Individuals with thrombocytopenia and/or platelet aggregation defects should avoid antiplatelet agents including aspirin and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen).
Individuals with thrombocytopenia and/or platelet aggregation defects should avoid contact sports or activities with a high risk of trauma.
Individuals with severe neutropenia should avoid close contact with persons who have a communicable disease to minimize risk of infection.
Individuals with significant splenomegaly should avoid contact sports, which increase the risk of traumatic splenic rupture.
## Evaluation of Relatives at Risk
Note: Evaluation of at-risk relatives can include a CBC to evaluate for thrombocytopenia, anemia, or neutropenia. However, platelet, erythrocyte, and neutrophil counts can vary significantly in individuals with
See
## Therapies Under Investigation
Correction of the
Search
## Other
Unlike immune-mediated platelet disorders such as immune thrombocytopenic purpura,
Supplemental erythropoietin therapy is unlikely to be effective because the anemia is secondary to ineffective erythropoiesis, not erythropoietin deficiency.
## Genetic Counseling
The father of an affected male will not have the disorder, nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygous and may manifest platelet abnormalities and/or mild anemia with mild-to-moderate symptoms such as menorrhagia or easy bruising (see Clinical Description,
If the proband represents a simplex case and if the
Identification of female heterozygotes typically requires prior identification of the
Note: Females who are heterozygotes for this X-linked disorder may develop clinical findings related to the disorder (see Clinical Description,
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder, nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygous and may manifest platelet abnormalities and/or mild anemia with mild-to-moderate symptoms such as menorrhagia or easy bruising (see Clinical Description,
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygous and may manifest platelet abnormalities and/or mild anemia with mild-to-moderate symptoms such as menorrhagia or easy bruising (see Clinical Description,
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygous and may manifest platelet abnormalities and/or mild anemia with mild-to-moderate symptoms such as menorrhagia or easy bruising (see Clinical Description,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Mode of Inheritance
## Risk to Family Members
The father of an affected male will not have the disorder, nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
If the mother of the proband has a
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygous and may manifest platelet abnormalities and/or mild anemia with mild-to-moderate symptoms such as menorrhagia or easy bruising (see Clinical Description,
If the proband represents a simplex case and if the
• The father of an affected male will not have the disorder, nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygous and may manifest platelet abnormalities and/or mild anemia with mild-to-moderate symptoms such as menorrhagia or easy bruising (see Clinical Description,
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygous and may manifest platelet abnormalities and/or mild anemia with mild-to-moderate symptoms such as menorrhagia or easy bruising (see Clinical Description,
• If the proband represents a simplex case and if the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygous and may manifest platelet abnormalities and/or mild anemia with mild-to-moderate symptoms such as menorrhagia or easy bruising (see Clinical Description,
## Heterozygote Detection
Identification of female heterozygotes typically requires prior identification of the
Note: Females who are heterozygotes for this X-linked disorder may develop clinical findings related to the disorder (see Clinical Description,
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
GATA1-Related Cytopenia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GATA1-Related Cytopenia (
Notable
Variants listed in the table have been provided by the authors.
Pathogenic variant affects initiation codon resulting in lack of full-length DNA.
In children with Down syndrome (DS, trisomy 21), somatic variants resulting in the production of GATA-1s exclusively are associated with transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (M7 subtype, DS-AMKL) [
Further, similar germline protein-truncating
One individual with severe anemia and thrombocytopenia caused by the
## Molecular Pathogenesis
Notable
Variants listed in the table have been provided by the authors.
Pathogenic variant affects initiation codon resulting in lack of full-length DNA.
## Cancer and Benign Tumors
In children with Down syndrome (DS, trisomy 21), somatic variants resulting in the production of GATA-1s exclusively are associated with transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (M7 subtype, DS-AMKL) [
Further, similar germline protein-truncating
One individual with severe anemia and thrombocytopenia caused by the
## Chapter Notes
Drs Kaoru Takasaki (
Contact Drs Takasaki, Weiss, or Chou to inquire about review of
This work was supported in part by NIH grants R01 HL151260 (STC), R01HL165798 (MJW), R01 AG082275 (MAK), R01 AG060621 (MAK), T32 HL007150 (KT), and the American Society of Hematology Research Training Award for Fellows (KT).
Stella T Chou, MD (2006-present)
Melissa A Kacena, PhD (2006-present)
Jessica Kirk, BS; Yale University School of Medicine (2006-2011)
Wendy H Raskind, MD, PhD (2006-present)
Kaoru Takasaki, MD (2023-present)
Mitchell J Weiss, MD, PhD (2006-present)
16 February 2023 (sw) Comprehensive update posted live
11 May 2017 (ha) Comprehensive update posted live
17 April 2014 (me) Comprehensive update posted live
22 March 2011 (me) Comprehensive update posted live
30 March 2007 (cd) Revision: prenatal testing clinically available
21 February 2007 (cd) Revision: clinical testing available
22 November 2006 (me) Review posted live
10 August 2006 (whr) Original submission
• 16 February 2023 (sw) Comprehensive update posted live
• 11 May 2017 (ha) Comprehensive update posted live
• 17 April 2014 (me) Comprehensive update posted live
• 22 March 2011 (me) Comprehensive update posted live
• 30 March 2007 (cd) Revision: prenatal testing clinically available
• 21 February 2007 (cd) Revision: clinical testing available
• 22 November 2006 (me) Review posted live
• 10 August 2006 (whr) Original submission
## Author Notes
Drs Kaoru Takasaki (
Contact Drs Takasaki, Weiss, or Chou to inquire about review of
## Acknowledgments
This work was supported in part by NIH grants R01 HL151260 (STC), R01HL165798 (MJW), R01 AG082275 (MAK), R01 AG060621 (MAK), T32 HL007150 (KT), and the American Society of Hematology Research Training Award for Fellows (KT).
## Author History
Stella T Chou, MD (2006-present)
Melissa A Kacena, PhD (2006-present)
Jessica Kirk, BS; Yale University School of Medicine (2006-2011)
Wendy H Raskind, MD, PhD (2006-present)
Kaoru Takasaki, MD (2023-present)
Mitchell J Weiss, MD, PhD (2006-present)
## Revision History
16 February 2023 (sw) Comprehensive update posted live
11 May 2017 (ha) Comprehensive update posted live
17 April 2014 (me) Comprehensive update posted live
22 March 2011 (me) Comprehensive update posted live
30 March 2007 (cd) Revision: prenatal testing clinically available
21 February 2007 (cd) Revision: clinical testing available
22 November 2006 (me) Review posted live
10 August 2006 (whr) Original submission
• 16 February 2023 (sw) Comprehensive update posted live
• 11 May 2017 (ha) Comprehensive update posted live
• 17 April 2014 (me) Comprehensive update posted live
• 22 March 2011 (me) Comprehensive update posted live
• 30 March 2007 (cd) Revision: prenatal testing clinically available
• 21 February 2007 (cd) Revision: clinical testing available
• 22 November 2006 (me) Review posted live
• 10 August 2006 (whr) Original submission
## Key Sections in this
## References
## Literature Cited
|
[] |
22/11/2006
|
16/2/2023
|
30/3/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
gaucher
|
gaucher
|
[
"Glucocerebrosidase Deficiency",
"Glucosylceramidase Deficiency",
"Glucocerebrosidase Deficiency",
"Glucosylceramidase Deficiency",
"Type 1 Gaucher Disease",
"Type 2 Gaucher disease (Acute; Infantile)",
"Type 3 Gaucher disease (Subacute; Juvenile)",
"Gaucher Disease, Perinatal-Lethal Form",
"Gaucher Disease, Cardiovascular Form",
"Lysosomal acid glucosylceramidase",
"GBA1",
"Gaucher Disease"
] |
Gaucher Disease
|
Derralynn A Hughes, Gregory M Pastores
|
Summary Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal-lethal disorder to an asymptomatic type. The characterization of three major clinical types (1, 2, and 3) and two clinical forms (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. Cardiopulmonary complications have been described with all the clinical phenotypes, although varying in frequency and severity. The The The diagnosis of GD relies on demonstration of deficient glucocerebrosidase (glucosylceramidase) enzyme activity in peripheral blood leukocytes or other nucleated cells, or by the identification of biallelic pathogenic variants in GD is inherited in an autosomal recessive manner. The parents of an affected individual are typically heterozygous for a
|
Type 1 Gaucher disease
Type 2 Gaucher disease (acute; infantile
Type 3 Gaucher disease (subacute; juvenile)
Perinatal-lethal form
Cardiovascular form
Saposin C deficiency can be associated with features characteristic of severe neuropathic Gaucher disease; see
• Type 1 Gaucher disease
• Type 2 Gaucher disease (acute; infantile
• Type 3 Gaucher disease (subacute; juvenile)
• Perinatal-lethal form
• Cardiovascular form
## Diagnosis
NBS for Gaucher disease (GD) is primarily based on quantification of glucocerebrosidase enzyme activity on dried blood spots.
Glucocerebrosidase enzyme activity values below the cutoff reported by the screening laboratory are considered positive, and additional testing is required to establish the diagnosis (see
GD encompasses a continuum of clinical findings from a perinatal-lethal disorder to type 1 GD with adult onset. GD
Gaucher Disease: Clinical Phenotypes
Splenomegaly
Hepatomegaly
Cytopenia
Pulmonary disease
Bulbar signs
Pyramidal signs
Cognitive impairment
Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease
Dermatologic changes
Oculomotor apraxia
Seizures
Progressive myoclonic epilepsy
Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease
Ichthyosiform or collodion skin changes
Nonimmune hydrops fetalis
Calcification of mitral & aortic valves
Corneal opacity
Mild splenomegaly
CNS = central nervous system
Osteopenia, focal lytic or sclerotic lesions, and/or osteonecrosis
Anemia, leukopenia, and/or thrombocytopenia
The diagnosis of GD
Note: (1) Molecular analysis of
Molecular testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Gaucher Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Due to the presence of a highly homologous pseudogene (
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Complex disease-causing alleles derived from
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that rely on hybridization, such as multiplex ligation-dependent probe amplification (MLPA) or gene-targeted microarray designed to detect single-exon deletions or duplications, may not detect deletions or duplications in regions of high homology between
Deletions of 3,925 bp including exons 1-2 and the 5' UTR (a region unique to
• Splenomegaly
• Hepatomegaly
• Cytopenia
• Pulmonary disease
• Bulbar signs
• Pyramidal signs
• Cognitive impairment
• Hepatomegaly
• Splenomegaly
• Cytopenia
• Pulmonary disease
• Dermatologic changes
• Oculomotor apraxia
• Seizures
• Progressive myoclonic epilepsy
• Hepatomegaly
• Splenomegaly
• Cytopenia
• Pulmonary disease
• Ichthyosiform or collodion skin changes
• Nonimmune hydrops fetalis
• Calcification of mitral & aortic valves
• Corneal opacity
• Mild splenomegaly
• For an introduction to multigene panels click
## Suggestive Findings
NBS for Gaucher disease (GD) is primarily based on quantification of glucocerebrosidase enzyme activity on dried blood spots.
Glucocerebrosidase enzyme activity values below the cutoff reported by the screening laboratory are considered positive, and additional testing is required to establish the diagnosis (see
GD encompasses a continuum of clinical findings from a perinatal-lethal disorder to type 1 GD with adult onset. GD
Gaucher Disease: Clinical Phenotypes
Splenomegaly
Hepatomegaly
Cytopenia
Pulmonary disease
Bulbar signs
Pyramidal signs
Cognitive impairment
Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease
Dermatologic changes
Oculomotor apraxia
Seizures
Progressive myoclonic epilepsy
Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease
Ichthyosiform or collodion skin changes
Nonimmune hydrops fetalis
Calcification of mitral & aortic valves
Corneal opacity
Mild splenomegaly
CNS = central nervous system
Osteopenia, focal lytic or sclerotic lesions, and/or osteonecrosis
Anemia, leukopenia, and/or thrombocytopenia
• Splenomegaly
• Hepatomegaly
• Cytopenia
• Pulmonary disease
• Bulbar signs
• Pyramidal signs
• Cognitive impairment
• Hepatomegaly
• Splenomegaly
• Cytopenia
• Pulmonary disease
• Dermatologic changes
• Oculomotor apraxia
• Seizures
• Progressive myoclonic epilepsy
• Hepatomegaly
• Splenomegaly
• Cytopenia
• Pulmonary disease
• Ichthyosiform or collodion skin changes
• Nonimmune hydrops fetalis
• Calcification of mitral & aortic valves
• Corneal opacity
• Mild splenomegaly
## Scenario 1: Abnormal Newborn Screening (NBS) Result
NBS for Gaucher disease (GD) is primarily based on quantification of glucocerebrosidase enzyme activity on dried blood spots.
Glucocerebrosidase enzyme activity values below the cutoff reported by the screening laboratory are considered positive, and additional testing is required to establish the diagnosis (see
## Scenario 2: Symptomatic Individual
GD encompasses a continuum of clinical findings from a perinatal-lethal disorder to type 1 GD with adult onset. GD
Gaucher Disease: Clinical Phenotypes
Splenomegaly
Hepatomegaly
Cytopenia
Pulmonary disease
Bulbar signs
Pyramidal signs
Cognitive impairment
Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease
Dermatologic changes
Oculomotor apraxia
Seizures
Progressive myoclonic epilepsy
Hepatomegaly
Splenomegaly
Cytopenia
Pulmonary disease
Ichthyosiform or collodion skin changes
Nonimmune hydrops fetalis
Calcification of mitral & aortic valves
Corneal opacity
Mild splenomegaly
CNS = central nervous system
Osteopenia, focal lytic or sclerotic lesions, and/or osteonecrosis
Anemia, leukopenia, and/or thrombocytopenia
• Splenomegaly
• Hepatomegaly
• Cytopenia
• Pulmonary disease
• Bulbar signs
• Pyramidal signs
• Cognitive impairment
• Hepatomegaly
• Splenomegaly
• Cytopenia
• Pulmonary disease
• Dermatologic changes
• Oculomotor apraxia
• Seizures
• Progressive myoclonic epilepsy
• Hepatomegaly
• Splenomegaly
• Cytopenia
• Pulmonary disease
• Ichthyosiform or collodion skin changes
• Nonimmune hydrops fetalis
• Calcification of mitral & aortic valves
• Corneal opacity
• Mild splenomegaly
## Establishing the Diagnosis
The diagnosis of GD
Note: (1) Molecular analysis of
Molecular testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Gaucher Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Due to the presence of a highly homologous pseudogene (
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Complex disease-causing alleles derived from
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that rely on hybridization, such as multiplex ligation-dependent probe amplification (MLPA) or gene-targeted microarray designed to detect single-exon deletions or duplications, may not detect deletions or duplications in regions of high homology between
Deletions of 3,925 bp including exons 1-2 and the 5' UTR (a region unique to
• For an introduction to multigene panels click
## Clinical Characteristics
Gaucher disease (GD) encompasses a spectrum of clinical findings from a perinatal-lethal form to an asymptomatic form. However, for the purposes of determining prognosis and management, the classification of GD by clinical type is still useful in describing the wide range of clinical findings and broad variability in presentation. Three major clinical types are delineated by the absence (type 1) or presence (types 2 and 3) of primary central nervous system (CNS) involvement (see
Acute bone pain manifests as "bone crises" or episodes of deep bone pain that are usually confined to one extremity or joint [
Conventional radiographs may reveal undertubulation (Erlenmeyer flask configuration) in the distal femur and endosteal scalloping as a sign of bone marrow infiltration. MRI reveals the extent of marrow involvement and the presence of fibrosis and/or infarction. In general, marrow infiltration extends from the axial to the appendicular skeleton, and greater involvement is often seen in the lower extremities and proximal sites of an affected bone. The epiphyses are usually spared, except in advanced disease. Bone densitometry studies enable quantitative assessment of the degree of osteopenia.
Bone disease in GD may not correlate with the severity of hematologic or visceral problems.
Peripheral neuropathy has been described in individuals with type 1 GD, when testing is performed; however, in most individuals this is a subclinical finding [
Thrombocytopenia may result from hypersplenism, splenic pooling of platelets, or marrow infiltration or infarction. Immune thrombocytopenia has also been reported and should be excluded in individuals with persistent thrombocytopenia despite GD-specific therapy. Thrombocytopenia may be associated with easy bruising or overt bleeding, particularly with trauma, surgery, or pregnancy. The risk for bleeding may be increased in the presence of clotting abnormalities.
Anemia may result from hypersplenism, hemodilution (e.g., pregnancy), iron deficiency, vitamin B
Leukopenia is rarely severe enough to require intervention. Deficient neutrophil function has been reported.
Interstitial lung disease
Alveolar/lobar consolidation
Pulmonary arterial hypertension (PAH) is well documented in individuals with liver disease and is presumably the result of inability to detoxify gut-derived factors, which somehow adversely affect the pulmonary endothelium with resultant pulmonary hypertension. PAH can also occur in individuals with GD without liver disease, although in most individuals it is not clinically significant and is not progressive [
Dyspnea and cyanosis with digital clubbing attributed to hepatopulmonary syndrome have been described in individuals with liver dysfunction; this is often caused by an intercurrent disease (e.g., viral hepatitis).
Note: Individuals with type 1 GD without evidence of pulmonary involvement who limit physical exertion because of easy fatigability may have impaired circulation [
In some women the diagnosis of GD is first identified during pregnancy due to exacerbation of hematologic features.
Epidemiologic studies have also suggested an elevated risk of additional malignancies including hepatocellular carcinoma [
Additional genetic risk factors may contribute to the risk of PD in those with type 1 GD. A recent study found that non-
Bulbar signs (i.e., stridor, squint, and swallowing difficulty) and pyramidal signs (i.e., opisthotonos, head retroflexion, spasticity, and trismus) in infancy are characteristic of type 2 GD.
Oculomotor apraxia, saccadic initiation failure, and opticokinetic nystagmus are common in type 3 GD [
Generalized tonic-clonic seizures and progressive myoclonic epilepsy have been observed in some individuals [
Dementia and ataxia have been observed in the later stages of chronic neurologic disease.
Brain stem auditory evoked response (BAER) testing may reveal abnormal wave forms (III and IV) [
The perinatal-lethal form of GD is associated with hepatosplenomegaly, pancytopenia, and microscopic skin changes (i.e., abnormalities in the stratum corneum attributed to altered glucosylceramide-to-ceramide ratio) and may present clinically with ichthyosiform or collodion skin abnormalities or as nonimmune hydrops fetalis [
Another rare severe variant of GD is associated with hydrocephalus, corneal opacities, deformed toes, gastroesophageal reflux, and fibrous thickening of splenic and hepatic capsules [
Individuals homozygous for
Family studies suggest that the incidence of parkinsonism is higher in obligate heterozygotes for a
The level of residual glucocerebrosidase enzyme activity as measured in vitro from extracts of nucleated cells does not correlate with disease type or severity.
Genotype-phenotype correlations in GD are imperfect. Significant overlap in the clinical manifestations found between individuals with the various genotypes precludes specific counseling about prognosis in individual cases [
Individuals with at least one
In general, individuals who are homozygous for the
Individuals who are homozygous for
In a study of 31 individuals with type 2 GD, p.Leu483Pro accounted for 25 alleles (40%) [
In another study, homozygosity for p.Leu483Pro was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [
In a study of affected individuals of Japanese and Korean ancestry with GD including type 1, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese individuals was
In individuals with GD and myoclonic epilepsy,
A second variant,
Homozygosity for recombinant alleles [
Compound heterozygosity for an insertion-type pathogenic variant and the pathogenic missense variant
Incidence and prevalence estimates for GD are scarce, except for reports regarding specific populations. Prevalence estimates are also variable, with higher prevalence in populations or regions with known founder variants (e.g., Ashkenazi Jews). A recent review, based on a targeted literature search conducted from January 2011 to September 2020, revealed incidence estimates including all GD subtypes ranging from 0.45-25.0:100,000 live births (16 studies); incidence was lowest for Asia-Pacific populations. The incidence of type 1 GD was estimated at 0.45-22.9:100,000 live births (Europe and North America) and type 3 GD at 1.36:100,000 live births (Asia-Pacific only). GD type-specific prevalence estimates per 100,000 population were type 1 GD: 0.26-0.63; type 2 GD and type 3 GD: 0.02-0.08 (Europe only). Estimates for GD type unspecified or overall ranged from 0.11-139.0:100,000 inhabitants (17 studies); the highest prevalence was in North America [
A founder effect for specific alleles underlies the observed occurrence of GD in specific populations:
Ashkenazi Jewish, Spanish, and Portuguese (
Swedish (
Jenin Arab, Greek, and Albanian (
Type 1 GD (non-neuropathic) is prevalent in the Ashkenazi Jewish population, with a disease prevalence of 1:855 and an estimated carrier frequency of 1/18.
As noted, the prevalence of types 2 and 3 GD (neuropathic) varies across ethnic groups but appears to be higher among those who are not of European origin.
• Interstitial lung disease
• Alveolar/lobar consolidation
• Pulmonary arterial hypertension (PAH) is well documented in individuals with liver disease and is presumably the result of inability to detoxify gut-derived factors, which somehow adversely affect the pulmonary endothelium with resultant pulmonary hypertension. PAH can also occur in individuals with GD without liver disease, although in most individuals it is not clinically significant and is not progressive [
• Dyspnea and cyanosis with digital clubbing attributed to hepatopulmonary syndrome have been described in individuals with liver dysfunction; this is often caused by an intercurrent disease (e.g., viral hepatitis).
• Individuals with at least one
• In general, individuals who are homozygous for the
• Individuals who are homozygous for
• In a study of 31 individuals with type 2 GD, p.Leu483Pro accounted for 25 alleles (40%) [
• In another study, homozygosity for p.Leu483Pro was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [
• In a study of affected individuals of Japanese and Korean ancestry with GD including type 1, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese individuals was
• In a study of 31 individuals with type 2 GD, p.Leu483Pro accounted for 25 alleles (40%) [
• In another study, homozygosity for p.Leu483Pro was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [
• In a study of affected individuals of Japanese and Korean ancestry with GD including type 1, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese individuals was
• In individuals with GD and myoclonic epilepsy,
• A second variant,
• In a study of 31 individuals with type 2 GD, p.Leu483Pro accounted for 25 alleles (40%) [
• In another study, homozygosity for p.Leu483Pro was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [
• In a study of affected individuals of Japanese and Korean ancestry with GD including type 1, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese individuals was
• Homozygosity for recombinant alleles [
• Compound heterozygosity for an insertion-type pathogenic variant and the pathogenic missense variant
• Ashkenazi Jewish, Spanish, and Portuguese (
• Swedish (
• Jenin Arab, Greek, and Albanian (
## Clinical Description
Gaucher disease (GD) encompasses a spectrum of clinical findings from a perinatal-lethal form to an asymptomatic form. However, for the purposes of determining prognosis and management, the classification of GD by clinical type is still useful in describing the wide range of clinical findings and broad variability in presentation. Three major clinical types are delineated by the absence (type 1) or presence (types 2 and 3) of primary central nervous system (CNS) involvement (see
Acute bone pain manifests as "bone crises" or episodes of deep bone pain that are usually confined to one extremity or joint [
Conventional radiographs may reveal undertubulation (Erlenmeyer flask configuration) in the distal femur and endosteal scalloping as a sign of bone marrow infiltration. MRI reveals the extent of marrow involvement and the presence of fibrosis and/or infarction. In general, marrow infiltration extends from the axial to the appendicular skeleton, and greater involvement is often seen in the lower extremities and proximal sites of an affected bone. The epiphyses are usually spared, except in advanced disease. Bone densitometry studies enable quantitative assessment of the degree of osteopenia.
Bone disease in GD may not correlate with the severity of hematologic or visceral problems.
Peripheral neuropathy has been described in individuals with type 1 GD, when testing is performed; however, in most individuals this is a subclinical finding [
Thrombocytopenia may result from hypersplenism, splenic pooling of platelets, or marrow infiltration or infarction. Immune thrombocytopenia has also been reported and should be excluded in individuals with persistent thrombocytopenia despite GD-specific therapy. Thrombocytopenia may be associated with easy bruising or overt bleeding, particularly with trauma, surgery, or pregnancy. The risk for bleeding may be increased in the presence of clotting abnormalities.
Anemia may result from hypersplenism, hemodilution (e.g., pregnancy), iron deficiency, vitamin B
Leukopenia is rarely severe enough to require intervention. Deficient neutrophil function has been reported.
Interstitial lung disease
Alveolar/lobar consolidation
Pulmonary arterial hypertension (PAH) is well documented in individuals with liver disease and is presumably the result of inability to detoxify gut-derived factors, which somehow adversely affect the pulmonary endothelium with resultant pulmonary hypertension. PAH can also occur in individuals with GD without liver disease, although in most individuals it is not clinically significant and is not progressive [
Dyspnea and cyanosis with digital clubbing attributed to hepatopulmonary syndrome have been described in individuals with liver dysfunction; this is often caused by an intercurrent disease (e.g., viral hepatitis).
Note: Individuals with type 1 GD without evidence of pulmonary involvement who limit physical exertion because of easy fatigability may have impaired circulation [
In some women the diagnosis of GD is first identified during pregnancy due to exacerbation of hematologic features.
Epidemiologic studies have also suggested an elevated risk of additional malignancies including hepatocellular carcinoma [
Additional genetic risk factors may contribute to the risk of PD in those with type 1 GD. A recent study found that non-
Bulbar signs (i.e., stridor, squint, and swallowing difficulty) and pyramidal signs (i.e., opisthotonos, head retroflexion, spasticity, and trismus) in infancy are characteristic of type 2 GD.
Oculomotor apraxia, saccadic initiation failure, and opticokinetic nystagmus are common in type 3 GD [
Generalized tonic-clonic seizures and progressive myoclonic epilepsy have been observed in some individuals [
Dementia and ataxia have been observed in the later stages of chronic neurologic disease.
Brain stem auditory evoked response (BAER) testing may reveal abnormal wave forms (III and IV) [
The perinatal-lethal form of GD is associated with hepatosplenomegaly, pancytopenia, and microscopic skin changes (i.e., abnormalities in the stratum corneum attributed to altered glucosylceramide-to-ceramide ratio) and may present clinically with ichthyosiform or collodion skin abnormalities or as nonimmune hydrops fetalis [
Another rare severe variant of GD is associated with hydrocephalus, corneal opacities, deformed toes, gastroesophageal reflux, and fibrous thickening of splenic and hepatic capsules [
Individuals homozygous for
Family studies suggest that the incidence of parkinsonism is higher in obligate heterozygotes for a
• Interstitial lung disease
• Alveolar/lobar consolidation
• Pulmonary arterial hypertension (PAH) is well documented in individuals with liver disease and is presumably the result of inability to detoxify gut-derived factors, which somehow adversely affect the pulmonary endothelium with resultant pulmonary hypertension. PAH can also occur in individuals with GD without liver disease, although in most individuals it is not clinically significant and is not progressive [
• Dyspnea and cyanosis with digital clubbing attributed to hepatopulmonary syndrome have been described in individuals with liver dysfunction; this is often caused by an intercurrent disease (e.g., viral hepatitis).
## Type 1 GD
Acute bone pain manifests as "bone crises" or episodes of deep bone pain that are usually confined to one extremity or joint [
Conventional radiographs may reveal undertubulation (Erlenmeyer flask configuration) in the distal femur and endosteal scalloping as a sign of bone marrow infiltration. MRI reveals the extent of marrow involvement and the presence of fibrosis and/or infarction. In general, marrow infiltration extends from the axial to the appendicular skeleton, and greater involvement is often seen in the lower extremities and proximal sites of an affected bone. The epiphyses are usually spared, except in advanced disease. Bone densitometry studies enable quantitative assessment of the degree of osteopenia.
Bone disease in GD may not correlate with the severity of hematologic or visceral problems.
Peripheral neuropathy has been described in individuals with type 1 GD, when testing is performed; however, in most individuals this is a subclinical finding [
Thrombocytopenia may result from hypersplenism, splenic pooling of platelets, or marrow infiltration or infarction. Immune thrombocytopenia has also been reported and should be excluded in individuals with persistent thrombocytopenia despite GD-specific therapy. Thrombocytopenia may be associated with easy bruising or overt bleeding, particularly with trauma, surgery, or pregnancy. The risk for bleeding may be increased in the presence of clotting abnormalities.
Anemia may result from hypersplenism, hemodilution (e.g., pregnancy), iron deficiency, vitamin B
Leukopenia is rarely severe enough to require intervention. Deficient neutrophil function has been reported.
Interstitial lung disease
Alveolar/lobar consolidation
Pulmonary arterial hypertension (PAH) is well documented in individuals with liver disease and is presumably the result of inability to detoxify gut-derived factors, which somehow adversely affect the pulmonary endothelium with resultant pulmonary hypertension. PAH can also occur in individuals with GD without liver disease, although in most individuals it is not clinically significant and is not progressive [
Dyspnea and cyanosis with digital clubbing attributed to hepatopulmonary syndrome have been described in individuals with liver dysfunction; this is often caused by an intercurrent disease (e.g., viral hepatitis).
Note: Individuals with type 1 GD without evidence of pulmonary involvement who limit physical exertion because of easy fatigability may have impaired circulation [
In some women the diagnosis of GD is first identified during pregnancy due to exacerbation of hematologic features.
Epidemiologic studies have also suggested an elevated risk of additional malignancies including hepatocellular carcinoma [
Additional genetic risk factors may contribute to the risk of PD in those with type 1 GD. A recent study found that non-
• Interstitial lung disease
• Alveolar/lobar consolidation
• Pulmonary arterial hypertension (PAH) is well documented in individuals with liver disease and is presumably the result of inability to detoxify gut-derived factors, which somehow adversely affect the pulmonary endothelium with resultant pulmonary hypertension. PAH can also occur in individuals with GD without liver disease, although in most individuals it is not clinically significant and is not progressive [
• Dyspnea and cyanosis with digital clubbing attributed to hepatopulmonary syndrome have been described in individuals with liver dysfunction; this is often caused by an intercurrent disease (e.g., viral hepatitis).
## Type 2 GD / Type 3 GD (Primary Neurologic Disease)
Bulbar signs (i.e., stridor, squint, and swallowing difficulty) and pyramidal signs (i.e., opisthotonos, head retroflexion, spasticity, and trismus) in infancy are characteristic of type 2 GD.
Oculomotor apraxia, saccadic initiation failure, and opticokinetic nystagmus are common in type 3 GD [
Generalized tonic-clonic seizures and progressive myoclonic epilepsy have been observed in some individuals [
Dementia and ataxia have been observed in the later stages of chronic neurologic disease.
Brain stem auditory evoked response (BAER) testing may reveal abnormal wave forms (III and IV) [
## Perinatal-Lethal Form
The perinatal-lethal form of GD is associated with hepatosplenomegaly, pancytopenia, and microscopic skin changes (i.e., abnormalities in the stratum corneum attributed to altered glucosylceramide-to-ceramide ratio) and may present clinically with ichthyosiform or collodion skin abnormalities or as nonimmune hydrops fetalis [
Another rare severe variant of GD is associated with hydrocephalus, corneal opacities, deformed toes, gastroesophageal reflux, and fibrous thickening of splenic and hepatic capsules [
## Cardiovascular Form
Individuals homozygous for
## Heterozygotes
Family studies suggest that the incidence of parkinsonism is higher in obligate heterozygotes for a
## Genotype-Phenotype Correlations
The level of residual glucocerebrosidase enzyme activity as measured in vitro from extracts of nucleated cells does not correlate with disease type or severity.
Genotype-phenotype correlations in GD are imperfect. Significant overlap in the clinical manifestations found between individuals with the various genotypes precludes specific counseling about prognosis in individual cases [
Individuals with at least one
In general, individuals who are homozygous for the
Individuals who are homozygous for
In a study of 31 individuals with type 2 GD, p.Leu483Pro accounted for 25 alleles (40%) [
In another study, homozygosity for p.Leu483Pro was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [
In a study of affected individuals of Japanese and Korean ancestry with GD including type 1, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese individuals was
In individuals with GD and myoclonic epilepsy,
A second variant,
Homozygosity for recombinant alleles [
Compound heterozygosity for an insertion-type pathogenic variant and the pathogenic missense variant
• Individuals with at least one
• In general, individuals who are homozygous for the
• Individuals who are homozygous for
• In a study of 31 individuals with type 2 GD, p.Leu483Pro accounted for 25 alleles (40%) [
• In another study, homozygosity for p.Leu483Pro was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [
• In a study of affected individuals of Japanese and Korean ancestry with GD including type 1, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese individuals was
• In a study of 31 individuals with type 2 GD, p.Leu483Pro accounted for 25 alleles (40%) [
• In another study, homozygosity for p.Leu483Pro was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [
• In a study of affected individuals of Japanese and Korean ancestry with GD including type 1, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese individuals was
• In individuals with GD and myoclonic epilepsy,
• A second variant,
• In a study of 31 individuals with type 2 GD, p.Leu483Pro accounted for 25 alleles (40%) [
• In another study, homozygosity for p.Leu483Pro was the most common genotype among individuals with type 3 GD (10/24 individuals, or 42%) [
• In a study of affected individuals of Japanese and Korean ancestry with GD including type 1, p.Leu483Pro accounted for 41% and 20.8% of alleles, respectively. The second most common allele among Japanese individuals was
• Homozygosity for recombinant alleles [
• Compound heterozygosity for an insertion-type pathogenic variant and the pathogenic missense variant
## Prevalence
Incidence and prevalence estimates for GD are scarce, except for reports regarding specific populations. Prevalence estimates are also variable, with higher prevalence in populations or regions with known founder variants (e.g., Ashkenazi Jews). A recent review, based on a targeted literature search conducted from January 2011 to September 2020, revealed incidence estimates including all GD subtypes ranging from 0.45-25.0:100,000 live births (16 studies); incidence was lowest for Asia-Pacific populations. The incidence of type 1 GD was estimated at 0.45-22.9:100,000 live births (Europe and North America) and type 3 GD at 1.36:100,000 live births (Asia-Pacific only). GD type-specific prevalence estimates per 100,000 population were type 1 GD: 0.26-0.63; type 2 GD and type 3 GD: 0.02-0.08 (Europe only). Estimates for GD type unspecified or overall ranged from 0.11-139.0:100,000 inhabitants (17 studies); the highest prevalence was in North America [
A founder effect for specific alleles underlies the observed occurrence of GD in specific populations:
Ashkenazi Jewish, Spanish, and Portuguese (
Swedish (
Jenin Arab, Greek, and Albanian (
Type 1 GD (non-neuropathic) is prevalent in the Ashkenazi Jewish population, with a disease prevalence of 1:855 and an estimated carrier frequency of 1/18.
As noted, the prevalence of types 2 and 3 GD (neuropathic) varies across ethnic groups but appears to be higher among those who are not of European origin.
• Ashkenazi Jewish, Spanish, and Portuguese (
• Swedish (
• Jenin Arab, Greek, and Albanian (
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Findings in Gaucher disease (GD) may overlap with some lysosomal storage diseases (see
Genes of Interest in the Differential Diagnosis of Gaucher Disease
Coarse facial features
Dysostosis multiplex on skeletal radiographs
Vacuolated lymphocytes on peripheral blood smear
Presence of a cherry-red spot on fundoscopy
White matter changes (leukodystrophy) on brain MRI
GD = Gaucher disease; GL1 = glucosylceramide; MPS = mucopolysaccharidoses
Lysosomal storage disorders are typically inherited in an autosomal recessive manner. An exception is mucopolysaccharidosis type II, which is inherited in an X-linked manner.
Saposin C is a cofactor for glucocerebrosidase in the hydrolysis of GL1.
• Coarse facial features
• Dysostosis multiplex on skeletal radiographs
• Vacuolated lymphocytes on peripheral blood smear
• Presence of a cherry-red spot on fundoscopy
• White matter changes (leukodystrophy) on brain MRI
## Lysosomal Storage Disorders
Findings in Gaucher disease (GD) may overlap with some lysosomal storage diseases (see
Genes of Interest in the Differential Diagnosis of Gaucher Disease
Coarse facial features
Dysostosis multiplex on skeletal radiographs
Vacuolated lymphocytes on peripheral blood smear
Presence of a cherry-red spot on fundoscopy
White matter changes (leukodystrophy) on brain MRI
GD = Gaucher disease; GL1 = glucosylceramide; MPS = mucopolysaccharidoses
Lysosomal storage disorders are typically inherited in an autosomal recessive manner. An exception is mucopolysaccharidosis type II, which is inherited in an X-linked manner.
Saposin C is a cofactor for glucocerebrosidase in the hydrolysis of GL1.
• Coarse facial features
• Dysostosis multiplex on skeletal radiographs
• Vacuolated lymphocytes on peripheral blood smear
• Presence of a cherry-red spot on fundoscopy
• White matter changes (leukodystrophy) on brain MRI
## Other Disorders
## Management
Clinical management guidelines for Gaucher disease (GD) have been published [
To establish the extent of disease and needs in an individual diagnosed with GD, the evaluations summarized in
Gaucher Disease: Recommended Evaluations Following Initial Diagnosis in Adults or Those with Type 1 Gaucher Disease
AP femora & lateral spine
Any symptomatic extremities (w/pain, swelling, or warmth to touch)
Bone age (left hand & wrist) in children w/growth & pubertal delay
Assess for clinical manifestations of gallstones: acute severe abdominal pain w/liver dysfunction (e.g., conjugated hyperbilirubinemia)
Ultrasound of gallbladder
Assess for clinical manifestations of pulmonary disease
EKG & echocardiogram to identify ↑ pulmonary artery pressure
AP = anterior posterior; DXA = dual-energy x-ray absorptiometry; GD = Gaucher disease; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Type 2 and Type 3 Gaucher Disease: Recommended Evaluations Following Initial Diagnosis in Neonates and Children
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assess for seizures.
Consider EEG if seizures are a concern.
Assess for bulbar involvement & abnormal ocular movements.
Community or
Social work involvement for parental support
Home nursing referral
GD = Gaucher disease
Targeted therapy includes enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and hematopoietic stem cell transplantation (HSCT). Note: Individuals with type 2 GD and those with hydrops fetalis are not appropriate candidates for ERT, SRT, or HSCT; although life may be prolonged by these therapeutic options, severe neurologic manifestations are not altered [
The optimal dose and frequency of ERT is not certain, mostly due to limited information regarding tissue half-life, distribution, and clinical disease markers. Intravenously infused enzyme may not reach adequate concentrations in certain body sites (e.g., brain, bones, and lungs). In the majority of individuals, treatment is initiated with a dose of 15-60 units of enzyme per kg of body weight administered intravenously every two weeks. The enzyme dose may be increased or decreased after initiation of treatment and during the maintenance phase, based on response (e.g., hematopoietic reconstitution, reduction of liver and spleen volumes, and stabilization or improvement of skeletal findings). Long-term data from the ICGG Registry have been published [
ERT has been demonstrated to be safe and effective in reversing features resulting from hematologic and visceral (liver/spleen) involvement. After prolonged treatment, ERT reduces the rate of bone loss in a dose-dependent manner [
It is likely that end-stage histologic changes (e.g., fibrosis, infarction) influence the response to ERT. Thrombocytopenia may persist in individuals with residual splenomegaly and/or the presence of splenic nodules [
ERT is well tolerated. Approximately 10%-15% of individuals develop antibodies to infused imiglucerase, whereas antibody formation has been reported in 1% of persons receiving velaglucerase. Four of 18 (22%) individuals in the taliglucerase trials developed anti-drug antibodies [
ERT does not alter the ultimate prognosis of neurologic disease in GD, although treatment can lead to significant improvement in systemic manifestations and quality of life [
Note: Affected individuals may require assistance with insurance-related issues and reimbursement because of the high cost of ERT.
Note: (1) Reported side effects of eliglustat were generally mild. (2) The use of eliglustat requires cytochrome P450 2D6 genotyping and avoidance of drugs that may interact through this metabolic pathway [
Note: SRT used in combination with ERT for type 3 GD with progressive neurologic disease does not appear to alter ultimate prognosis. Moreover, residual somatic symptoms, including kyphosis and lymphadenopathy, may also be observed [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields through a Comprehensive Gaucher Center (see
Gaucher Disease: Treatment of Manifestations
Referral to orthopedist to eval for mechanical problem (e.g., pathologic fracture or joint collapse secondary to osteonecrosis, degenerative arthritis)
Analgesics
Joint replacement surgery as needed
Referral to metabolic bone specialist
Calcium & vitamin D
Anti-bone-resorbing agents may be indicated.
Massive splenomegaly
Significant areas of splenic fibrosis
Persistent severe thrombocytopenia w/high risk of bleeding
Partial or toral splenectomy may be needed in those w/massive spleen, areas of fibrosis, & persistent significant thrombocytopenia (platelets <30,000/mm
Splenectomy is not recommended where ERT/SRT is available, & there is no emergency bleeding, as it is assoc w/↑ bone disease.
Transfusion of blood products as needed for severe anemia &/or bleeding diathesis
Eval by hematologist prior to any major surgery, dental procedure, or parturition.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
GD = Gaucher disease; ERT = enzyme replacement therapy; SRT = substrate reduction therapy
Physicians who are the US regional coordinators for the International Collaborative Gaucher Group Registry (ICGG) and other groups have published recommendations for comprehensive serial monitoring of the severity and rate of disease progression [
Gaucher Disease: Recommended Surveillance
Lyso-Gb1
Plasma activity of chitotriosidase (a macrophage-derived chitin-fragmenting hydrolase)
Plasma PARC/CCL18
T
T
In those w/suspected osteoporosis
At least every 2 yrs, in persons w/osteoporosis identified on previous DXA scan
Assessment of spleen & liver volumes (& parenchymal abnl) by abdominal MRI or ultrasound (if MRI is not available)
Assessment for gallstones
At least every 1-2 yrs
Persons w/gallstones may need more frequent follow up by ultrasound.
At least every 6-12 mos
If abnormal results are obtained, consider referral to gastroenterologist.
Hemoglobin
Platelet count
Coagulation indices
Prior to surgical or dental procedures
Additional testing based on symptoms & treatment status
Assessment for shortness of breath
Pulmonary exam
Assessment for fatigue
Clinical cardiac exam
DXA = dual-energy x-ray absorptiometry; lyso-Gb1 = glucosylsphingosine
Levels are typically elevated and are felt to correlate with body-wide burden of disease. An enzyme dose-dependent decrease in plasma chitotriosidase activity has been observed in affected individuals on ERT or SRT; however, up to 40% of affected individuals of European origin are homozygous or heterozygous for a common null variant, confounding interpretation of test results [
Nonsteroidal anti-inflammatory drugs should be avoided in individuals with moderate-to-severe thrombocytopenia. The use of anticoagulants in individuals with severe thrombocytopenia and/or coagulopathy should be discussed with a hematologist to avoid the possibility of excessive bleeding.
It is appropriate to evaluate asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and targeted therapy to reduce morbidity. Evaluations can include:
Assay of glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells;
Molecular genetic testing if the pathogenic variants in the family are known.
See
Pregnancy may affect the course of GD both by exacerbating preexisting symptoms and by triggering new features such as bone pain. Women with severe thrombocytopenia and/or clotting abnormalities may be at an increased risk for bleeding around the time of delivery; therefore, evaluation by a hematologist prior to delivery is recommended [
Although eliglustat use is not contraindicated during pregnancy and breastfeeding, the lack of controlled studies demonstrating the safety of eliglustat during human pregnancy and lactation has led to a recommendation to avoid this treatment during pregnancy, if possible [
See
Ambroxol, a mucolytic agent, is also a potential pharmacologic glucocerebrosidase chaperone. An open-label pilot study of high-dose oral ambroxol in combination with ERT in five affected individuals found that ambroxol had a good safety and tolerability profile. Significantly increased lymphocyte glucocerebrosidase activity and decreased glucosylsphingosine levels in the cerebrospinal fluid were also noted. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all affected individuals. Relief from myoclonus led to impressive recovery of gross motor function in two individuals, allowing them to walk again [
Search
The elevation of the serum concentration of several serologic markers (e.g., CCL18/PARC, chitotriosidase) in individuals with GD is considered a possible surrogate indicator of disease burden that could be used in monitoring treatment response [
Glucosylsphingosine (lyso-Gb1), a deacylated lysolipid, has been found to be massively elevated in the plasma of individuals with type 1 GD (n=169), with marked reduction observed following treatment with ERT or SRT [
Elevation of the protein glycoprotein non-metastatic B, found in brain samples from individuals with type 2 and 3 GD, may be used as a marker to quantify neuropathology in those with GD and as a marker of treatment efficacy once suitable treatments are initiated [
• AP femora & lateral spine
• Any symptomatic extremities (w/pain, swelling, or warmth to touch)
• Bone age (left hand & wrist) in children w/growth & pubertal delay
• Assess for clinical manifestations of gallstones: acute severe abdominal pain w/liver dysfunction (e.g., conjugated hyperbilirubinemia)
• Ultrasound of gallbladder
• Assess for clinical manifestations of pulmonary disease
• EKG & echocardiogram to identify ↑ pulmonary artery pressure
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assess for seizures.
• Consider EEG if seizures are a concern.
• Assess for bulbar involvement & abnormal ocular movements.
• Community or
• Social work involvement for parental support
• Home nursing referral
• The optimal dose and frequency of ERT is not certain, mostly due to limited information regarding tissue half-life, distribution, and clinical disease markers. Intravenously infused enzyme may not reach adequate concentrations in certain body sites (e.g., brain, bones, and lungs). In the majority of individuals, treatment is initiated with a dose of 15-60 units of enzyme per kg of body weight administered intravenously every two weeks. The enzyme dose may be increased or decreased after initiation of treatment and during the maintenance phase, based on response (e.g., hematopoietic reconstitution, reduction of liver and spleen volumes, and stabilization or improvement of skeletal findings). Long-term data from the ICGG Registry have been published [
• ERT has been demonstrated to be safe and effective in reversing features resulting from hematologic and visceral (liver/spleen) involvement. After prolonged treatment, ERT reduces the rate of bone loss in a dose-dependent manner [
• It is likely that end-stage histologic changes (e.g., fibrosis, infarction) influence the response to ERT. Thrombocytopenia may persist in individuals with residual splenomegaly and/or the presence of splenic nodules [
• ERT does not alter the ultimate prognosis of neurologic disease in GD, although treatment can lead to significant improvement in systemic manifestations and quality of life [
• Note: (1) Reported side effects of eliglustat were generally mild. (2) The use of eliglustat requires cytochrome P450 2D6 genotyping and avoidance of drugs that may interact through this metabolic pathway [
• Referral to orthopedist to eval for mechanical problem (e.g., pathologic fracture or joint collapse secondary to osteonecrosis, degenerative arthritis)
• Analgesics
• Joint replacement surgery as needed
• Referral to metabolic bone specialist
• Calcium & vitamin D
• Anti-bone-resorbing agents may be indicated.
• Massive splenomegaly
• Significant areas of splenic fibrosis
• Persistent severe thrombocytopenia w/high risk of bleeding
• Partial or toral splenectomy may be needed in those w/massive spleen, areas of fibrosis, & persistent significant thrombocytopenia (platelets <30,000/mm
• Splenectomy is not recommended where ERT/SRT is available, & there is no emergency bleeding, as it is assoc w/↑ bone disease.
• Transfusion of blood products as needed for severe anemia &/or bleeding diathesis
• Eval by hematologist prior to any major surgery, dental procedure, or parturition.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• Lyso-Gb1
• Plasma activity of chitotriosidase (a macrophage-derived chitin-fragmenting hydrolase)
• Plasma PARC/CCL18
• T
• T
• In those w/suspected osteoporosis
• At least every 2 yrs, in persons w/osteoporosis identified on previous DXA scan
• Assessment of spleen & liver volumes (& parenchymal abnl) by abdominal MRI or ultrasound (if MRI is not available)
• Assessment for gallstones
• At least every 1-2 yrs
• Persons w/gallstones may need more frequent follow up by ultrasound.
• At least every 6-12 mos
• If abnormal results are obtained, consider referral to gastroenterologist.
• Hemoglobin
• Platelet count
• Coagulation indices
• Prior to surgical or dental procedures
• Additional testing based on symptoms & treatment status
• Assessment for shortness of breath
• Pulmonary exam
• Assessment for fatigue
• Clinical cardiac exam
• Assay of glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells;
• Molecular genetic testing if the pathogenic variants in the family are known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with GD, the evaluations summarized in
Gaucher Disease: Recommended Evaluations Following Initial Diagnosis in Adults or Those with Type 1 Gaucher Disease
AP femora & lateral spine
Any symptomatic extremities (w/pain, swelling, or warmth to touch)
Bone age (left hand & wrist) in children w/growth & pubertal delay
Assess for clinical manifestations of gallstones: acute severe abdominal pain w/liver dysfunction (e.g., conjugated hyperbilirubinemia)
Ultrasound of gallbladder
Assess for clinical manifestations of pulmonary disease
EKG & echocardiogram to identify ↑ pulmonary artery pressure
AP = anterior posterior; DXA = dual-energy x-ray absorptiometry; GD = Gaucher disease; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Type 2 and Type 3 Gaucher Disease: Recommended Evaluations Following Initial Diagnosis in Neonates and Children
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assess for seizures.
Consider EEG if seizures are a concern.
Assess for bulbar involvement & abnormal ocular movements.
Community or
Social work involvement for parental support
Home nursing referral
GD = Gaucher disease
• AP femora & lateral spine
• Any symptomatic extremities (w/pain, swelling, or warmth to touch)
• Bone age (left hand & wrist) in children w/growth & pubertal delay
• Assess for clinical manifestations of gallstones: acute severe abdominal pain w/liver dysfunction (e.g., conjugated hyperbilirubinemia)
• Ultrasound of gallbladder
• Assess for clinical manifestations of pulmonary disease
• EKG & echocardiogram to identify ↑ pulmonary artery pressure
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assess for seizures.
• Consider EEG if seizures are a concern.
• Assess for bulbar involvement & abnormal ocular movements.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Targeted therapy includes enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and hematopoietic stem cell transplantation (HSCT). Note: Individuals with type 2 GD and those with hydrops fetalis are not appropriate candidates for ERT, SRT, or HSCT; although life may be prolonged by these therapeutic options, severe neurologic manifestations are not altered [
The optimal dose and frequency of ERT is not certain, mostly due to limited information regarding tissue half-life, distribution, and clinical disease markers. Intravenously infused enzyme may not reach adequate concentrations in certain body sites (e.g., brain, bones, and lungs). In the majority of individuals, treatment is initiated with a dose of 15-60 units of enzyme per kg of body weight administered intravenously every two weeks. The enzyme dose may be increased or decreased after initiation of treatment and during the maintenance phase, based on response (e.g., hematopoietic reconstitution, reduction of liver and spleen volumes, and stabilization or improvement of skeletal findings). Long-term data from the ICGG Registry have been published [
ERT has been demonstrated to be safe and effective in reversing features resulting from hematologic and visceral (liver/spleen) involvement. After prolonged treatment, ERT reduces the rate of bone loss in a dose-dependent manner [
It is likely that end-stage histologic changes (e.g., fibrosis, infarction) influence the response to ERT. Thrombocytopenia may persist in individuals with residual splenomegaly and/or the presence of splenic nodules [
ERT is well tolerated. Approximately 10%-15% of individuals develop antibodies to infused imiglucerase, whereas antibody formation has been reported in 1% of persons receiving velaglucerase. Four of 18 (22%) individuals in the taliglucerase trials developed anti-drug antibodies [
ERT does not alter the ultimate prognosis of neurologic disease in GD, although treatment can lead to significant improvement in systemic manifestations and quality of life [
Note: Affected individuals may require assistance with insurance-related issues and reimbursement because of the high cost of ERT.
Note: (1) Reported side effects of eliglustat were generally mild. (2) The use of eliglustat requires cytochrome P450 2D6 genotyping and avoidance of drugs that may interact through this metabolic pathway [
Note: SRT used in combination with ERT for type 3 GD with progressive neurologic disease does not appear to alter ultimate prognosis. Moreover, residual somatic symptoms, including kyphosis and lymphadenopathy, may also be observed [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields through a Comprehensive Gaucher Center (see
Gaucher Disease: Treatment of Manifestations
Referral to orthopedist to eval for mechanical problem (e.g., pathologic fracture or joint collapse secondary to osteonecrosis, degenerative arthritis)
Analgesics
Joint replacement surgery as needed
Referral to metabolic bone specialist
Calcium & vitamin D
Anti-bone-resorbing agents may be indicated.
Massive splenomegaly
Significant areas of splenic fibrosis
Persistent severe thrombocytopenia w/high risk of bleeding
Partial or toral splenectomy may be needed in those w/massive spleen, areas of fibrosis, & persistent significant thrombocytopenia (platelets <30,000/mm
Splenectomy is not recommended where ERT/SRT is available, & there is no emergency bleeding, as it is assoc w/↑ bone disease.
Transfusion of blood products as needed for severe anemia &/or bleeding diathesis
Eval by hematologist prior to any major surgery, dental procedure, or parturition.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
GD = Gaucher disease; ERT = enzyme replacement therapy; SRT = substrate reduction therapy
• The optimal dose and frequency of ERT is not certain, mostly due to limited information regarding tissue half-life, distribution, and clinical disease markers. Intravenously infused enzyme may not reach adequate concentrations in certain body sites (e.g., brain, bones, and lungs). In the majority of individuals, treatment is initiated with a dose of 15-60 units of enzyme per kg of body weight administered intravenously every two weeks. The enzyme dose may be increased or decreased after initiation of treatment and during the maintenance phase, based on response (e.g., hematopoietic reconstitution, reduction of liver and spleen volumes, and stabilization or improvement of skeletal findings). Long-term data from the ICGG Registry have been published [
• ERT has been demonstrated to be safe and effective in reversing features resulting from hematologic and visceral (liver/spleen) involvement. After prolonged treatment, ERT reduces the rate of bone loss in a dose-dependent manner [
• It is likely that end-stage histologic changes (e.g., fibrosis, infarction) influence the response to ERT. Thrombocytopenia may persist in individuals with residual splenomegaly and/or the presence of splenic nodules [
• ERT does not alter the ultimate prognosis of neurologic disease in GD, although treatment can lead to significant improvement in systemic manifestations and quality of life [
• Note: (1) Reported side effects of eliglustat were generally mild. (2) The use of eliglustat requires cytochrome P450 2D6 genotyping and avoidance of drugs that may interact through this metabolic pathway [
• Referral to orthopedist to eval for mechanical problem (e.g., pathologic fracture or joint collapse secondary to osteonecrosis, degenerative arthritis)
• Analgesics
• Joint replacement surgery as needed
• Referral to metabolic bone specialist
• Calcium & vitamin D
• Anti-bone-resorbing agents may be indicated.
• Massive splenomegaly
• Significant areas of splenic fibrosis
• Persistent severe thrombocytopenia w/high risk of bleeding
• Partial or toral splenectomy may be needed in those w/massive spleen, areas of fibrosis, & persistent significant thrombocytopenia (platelets <30,000/mm
• Splenectomy is not recommended where ERT/SRT is available, & there is no emergency bleeding, as it is assoc w/↑ bone disease.
• Transfusion of blood products as needed for severe anemia &/or bleeding diathesis
• Eval by hematologist prior to any major surgery, dental procedure, or parturition.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
## Targeted Therapy
Targeted therapy includes enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and hematopoietic stem cell transplantation (HSCT). Note: Individuals with type 2 GD and those with hydrops fetalis are not appropriate candidates for ERT, SRT, or HSCT; although life may be prolonged by these therapeutic options, severe neurologic manifestations are not altered [
The optimal dose and frequency of ERT is not certain, mostly due to limited information regarding tissue half-life, distribution, and clinical disease markers. Intravenously infused enzyme may not reach adequate concentrations in certain body sites (e.g., brain, bones, and lungs). In the majority of individuals, treatment is initiated with a dose of 15-60 units of enzyme per kg of body weight administered intravenously every two weeks. The enzyme dose may be increased or decreased after initiation of treatment and during the maintenance phase, based on response (e.g., hematopoietic reconstitution, reduction of liver and spleen volumes, and stabilization or improvement of skeletal findings). Long-term data from the ICGG Registry have been published [
ERT has been demonstrated to be safe and effective in reversing features resulting from hematologic and visceral (liver/spleen) involvement. After prolonged treatment, ERT reduces the rate of bone loss in a dose-dependent manner [
It is likely that end-stage histologic changes (e.g., fibrosis, infarction) influence the response to ERT. Thrombocytopenia may persist in individuals with residual splenomegaly and/or the presence of splenic nodules [
ERT is well tolerated. Approximately 10%-15% of individuals develop antibodies to infused imiglucerase, whereas antibody formation has been reported in 1% of persons receiving velaglucerase. Four of 18 (22%) individuals in the taliglucerase trials developed anti-drug antibodies [
ERT does not alter the ultimate prognosis of neurologic disease in GD, although treatment can lead to significant improvement in systemic manifestations and quality of life [
Note: Affected individuals may require assistance with insurance-related issues and reimbursement because of the high cost of ERT.
Note: (1) Reported side effects of eliglustat were generally mild. (2) The use of eliglustat requires cytochrome P450 2D6 genotyping and avoidance of drugs that may interact through this metabolic pathway [
Note: SRT used in combination with ERT for type 3 GD with progressive neurologic disease does not appear to alter ultimate prognosis. Moreover, residual somatic symptoms, including kyphosis and lymphadenopathy, may also be observed [
• The optimal dose and frequency of ERT is not certain, mostly due to limited information regarding tissue half-life, distribution, and clinical disease markers. Intravenously infused enzyme may not reach adequate concentrations in certain body sites (e.g., brain, bones, and lungs). In the majority of individuals, treatment is initiated with a dose of 15-60 units of enzyme per kg of body weight administered intravenously every two weeks. The enzyme dose may be increased or decreased after initiation of treatment and during the maintenance phase, based on response (e.g., hematopoietic reconstitution, reduction of liver and spleen volumes, and stabilization or improvement of skeletal findings). Long-term data from the ICGG Registry have been published [
• ERT has been demonstrated to be safe and effective in reversing features resulting from hematologic and visceral (liver/spleen) involvement. After prolonged treatment, ERT reduces the rate of bone loss in a dose-dependent manner [
• It is likely that end-stage histologic changes (e.g., fibrosis, infarction) influence the response to ERT. Thrombocytopenia may persist in individuals with residual splenomegaly and/or the presence of splenic nodules [
• ERT does not alter the ultimate prognosis of neurologic disease in GD, although treatment can lead to significant improvement in systemic manifestations and quality of life [
• Note: (1) Reported side effects of eliglustat were generally mild. (2) The use of eliglustat requires cytochrome P450 2D6 genotyping and avoidance of drugs that may interact through this metabolic pathway [
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields through a Comprehensive Gaucher Center (see
Gaucher Disease: Treatment of Manifestations
Referral to orthopedist to eval for mechanical problem (e.g., pathologic fracture or joint collapse secondary to osteonecrosis, degenerative arthritis)
Analgesics
Joint replacement surgery as needed
Referral to metabolic bone specialist
Calcium & vitamin D
Anti-bone-resorbing agents may be indicated.
Massive splenomegaly
Significant areas of splenic fibrosis
Persistent severe thrombocytopenia w/high risk of bleeding
Partial or toral splenectomy may be needed in those w/massive spleen, areas of fibrosis, & persistent significant thrombocytopenia (platelets <30,000/mm
Splenectomy is not recommended where ERT/SRT is available, & there is no emergency bleeding, as it is assoc w/↑ bone disease.
Transfusion of blood products as needed for severe anemia &/or bleeding diathesis
Eval by hematologist prior to any major surgery, dental procedure, or parturition.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
GD = Gaucher disease; ERT = enzyme replacement therapy; SRT = substrate reduction therapy
• Referral to orthopedist to eval for mechanical problem (e.g., pathologic fracture or joint collapse secondary to osteonecrosis, degenerative arthritis)
• Analgesics
• Joint replacement surgery as needed
• Referral to metabolic bone specialist
• Calcium & vitamin D
• Anti-bone-resorbing agents may be indicated.
• Massive splenomegaly
• Significant areas of splenic fibrosis
• Persistent severe thrombocytopenia w/high risk of bleeding
• Partial or toral splenectomy may be needed in those w/massive spleen, areas of fibrosis, & persistent significant thrombocytopenia (platelets <30,000/mm
• Splenectomy is not recommended where ERT/SRT is available, & there is no emergency bleeding, as it is assoc w/↑ bone disease.
• Transfusion of blood products as needed for severe anemia &/or bleeding diathesis
• Eval by hematologist prior to any major surgery, dental procedure, or parturition.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
## Surveillance
Physicians who are the US regional coordinators for the International Collaborative Gaucher Group Registry (ICGG) and other groups have published recommendations for comprehensive serial monitoring of the severity and rate of disease progression [
Gaucher Disease: Recommended Surveillance
Lyso-Gb1
Plasma activity of chitotriosidase (a macrophage-derived chitin-fragmenting hydrolase)
Plasma PARC/CCL18
T
T
In those w/suspected osteoporosis
At least every 2 yrs, in persons w/osteoporosis identified on previous DXA scan
Assessment of spleen & liver volumes (& parenchymal abnl) by abdominal MRI or ultrasound (if MRI is not available)
Assessment for gallstones
At least every 1-2 yrs
Persons w/gallstones may need more frequent follow up by ultrasound.
At least every 6-12 mos
If abnormal results are obtained, consider referral to gastroenterologist.
Hemoglobin
Platelet count
Coagulation indices
Prior to surgical or dental procedures
Additional testing based on symptoms & treatment status
Assessment for shortness of breath
Pulmonary exam
Assessment for fatigue
Clinical cardiac exam
DXA = dual-energy x-ray absorptiometry; lyso-Gb1 = glucosylsphingosine
Levels are typically elevated and are felt to correlate with body-wide burden of disease. An enzyme dose-dependent decrease in plasma chitotriosidase activity has been observed in affected individuals on ERT or SRT; however, up to 40% of affected individuals of European origin are homozygous or heterozygous for a common null variant, confounding interpretation of test results [
• Lyso-Gb1
• Plasma activity of chitotriosidase (a macrophage-derived chitin-fragmenting hydrolase)
• Plasma PARC/CCL18
• T
• T
• In those w/suspected osteoporosis
• At least every 2 yrs, in persons w/osteoporosis identified on previous DXA scan
• Assessment of spleen & liver volumes (& parenchymal abnl) by abdominal MRI or ultrasound (if MRI is not available)
• Assessment for gallstones
• At least every 1-2 yrs
• Persons w/gallstones may need more frequent follow up by ultrasound.
• At least every 6-12 mos
• If abnormal results are obtained, consider referral to gastroenterologist.
• Hemoglobin
• Platelet count
• Coagulation indices
• Prior to surgical or dental procedures
• Additional testing based on symptoms & treatment status
• Assessment for shortness of breath
• Pulmonary exam
• Assessment for fatigue
• Clinical cardiac exam
## Agents/Circumstances to Avoid
Nonsteroidal anti-inflammatory drugs should be avoided in individuals with moderate-to-severe thrombocytopenia. The use of anticoagulants in individuals with severe thrombocytopenia and/or coagulopathy should be discussed with a hematologist to avoid the possibility of excessive bleeding.
## Evaluation of Relatives at Risk
It is appropriate to evaluate asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and targeted therapy to reduce morbidity. Evaluations can include:
Assay of glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells;
Molecular genetic testing if the pathogenic variants in the family are known.
See
• Assay of glucocerebrosidase enzyme activity in peripheral blood leukocytes or other nucleated cells;
• Molecular genetic testing if the pathogenic variants in the family are known.
## Pregnancy Management
Pregnancy may affect the course of GD both by exacerbating preexisting symptoms and by triggering new features such as bone pain. Women with severe thrombocytopenia and/or clotting abnormalities may be at an increased risk for bleeding around the time of delivery; therefore, evaluation by a hematologist prior to delivery is recommended [
Although eliglustat use is not contraindicated during pregnancy and breastfeeding, the lack of controlled studies demonstrating the safety of eliglustat during human pregnancy and lactation has led to a recommendation to avoid this treatment during pregnancy, if possible [
See
## Therapies Under Investigation
Ambroxol, a mucolytic agent, is also a potential pharmacologic glucocerebrosidase chaperone. An open-label pilot study of high-dose oral ambroxol in combination with ERT in five affected individuals found that ambroxol had a good safety and tolerability profile. Significantly increased lymphocyte glucocerebrosidase activity and decreased glucosylsphingosine levels in the cerebrospinal fluid were also noted. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all affected individuals. Relief from myoclonus led to impressive recovery of gross motor function in two individuals, allowing them to walk again [
Search
## Other
The elevation of the serum concentration of several serologic markers (e.g., CCL18/PARC, chitotriosidase) in individuals with GD is considered a possible surrogate indicator of disease burden that could be used in monitoring treatment response [
Glucosylsphingosine (lyso-Gb1), a deacylated lysolipid, has been found to be massively elevated in the plasma of individuals with type 1 GD (n=169), with marked reduction observed following treatment with ERT or SRT [
Elevation of the protein glycoprotein non-metastatic B, found in brain samples from individuals with type 2 and 3 GD, may be used as a marker to quantify neuropathology in those with GD and as a marker of treatment efficacy once suitable treatments are initiated [
## Genetic Counseling
Gaucher disease (GD) is inherited in an autosomal recessive manner.
The parents of an affected individual are typically heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description,
If both parents are known to be heterozygous for a
If one parent has biallelic
Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description,
Unless an affected individual's reproductive partner also has GD or is a carrier (see
A higher carrier rate for GD exists in populations or regions with known founder variants (see
Note: Measurement of glucocerebrosidase enzyme activity in peripheral blood leukocytes is unreliable for carrier determination because of significant overlap in residual enzyme activity levels between obligate carriers and the general (non-carrier) population.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
The American Academy of Medical Genetics includes GD among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
With the exception of families in which a previously affected sib had neurologic disease (i.e., types 2 or 3), it is not possible to be certain of the phenotypic severity in a pregnancy at risk. Individuals with GD with acute neurologic disease (i.e., type 2) tend to have a similar disease course. However, it should be noted that individuals with GD and chronic neurologic involvement (i.e., type 3) could show variable rates of disease progression, even when they are members of the same family.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are typically heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description,
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• If one parent has biallelic
• Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description,
• Unless an affected individual's reproductive partner also has GD or is a carrier (see
• A higher carrier rate for GD exists in populations or regions with known founder variants (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The American Academy of Medical Genetics includes GD among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
## Mode of Inheritance
Gaucher disease (GD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are typically heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description,
If both parents are known to be heterozygous for a
If one parent has biallelic
Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description,
Unless an affected individual's reproductive partner also has GD or is a carrier (see
A higher carrier rate for GD exists in populations or regions with known founder variants (see
• The parents of an affected individual are typically heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description,
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• If one parent has biallelic
• Heterozygotes are not at risk of developing GD. However, family studies suggest that the incidence of parkinsonism may be higher in obligate heterozygotes for GD (see Clinical Description,
• Unless an affected individual's reproductive partner also has GD or is a carrier (see
• A higher carrier rate for GD exists in populations or regions with known founder variants (see
## Carrier Detection
Note: Measurement of glucocerebrosidase enzyme activity in peripheral blood leukocytes is unreliable for carrier determination because of significant overlap in residual enzyme activity levels between obligate carriers and the general (non-carrier) population.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
The American Academy of Medical Genetics includes GD among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The American Academy of Medical Genetics includes GD among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
## Prenatal Testing and Preimplantation Genetic Testing
With the exception of families in which a previously affected sib had neurologic disease (i.e., types 2 or 3), it is not possible to be certain of the phenotypic severity in a pregnancy at risk. Individuals with GD with acute neurologic disease (i.e., type 2) tend to have a similar disease course. However, it should be noted that individuals with GD and chronic neurologic involvement (i.e., type 3) could show variable rates of disease progression, even when they are members of the same family.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
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## Molecular Genetics
Gaucher Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Gaucher Disease (
Glucocerebrosidase enzyme activity is stimulated by interaction with the lipid phosphatidylserine and the protein saposin C. Structural predictions (based on hydrophobic cluster analysis) indicate that the glutamine residues 235 and 340 play key roles in the active site of human glucocerebrosidase [
Gaucher disease (GD) is caused by deficient glucocerebrosidase activity and the resultant accumulation of its undegraded substrate, GL1, and other glycolipids. The major peripheral substrate source is the breakdown of senescent blood cells and tissue debris; the incompletely metabolized GL1 substrate is stored in cells of monocyte/macrophage lineage of the reticuloendothelial system. In the central nervous system, GL1 is believed to originate from the turnover of membrane gangliosides, although neuronal cell death may be the basis of neuropathic involvement [
Two different upstream ATG codons are utilized as translation initiation sites.
A highly homologous (96% identity) pseudogene,
See
Accounts for 14% of pathogenic variants among Japanese persons w/GD [
Common variant in Ashkenazi Jewish persons w/type 1 GD
Accounts for 41% of pathogenic variants among Japanese persons & 54% of Chinese persons w/GD [
GD = Gaucher disease
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
In the common variant names, amino acid number 1 is the first residue (Ala) of the mature protein. In contrast, the standard naming convention designates amino acid number 1 as the first residue (Met) of the signal sequence.
Variants in the signal sequence
The variants p.Asn409Ser, c.84dupG, c.115+1G>A, and p.Leu483Pro account for 90% of pathogenic variants in Ashkenazi Jewish individuals with type 1 GD and 50%-60% of pathogenic variants in non-Ashkenazi Jewish individuals with type 1 GD.
Recombinant allele derived from a recombination between functional
• Two different upstream ATG codons are utilized as translation initiation sites.
• A highly homologous (96% identity) pseudogene,
• See
• Accounts for 14% of pathogenic variants among Japanese persons w/GD [
• Common variant in Ashkenazi Jewish persons w/type 1 GD
• Accounts for 41% of pathogenic variants among Japanese persons & 54% of Chinese persons w/GD [
## Molecular Pathogenesis
Glucocerebrosidase enzyme activity is stimulated by interaction with the lipid phosphatidylserine and the protein saposin C. Structural predictions (based on hydrophobic cluster analysis) indicate that the glutamine residues 235 and 340 play key roles in the active site of human glucocerebrosidase [
Gaucher disease (GD) is caused by deficient glucocerebrosidase activity and the resultant accumulation of its undegraded substrate, GL1, and other glycolipids. The major peripheral substrate source is the breakdown of senescent blood cells and tissue debris; the incompletely metabolized GL1 substrate is stored in cells of monocyte/macrophage lineage of the reticuloendothelial system. In the central nervous system, GL1 is believed to originate from the turnover of membrane gangliosides, although neuronal cell death may be the basis of neuropathic involvement [
Two different upstream ATG codons are utilized as translation initiation sites.
A highly homologous (96% identity) pseudogene,
See
Accounts for 14% of pathogenic variants among Japanese persons w/GD [
Common variant in Ashkenazi Jewish persons w/type 1 GD
Accounts for 41% of pathogenic variants among Japanese persons & 54% of Chinese persons w/GD [
GD = Gaucher disease
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
In the common variant names, amino acid number 1 is the first residue (Ala) of the mature protein. In contrast, the standard naming convention designates amino acid number 1 as the first residue (Met) of the signal sequence.
Variants in the signal sequence
The variants p.Asn409Ser, c.84dupG, c.115+1G>A, and p.Leu483Pro account for 90% of pathogenic variants in Ashkenazi Jewish individuals with type 1 GD and 50%-60% of pathogenic variants in non-Ashkenazi Jewish individuals with type 1 GD.
Recombinant allele derived from a recombination between functional
• Two different upstream ATG codons are utilized as translation initiation sites.
• A highly homologous (96% identity) pseudogene,
• See
• Accounts for 14% of pathogenic variants among Japanese persons w/GD [
• Common variant in Ashkenazi Jewish persons w/type 1 GD
• Accounts for 41% of pathogenic variants among Japanese persons & 54% of Chinese persons w/GD [
## Chapter Notes
7 December 2023 (sw) Comprehensive update posted live
21 June 2018 (ma) Comprehensive update posted live
19 September 2013 (me) Comprehensive update posted live
1 February 2011 (me) Comprehensive update posted live
13 March 2008 (me) Comprehensive update posted live
2 June 2005 (me) Comprehensive update posted live
8 April 2003 (me) Comprehensive update posted live
27 July 2000 (me) Review posted live
23 March 2000 (gp) Original submission
• 7 December 2023 (sw) Comprehensive update posted live
• 21 June 2018 (ma) Comprehensive update posted live
• 19 September 2013 (me) Comprehensive update posted live
• 1 February 2011 (me) Comprehensive update posted live
• 13 March 2008 (me) Comprehensive update posted live
• 2 June 2005 (me) Comprehensive update posted live
• 8 April 2003 (me) Comprehensive update posted live
• 27 July 2000 (me) Review posted live
• 23 March 2000 (gp) Original submission
## Revision History
7 December 2023 (sw) Comprehensive update posted live
21 June 2018 (ma) Comprehensive update posted live
19 September 2013 (me) Comprehensive update posted live
1 February 2011 (me) Comprehensive update posted live
13 March 2008 (me) Comprehensive update posted live
2 June 2005 (me) Comprehensive update posted live
8 April 2003 (me) Comprehensive update posted live
27 July 2000 (me) Review posted live
23 March 2000 (gp) Original submission
• 7 December 2023 (sw) Comprehensive update posted live
• 21 June 2018 (ma) Comprehensive update posted live
• 19 September 2013 (me) Comprehensive update posted live
• 1 February 2011 (me) Comprehensive update posted live
• 13 March 2008 (me) Comprehensive update posted live
• 2 June 2005 (me) Comprehensive update posted live
• 8 April 2003 (me) Comprehensive update posted live
• 27 July 2000 (me) Review posted live
• 23 March 2000 (gp) Original submission
## Key Sections in this
## References
Belmatoug N, Di Rocco M, Fraga C, Giraldo P, Hughes D, Lukina E, Maison-Blanche P, Merkel M, Niederau C, Plӧckinger U, Richter J, Stulnig TM, Vom Dahl S, Cox TM. Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe. Eur J Intern Med. 2017;37:25-32. [
Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E, Fuller M, Revel-Vilk S, Hughes D, Cox T, Aerts J; International Working Group of Gaucher Disease (IWGGD). Patient centered guidelines for the laboratory diagnosis of Gaucher diseasetype 1. Orphanet J Rare Dis. 2022;17:442. [
Kishnani PS, Al-Hertani W, Balwani M, Göker-Alpan Ö, Lau HA, Wasserstein M, Weinreb NJ, Grabowski G. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus. Mol Genet Metab. 2022;135:154-162. [
• Belmatoug N, Di Rocco M, Fraga C, Giraldo P, Hughes D, Lukina E, Maison-Blanche P, Merkel M, Niederau C, Plӧckinger U, Richter J, Stulnig TM, Vom Dahl S, Cox TM. Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe. Eur J Intern Med. 2017;37:25-32. [
• Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E, Fuller M, Revel-Vilk S, Hughes D, Cox T, Aerts J; International Working Group of Gaucher Disease (IWGGD). Patient centered guidelines for the laboratory diagnosis of Gaucher diseasetype 1. Orphanet J Rare Dis. 2022;17:442. [
• Kishnani PS, Al-Hertani W, Balwani M, Göker-Alpan Ö, Lau HA, Wasserstein M, Weinreb NJ, Grabowski G. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus. Mol Genet Metab. 2022;135:154-162. [
## Published Guidelines / Consensus Statements
Belmatoug N, Di Rocco M, Fraga C, Giraldo P, Hughes D, Lukina E, Maison-Blanche P, Merkel M, Niederau C, Plӧckinger U, Richter J, Stulnig TM, Vom Dahl S, Cox TM. Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe. Eur J Intern Med. 2017;37:25-32. [
Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E, Fuller M, Revel-Vilk S, Hughes D, Cox T, Aerts J; International Working Group of Gaucher Disease (IWGGD). Patient centered guidelines for the laboratory diagnosis of Gaucher diseasetype 1. Orphanet J Rare Dis. 2022;17:442. [
Kishnani PS, Al-Hertani W, Balwani M, Göker-Alpan Ö, Lau HA, Wasserstein M, Weinreb NJ, Grabowski G. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus. Mol Genet Metab. 2022;135:154-162. [
• Belmatoug N, Di Rocco M, Fraga C, Giraldo P, Hughes D, Lukina E, Maison-Blanche P, Merkel M, Niederau C, Plӧckinger U, Richter J, Stulnig TM, Vom Dahl S, Cox TM. Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe. Eur J Intern Med. 2017;37:25-32. [
• Dardis A, Michelakakis H, Rozenfeld P, Fumic K, Wagner J, Pavan E, Fuller M, Revel-Vilk S, Hughes D, Cox T, Aerts J; International Working Group of Gaucher Disease (IWGGD). Patient centered guidelines for the laboratory diagnosis of Gaucher diseasetype 1. Orphanet J Rare Dis. 2022;17:442. [
• Kishnani PS, Al-Hertani W, Balwani M, Göker-Alpan Ö, Lau HA, Wasserstein M, Weinreb NJ, Grabowski G. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: Results from a Delphi consensus. Mol Genet Metab. 2022;135:154-162. [
## Literature Cited
|
[] |
27/7/2000
|
7/12/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
gcps
|
gcps
|
[
"Transcriptional activator GLI3",
"GLI3",
"Greig Cephalopolysyndactyly Syndrome"
] |
Greig Cephalopolysyndactyly Syndrome
|
Leslie G Biesecker, Jennifer J Johnston
|
Summary Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by macrocephaly, widely spaced eyes associated with increased interpupillary distance, preaxial polydactyly with or without postaxial polydactyly, and cutaneous syndactyly. Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (~300-kb) deletions that encompass The diagnosis of GCPS is established in a proband who has typical clinical findings and either a heterozygous pathogenic variant of GCPS is inherited in an autosomal dominant manner and is caused by either a pathogenic variant involving
|
## Diagnosis
Greig cephalopolysyndactyly syndrome (GCPS)
Macrocephaly
Widely spaced eyes associated with increased interpupillary distance (>97th centile)
Preaxial polydactyly with or without postaxial polydactyly
Cutaneous syndactyly
The diagnosis of GCPS
A heterozygous pathogenic (or likely pathogenic) variant of
A heterozygous deletion of chromosome 7p14.1 involving
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings of GCPS described in
Note: If the affected individual has significant developmental delay or intellectual disability or if there is a history of recurrent pregnancy losses for the parents of the proband, CMA should be considered first, followed by sequence analysis of
When the phenotypic findings suggest the diagnosis of GCPS, molecular genetic testing approaches can include
Note: A small number of individuals with translocations involving 7p14.1 have been reported [
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by polydactyly and/or macrocephaly,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Greig Cephalopolysyndactyly Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Some laboratories offer deletion/duplication analysis using exome or genome sequence data. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
A small number of individuals with translocations involving 7p14.1 have been reported [
• Macrocephaly
• Widely spaced eyes associated with increased interpupillary distance (>97th centile)
• Preaxial polydactyly with or without postaxial polydactyly
• Cutaneous syndactyly
• A heterozygous pathogenic (or likely pathogenic) variant of
• A heterozygous deletion of chromosome 7p14.1 involving
• Note: A small number of individuals with translocations involving 7p14.1 have been reported [
• For an introduction to multigene panels click
## Suggestive Findings
Greig cephalopolysyndactyly syndrome (GCPS)
Macrocephaly
Widely spaced eyes associated with increased interpupillary distance (>97th centile)
Preaxial polydactyly with or without postaxial polydactyly
Cutaneous syndactyly
• Macrocephaly
• Widely spaced eyes associated with increased interpupillary distance (>97th centile)
• Preaxial polydactyly with or without postaxial polydactyly
• Cutaneous syndactyly
## Establishing the Diagnosis
The diagnosis of GCPS
A heterozygous pathogenic (or likely pathogenic) variant of
A heterozygous deletion of chromosome 7p14.1 involving
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings of GCPS described in
Note: If the affected individual has significant developmental delay or intellectual disability or if there is a history of recurrent pregnancy losses for the parents of the proband, CMA should be considered first, followed by sequence analysis of
When the phenotypic findings suggest the diagnosis of GCPS, molecular genetic testing approaches can include
Note: A small number of individuals with translocations involving 7p14.1 have been reported [
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by polydactyly and/or macrocephaly,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Greig Cephalopolysyndactyly Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Some laboratories offer deletion/duplication analysis using exome or genome sequence data. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
A small number of individuals with translocations involving 7p14.1 have been reported [
• A heterozygous pathogenic (or likely pathogenic) variant of
• A heterozygous deletion of chromosome 7p14.1 involving
• Note: A small number of individuals with translocations involving 7p14.1 have been reported [
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of GCPS, molecular genetic testing approaches can include
Note: A small number of individuals with translocations involving 7p14.1 have been reported [
For an introduction to multigene panels click
• Note: A small number of individuals with translocations involving 7p14.1 have been reported [
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by polydactyly and/or macrocephaly,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Greig Cephalopolysyndactyly Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Some laboratories offer deletion/duplication analysis using exome or genome sequence data. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
A small number of individuals with translocations involving 7p14.1 have been reported [
## Clinical Characteristics
To date, more than 200 individuals with Greig cephalopolysyndactyly syndrome (GCPS) have been reported with a pathogenic variant in
Select Features of Greig Cephalopolysyndactyly Syndrome
Some individuals with GCPS have a high anterior hairline, and a prominent (or bossed) forehead.
Preaxial polydactyly (duplication of all or part of the first ray)
A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)
A markedly broad thumb (increased thumb width without increased dorso-ventral dimension)
Other limbs may manifest preaxial or postaxial polydactyly and some limbs may have five normal digits. The postaxial polydactyly may be type A, type B, or intermediate forms.
Postaxial polydactyly type A (PAP-A) is the presence of a well-formed digit on the ulnar or fibular aspect of the limb.
Postaxial polydactyly type B (PAP-B) is the presence of a rudimentary digit or nubbin in the same location. The finding of postaxial polydactyly type B must be evaluated critically when present in an individual of west-central African descent as that feature is a common variant (1% prevalence).
Some individuals have widening of the first digit apparent only on radiograph. This is difficult to assess when diagnosing a proband.
Individuals who have GCPS associated with a large (>300 kb) deletion have a more severe phenotype than those with single-nucleotide variants in
Hypoplasia/agenesis of the corpus callosum may be more common in individuals with truncating variants in the 3' end of the gene [
Note: GCPS has an allelic disorder,
Apparent non-penetrance has been reported [
The term "Greig syndrome" describes the dyad of widely spaced eyes and macrocephaly. Because that dyad of anomalies is nonspecific, the term should not be used as a synonym for GCPS [
GCPS is rare; the prevalence is unknown. Approximately 200 affected individuals are known to these authors. It is suspected that many individuals with preaxial polydactyly with syndactyly and mild craniofacial features are misdiagnosed as having isolated preaxial polydactyly instead of GCPS (see
• Preaxial polydactyly (duplication of all or part of the first ray)
• A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)
• A markedly broad thumb (increased thumb width without increased dorso-ventral dimension)
• Preaxial polydactyly (duplication of all or part of the first ray)
• A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)
• A markedly broad thumb (increased thumb width without increased dorso-ventral dimension)
• Other limbs may manifest preaxial or postaxial polydactyly and some limbs may have five normal digits. The postaxial polydactyly may be type A, type B, or intermediate forms.
• Postaxial polydactyly type A (PAP-A) is the presence of a well-formed digit on the ulnar or fibular aspect of the limb.
• Postaxial polydactyly type B (PAP-B) is the presence of a rudimentary digit or nubbin in the same location. The finding of postaxial polydactyly type B must be evaluated critically when present in an individual of west-central African descent as that feature is a common variant (1% prevalence).
• Some individuals have widening of the first digit apparent only on radiograph. This is difficult to assess when diagnosing a proband.
• Preaxial polydactyly (duplication of all or part of the first ray)
• A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)
• A markedly broad thumb (increased thumb width without increased dorso-ventral dimension)
## Clinical Description
To date, more than 200 individuals with Greig cephalopolysyndactyly syndrome (GCPS) have been reported with a pathogenic variant in
Select Features of Greig Cephalopolysyndactyly Syndrome
Some individuals with GCPS have a high anterior hairline, and a prominent (or bossed) forehead.
Preaxial polydactyly (duplication of all or part of the first ray)
A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)
A markedly broad thumb (increased thumb width without increased dorso-ventral dimension)
Other limbs may manifest preaxial or postaxial polydactyly and some limbs may have five normal digits. The postaxial polydactyly may be type A, type B, or intermediate forms.
Postaxial polydactyly type A (PAP-A) is the presence of a well-formed digit on the ulnar or fibular aspect of the limb.
Postaxial polydactyly type B (PAP-B) is the presence of a rudimentary digit or nubbin in the same location. The finding of postaxial polydactyly type B must be evaluated critically when present in an individual of west-central African descent as that feature is a common variant (1% prevalence).
Some individuals have widening of the first digit apparent only on radiograph. This is difficult to assess when diagnosing a proband.
• Preaxial polydactyly (duplication of all or part of the first ray)
• A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)
• A markedly broad thumb (increased thumb width without increased dorso-ventral dimension)
• Preaxial polydactyly (duplication of all or part of the first ray)
• A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)
• A markedly broad thumb (increased thumb width without increased dorso-ventral dimension)
• Other limbs may manifest preaxial or postaxial polydactyly and some limbs may have five normal digits. The postaxial polydactyly may be type A, type B, or intermediate forms.
• Postaxial polydactyly type A (PAP-A) is the presence of a well-formed digit on the ulnar or fibular aspect of the limb.
• Postaxial polydactyly type B (PAP-B) is the presence of a rudimentary digit or nubbin in the same location. The finding of postaxial polydactyly type B must be evaluated critically when present in an individual of west-central African descent as that feature is a common variant (1% prevalence).
• Some individuals have widening of the first digit apparent only on radiograph. This is difficult to assess when diagnosing a proband.
• Preaxial polydactyly (duplication of all or part of the first ray)
• A markedly broad hallux (visible increase in width of the hallux without an increase in the dorso-ventral dimension)
• A markedly broad thumb (increased thumb width without increased dorso-ventral dimension)
## Genotype-Phenotype Correlations
Individuals who have GCPS associated with a large (>300 kb) deletion have a more severe phenotype than those with single-nucleotide variants in
Hypoplasia/agenesis of the corpus callosum may be more common in individuals with truncating variants in the 3' end of the gene [
Note: GCPS has an allelic disorder,
## Penetrance
Apparent non-penetrance has been reported [
## Nomenclature
The term "Greig syndrome" describes the dyad of widely spaced eyes and macrocephaly. Because that dyad of anomalies is nonspecific, the term should not be used as a synonym for GCPS [
## Prevalence
GCPS is rare; the prevalence is unknown. Approximately 200 affected individuals are known to these authors. It is suspected that many individuals with preaxial polydactyly with syndactyly and mild craniofacial features are misdiagnosed as having isolated preaxial polydactyly instead of GCPS (see
## Genetically Related (Allelic) Disorders
Other phenotypes known to be associated with germline pathogenic variants in
Note: Haploinsufficiency for
Wide range of severity
Central or postaxial polydactyly, hypothalamic hamartoma, bifid epiglottis, imperforate anus or anal stenosis, & other anomalies
In a minority of individuals: multiple severe anomalies (e.g., pituitary dysplasia w/pan hypopituitarism & laryngeal clefts or other airway anomalies, which may be life threatening in the neonatal period)
Preaxial polydactyly of hands &/or feet w/o other malformations (typically the same pattern of syndactyly in hands & feet as those w/GCPS)
Severity is highly variable.
PPD-IV is essentially GCPS w/o craniofacial manifestations.
Because macrocephaly occurs in the general population & is common in GCPS, the presence of macrocephaly in a person w/apparently isolated PPD-IV may be difficult to interpret.
GCPS = Greig cephalopolysyndactyly syndrome
• Wide range of severity
• Central or postaxial polydactyly, hypothalamic hamartoma, bifid epiglottis, imperforate anus or anal stenosis, & other anomalies
• In a minority of individuals: multiple severe anomalies (e.g., pituitary dysplasia w/pan hypopituitarism & laryngeal clefts or other airway anomalies, which may be life threatening in the neonatal period)
• Preaxial polydactyly of hands &/or feet w/o other malformations (typically the same pattern of syndactyly in hands & feet as those w/GCPS)
• Severity is highly variable.
• PPD-IV is essentially GCPS w/o craniofacial manifestations.
• Because macrocephaly occurs in the general population & is common in GCPS, the presence of macrocephaly in a person w/apparently isolated PPD-IV may be difficult to interpret.
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Greig Cephalopolysyndactyly Syndrome
In females: frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, abnormalities of the thoracic skeleton
In males: widely spaced eyes
AD = autosomal dominant; AR = autosomal recessive; GCPS = Greig cephalopolysyndactyly syndrome; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
Inheritance of
Oral-facial-digital syndrome type 1 is caused by pathogenic variants in
• In females: frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, abnormalities of the thoracic skeleton
• In males: widely spaced eyes
## Management
To establish the extent of disease and needs in an individual diagnosed with Greig cephalopolysyndactyly syndrome (GCPS), the evaluations summarized in
Greig Cephalopolysyndactyly Syndrome: Recommended Evaluations Following Initial Diagnosis
Greig Cephalopolysyndactyly Syndrome: Treatment of Manifestations
Undertaken on an elective basis
Preaxial polydactyly of the hands is considered higher priority for surgical correction than postaxial polydactyly of the hand or any type of polydactyly of the foot due to importance of early & proper development of prehensile grasp.
As for any malformation of the feet, surgical correction must be carefully considered; cosmetic benefits & easier fitting of shoes can be outweighed by potential orthopedic complication.
ASM = anti-seizure medication
Greig Cephalopolysyndactyly Syndrome: Recommended Surveillance
As is true for any malformation of the feet, surgical correction must be carefully considered. Cosmetic benefits and easier fitting of shoes can be outweighed by potential orthopedic complications.
See
Search
• Undertaken on an elective basis
• Preaxial polydactyly of the hands is considered higher priority for surgical correction than postaxial polydactyly of the hand or any type of polydactyly of the foot due to importance of early & proper development of prehensile grasp.
• As for any malformation of the feet, surgical correction must be carefully considered; cosmetic benefits & easier fitting of shoes can be outweighed by potential orthopedic complication.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Greig cephalopolysyndactyly syndrome (GCPS), the evaluations summarized in
Greig Cephalopolysyndactyly Syndrome: Recommended Evaluations Following Initial Diagnosis
## Treatment of Manifestations
Greig Cephalopolysyndactyly Syndrome: Treatment of Manifestations
Undertaken on an elective basis
Preaxial polydactyly of the hands is considered higher priority for surgical correction than postaxial polydactyly of the hand or any type of polydactyly of the foot due to importance of early & proper development of prehensile grasp.
As for any malformation of the feet, surgical correction must be carefully considered; cosmetic benefits & easier fitting of shoes can be outweighed by potential orthopedic complication.
ASM = anti-seizure medication
• Undertaken on an elective basis
• Preaxial polydactyly of the hands is considered higher priority for surgical correction than postaxial polydactyly of the hand or any type of polydactyly of the foot due to importance of early & proper development of prehensile grasp.
• As for any malformation of the feet, surgical correction must be carefully considered; cosmetic benefits & easier fitting of shoes can be outweighed by potential orthopedic complication.
## Surveillance
Greig Cephalopolysyndactyly Syndrome: Recommended Surveillance
## Agents/Circumstances to Avoid
As is true for any malformation of the feet, surgical correction must be carefully considered. Cosmetic benefits and easier fitting of shoes can be outweighed by potential orthopedic complications.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Greig cephalopolysyndactyly syndrome (GCPS) is inherited in an autosomal dominant manner and is caused by either a pathogenic variant involving
Some individuals diagnosed with GCPS have the disorder as the result of a genetic alteration inherited from a parent.
Some individuals diagnosed with GCPS have the disorder as the result of a
Recommendations for the evaluation of parents of a child with GCPS and no known family history of GCPS consist of clinical examination and radiographs of hands and feet unless physical signs suggest the need for other studies (e.g., neuroimaging for possible hydrocephalus in a parent). Molecular genetic testing of the parents is indicated if the GCPS-causing genetic alteration has been identified in the proband.
If the proband has a known genetic alteration that cannot be detected in the leukocyte DNA of either parent, possible explanations include a
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with GCPS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the pathogenic variant and may be mildly/minimally affected; affected offspring of a parent with mosaicism would be nonmosaic and thus could have a more severe phenotype than the parent.
If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs is 50%. (See
If the parents of a proband are clinically unaffected but their genetic status is unknown (either because the genetic etiology in the proband is unknown or because the parents have not undergone molecular genetic testing), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for GCPS because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Some individuals diagnosed with GCPS have the disorder as the result of a genetic alteration inherited from a parent.
• Some individuals diagnosed with GCPS have the disorder as the result of a
• Recommendations for the evaluation of parents of a child with GCPS and no known family history of GCPS consist of clinical examination and radiographs of hands and feet unless physical signs suggest the need for other studies (e.g., neuroimaging for possible hydrocephalus in a parent). Molecular genetic testing of the parents is indicated if the GCPS-causing genetic alteration has been identified in the proband.
• If the proband has a known genetic alteration that cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with GCPS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the pathogenic variant and may be mildly/minimally affected; affected offspring of a parent with mosaicism would be nonmosaic and thus could have a more severe phenotype than the parent.
• If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs is 50%. (See
• If the parents of a proband are clinically unaffected but their genetic status is unknown (either because the genetic etiology in the proband is unknown or because the parents have not undergone molecular genetic testing), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for GCPS because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Mode of Inheritance
Greig cephalopolysyndactyly syndrome (GCPS) is inherited in an autosomal dominant manner and is caused by either a pathogenic variant involving
## Risk to Family Members
Some individuals diagnosed with GCPS have the disorder as the result of a genetic alteration inherited from a parent.
Some individuals diagnosed with GCPS have the disorder as the result of a
Recommendations for the evaluation of parents of a child with GCPS and no known family history of GCPS consist of clinical examination and radiographs of hands and feet unless physical signs suggest the need for other studies (e.g., neuroimaging for possible hydrocephalus in a parent). Molecular genetic testing of the parents is indicated if the GCPS-causing genetic alteration has been identified in the proband.
If the proband has a known genetic alteration that cannot be detected in the leukocyte DNA of either parent, possible explanations include a
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with GCPS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the pathogenic variant and may be mildly/minimally affected; affected offspring of a parent with mosaicism would be nonmosaic and thus could have a more severe phenotype than the parent.
If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs is 50%. (See
If the parents of a proband are clinically unaffected but their genetic status is unknown (either because the genetic etiology in the proband is unknown or because the parents have not undergone molecular genetic testing), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for GCPS because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
• Some individuals diagnosed with GCPS have the disorder as the result of a genetic alteration inherited from a parent.
• Some individuals diagnosed with GCPS have the disorder as the result of a
• Recommendations for the evaluation of parents of a child with GCPS and no known family history of GCPS consist of clinical examination and radiographs of hands and feet unless physical signs suggest the need for other studies (e.g., neuroimaging for possible hydrocephalus in a parent). Molecular genetic testing of the parents is indicated if the GCPS-causing genetic alteration has been identified in the proband.
• If the proband has a known genetic alteration that cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with GCPS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the pathogenic variant and may be mildly/minimally affected; affected offspring of a parent with mosaicism would be nonmosaic and thus could have a more severe phenotype than the parent.
• If a parent of the proband is affected and/or is known to have the genetic alteration identified in the proband, the risk to the sibs is 50%. (See
• If the parents of a proband are clinically unaffected but their genetic status is unknown (either because the genetic etiology in the proband is unknown or because the parents have not undergone molecular genetic testing), the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for GCPS because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
GLI3-Related Greig Cephalopolysyndactyly Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GLI3-Related Greig Cephalopolysyndactyly Syndrome (
GCPS = Greig cephalopolysyndactyly syndrome; PHS = Pallister-Hall syndrome
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
GCPS = Greig cephalopolysyndactyly syndrome; PHS = Pallister-Hall syndrome
Variants listed in the table have been provided by the authors.
## Chapter Notes
Leslie H Biesecker, MD (2001-present)Jennifer J Johnston, PhD (2020-present)
15 February 2024 (jj) Revision: information regarding
7 May 2020 (ha) Comprehensive update posted live
19 June 2014 (me) Comprehensive update posted live
30 April 2009 (me) Comprehensive update posted live
20 September 2005 (me) Comprehensive update posted live
25 August 2003 (me) Comprehensive update posted live
9 July 2001 (me) Review posted live
20 February 2001 (lgb) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 15 February 2024 (jj) Revision: information regarding
• 7 May 2020 (ha) Comprehensive update posted live
• 19 June 2014 (me) Comprehensive update posted live
• 30 April 2009 (me) Comprehensive update posted live
• 20 September 2005 (me) Comprehensive update posted live
• 25 August 2003 (me) Comprehensive update posted live
• 9 July 2001 (me) Review posted live
• 20 February 2001 (lgb) Original submission
## Author Notes
## Author History
Leslie H Biesecker, MD (2001-present)Jennifer J Johnston, PhD (2020-present)
## Revision History
15 February 2024 (jj) Revision: information regarding
7 May 2020 (ha) Comprehensive update posted live
19 June 2014 (me) Comprehensive update posted live
30 April 2009 (me) Comprehensive update posted live
20 September 2005 (me) Comprehensive update posted live
25 August 2003 (me) Comprehensive update posted live
9 July 2001 (me) Review posted live
20 February 2001 (lgb) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 15 February 2024 (jj) Revision: information regarding
• 7 May 2020 (ha) Comprehensive update posted live
• 19 June 2014 (me) Comprehensive update posted live
• 30 April 2009 (me) Comprehensive update posted live
• 20 September 2005 (me) Comprehensive update posted live
• 25 August 2003 (me) Comprehensive update posted live
• 9 July 2001 (me) Review posted live
• 20 February 2001 (lgb) Original submission
## References
## Literature Cited
A. The spectra of GCPS-associated and PHS-associated pathogenic variants are distinct. GCPS is caused by pathogenic variants of all types, whereas PHS is only caused by truncating variants and one splice variant that generates a frameshift and a truncation.
B. Within the frameshift variant category there is a correlation of the position of the truncation and the phenotype. GCPS is primarily caused by pathogenic variants 5' of nt 1998 and 3' of 3481, whereas PHS is exclusively caused by truncations between 1998 and 3481. Note that a single truncating variant in the PHS region can cause GCPS and has been observed in six apparently unrelated families.
Reproduced with permission from
|
[] |
9/7/2001
|
7/5/2020
|
15/2/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
gefs
|
gefs
|
[
"Severe Myoclonic Epilepsy in Infancy (SMEI)",
"Generalized Epilepsy with Febrile Seizures Plus (GEFS+)",
"Simple Febrile Seizures",
"Intractable Childhood Epilepsy with Generalized Tonic-Clonic Seizures (ICE-GTC)",
"Intractable Infantile Partial Seizures",
"Myoclonic-Astatic Epilepsy (MAE)",
"SCN1A-Related Dravet Syndrome",
"Sodium channel protein type 1 subunit alpha",
"SCN1A",
"SCN1A Seizure Disorders"
] |
Ian O Miller, Marcio A Sotero de Menezes
|
Summary The diagnosis of an
|
## GeneReview Scope
Generalized epilepsy with febrile seizures plus (GEFS+)
Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC)
Intractable infantile partial seizures
Myoclonic astatic epilepsy (MAE)
Severe myoclonic epilepsy in infancy (SMEI) / Dravet Syndrome (DS)
Simple febrile seizures
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• Generalized epilepsy with febrile seizures plus (GEFS+)
• Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC)
• Intractable infantile partial seizures
• Myoclonic astatic epilepsy (MAE)
• Severe myoclonic epilepsy in infancy (SMEI) / Dravet Syndrome (DS)
• Simple febrile seizures
## Diagnosis
Precipitation of seizure with fever, warmth, or vaccination
Prolonged or hemiconvulsive seizures
Seizure provocation with overstimulation or flashing/patterned visual stimulus
Worsening of seizures with medications that inhibit sodium channel function as the primary mechanism of action (e.g., carbamazepine, oxcarbazepine, phenytoin, lamotrigine)
These features can be seen in any one of several clinical epilepsy syndromes that can occur in individuals with a heterozygous
Epilepsy with focal seizures
Myoclonic-astatic epilepsy (MAE, Doose syndrome)
Lennox-Gastaut syndrome
Infantile spasms
Vaccine-related encephalopathy and seizures
The diagnosis of an
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Estimated value based on subtracting experimental values of deletion frequencies of 8%-27% from 100% (see footnote 5).
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Using a variety of methods to identify deletions encompassing the
It is not known if the percent of exon and whole-gene deletions is the same for the other phenotypes in the spectrum of
• Precipitation of seizure with fever, warmth, or vaccination
• Prolonged or hemiconvulsive seizures
• Seizure provocation with overstimulation or flashing/patterned visual stimulus
• Worsening of seizures with medications that inhibit sodium channel function as the primary mechanism of action (e.g., carbamazepine, oxcarbazepine, phenytoin, lamotrigine)
•
•
•
•
•
• Epilepsy with focal seizures
• Myoclonic-astatic epilepsy (MAE, Doose syndrome)
• Lennox-Gastaut syndrome
• Infantile spasms
• Vaccine-related encephalopathy and seizures
• For an introduction to multigene panels click
## Suggestive Findings
Precipitation of seizure with fever, warmth, or vaccination
Prolonged or hemiconvulsive seizures
Seizure provocation with overstimulation or flashing/patterned visual stimulus
Worsening of seizures with medications that inhibit sodium channel function as the primary mechanism of action (e.g., carbamazepine, oxcarbazepine, phenytoin, lamotrigine)
These features can be seen in any one of several clinical epilepsy syndromes that can occur in individuals with a heterozygous
Epilepsy with focal seizures
Myoclonic-astatic epilepsy (MAE, Doose syndrome)
Lennox-Gastaut syndrome
Infantile spasms
Vaccine-related encephalopathy and seizures
• Precipitation of seizure with fever, warmth, or vaccination
• Prolonged or hemiconvulsive seizures
• Seizure provocation with overstimulation or flashing/patterned visual stimulus
• Worsening of seizures with medications that inhibit sodium channel function as the primary mechanism of action (e.g., carbamazepine, oxcarbazepine, phenytoin, lamotrigine)
•
•
•
•
•
• Epilepsy with focal seizures
• Myoclonic-astatic epilepsy (MAE, Doose syndrome)
• Lennox-Gastaut syndrome
• Infantile spasms
• Vaccine-related encephalopathy and seizures
## Establishing the Diagnosis
The diagnosis of an
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Estimated value based on subtracting experimental values of deletion frequencies of 8%-27% from 100% (see footnote 5).
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Using a variety of methods to identify deletions encompassing the
It is not known if the percent of exon and whole-gene deletions is the same for the other phenotypes in the spectrum of
• For an introduction to multigene panels click
## Clinical Characteristics
The natural history of
Features associated with poor cognitive outcome include early myoclonic and absence seizures [
Phenotypes with intractable seizures (e.g., Dravet syndrome) usually cause epileptic encephalopathy, a form of progressive dementia. The root cause of the encephalopathy is unknown: the effects on cognition of seizures, the most obvious explanation, cannot be separated from the effects of medication or of an
In addition to having seizures in response to strong environmental stimuli, individuals with
The phenotypes in
Seizure Phenotypes in
The initial EEGs are often normal or show nonspecific changes such as generalized slowing, but over time epileptiform activity appears. Patterns can include generalized spike and wave discharges, multiple spike and wave (also referred to as polyspike and wave) discharges, and multifocal spikes (see
The myoclonic seizures that tend to appear later in the course often coincide with the appearance of cognitive dysfunction, ataxia, and psychomotor regression. Some degree of cognitive impairment is always seen, ranging from moderate to severe, often with marked inattention, impulsivity, and distractibility. Anxiety, obsessive personality traits, and autism spectrum disorder are common. Crouched gait, hypotonia, incoordination, and impaired dexterity are typically evident by age three to four years. Parkinsonian features of bradykinesia, tremor, and antecollis have been reported in adults with Dravet syndrome [
Individuals with Dravet syndrome often develop a crouched gait. In spite of the gait being commonly described as "ataxic," affected individuals are more mobile than one would expect from how crouched they appear. The gait changes tend to be more prevalent in older children. In one study these changes were absent before age five years, but present in 5/10 children ages 6-12 years and in 8/9 children age 13 years or older [
Onset before age one year
Persistence beyond age six years
Unusual severity (including status epilepticus)
Occurrence of unprovoked (i.e., afebrile) seizures of any kind
Onset on or after age six months
Resolution by age five years
Fever higher than 38°C (without other evidence of CNS infection)
No other identifiable cause
Febrile seizures are divided into simple febrile seizures and complex febrile seizures. Febrile seizures are considered complex if any of the following is present:
Duration longer than 15 minutes
Occurrence of more than one seizure within 24 hours
Presence of any partial (focal) features during the seizure
Febrile seizures with the following criteria are associated with a higher risk for developing Dravet syndrome [
Febrile seizure onset before age seven months
Five or more febrile seizures
Prolonged seizure(s) lasting more than ten minutes
The febrile seizure characteristics include hemiconvulsions, partial seizures, myoclonic seizures, and hot water-induced seizures.
Given the variable expressivity of
Pathogenic nonsense variants and missense variants in the voltage sensor or pore region often lead to a more severe phenotype [
Affected individuals with missense variants in the pore-forming region and truncations in the SCN1A protein are more likely to have gait changes [
Variants in
Generalized epilepsy with febrile seizures plus has been referred to as GEFS+, type 2 related to
Intractable infantile partial seizures has been referred to as ICE-GTC.
Dravet syndrome is also known as severe myoclonic epilepsy in infancy (SMEI) or polymorphic myoclonic epilepsy in infancy (PMEI). The term "Dravet syndrome" is preferred over the descriptive names because myoclonic seizures can be absent in children whose seizures are otherwise similar.
Penetrance varies by phenotype. For example,
• Onset before age one year
• Persistence beyond age six years
• Unusual severity (including status epilepticus)
• Occurrence of unprovoked (i.e., afebrile) seizures of any kind
• Onset on or after age six months
• Resolution by age five years
• Fever higher than 38°C (without other evidence of CNS infection)
• No other identifiable cause
• Duration longer than 15 minutes
• Occurrence of more than one seizure within 24 hours
• Presence of any partial (focal) features during the seizure
• Febrile seizure onset before age seven months
• Five or more febrile seizures
• Prolonged seizure(s) lasting more than ten minutes
## Clinical Description
The natural history of
Features associated with poor cognitive outcome include early myoclonic and absence seizures [
Phenotypes with intractable seizures (e.g., Dravet syndrome) usually cause epileptic encephalopathy, a form of progressive dementia. The root cause of the encephalopathy is unknown: the effects on cognition of seizures, the most obvious explanation, cannot be separated from the effects of medication or of an
In addition to having seizures in response to strong environmental stimuli, individuals with
The phenotypes in
Seizure Phenotypes in
The initial EEGs are often normal or show nonspecific changes such as generalized slowing, but over time epileptiform activity appears. Patterns can include generalized spike and wave discharges, multiple spike and wave (also referred to as polyspike and wave) discharges, and multifocal spikes (see
The myoclonic seizures that tend to appear later in the course often coincide with the appearance of cognitive dysfunction, ataxia, and psychomotor regression. Some degree of cognitive impairment is always seen, ranging from moderate to severe, often with marked inattention, impulsivity, and distractibility. Anxiety, obsessive personality traits, and autism spectrum disorder are common. Crouched gait, hypotonia, incoordination, and impaired dexterity are typically evident by age three to four years. Parkinsonian features of bradykinesia, tremor, and antecollis have been reported in adults with Dravet syndrome [
Individuals with Dravet syndrome often develop a crouched gait. In spite of the gait being commonly described as "ataxic," affected individuals are more mobile than one would expect from how crouched they appear. The gait changes tend to be more prevalent in older children. In one study these changes were absent before age five years, but present in 5/10 children ages 6-12 years and in 8/9 children age 13 years or older [
Onset before age one year
Persistence beyond age six years
Unusual severity (including status epilepticus)
Occurrence of unprovoked (i.e., afebrile) seizures of any kind
Onset on or after age six months
Resolution by age five years
Fever higher than 38°C (without other evidence of CNS infection)
No other identifiable cause
Febrile seizures are divided into simple febrile seizures and complex febrile seizures. Febrile seizures are considered complex if any of the following is present:
Duration longer than 15 minutes
Occurrence of more than one seizure within 24 hours
Presence of any partial (focal) features during the seizure
Febrile seizures with the following criteria are associated with a higher risk for developing Dravet syndrome [
Febrile seizure onset before age seven months
Five or more febrile seizures
Prolonged seizure(s) lasting more than ten minutes
The febrile seizure characteristics include hemiconvulsions, partial seizures, myoclonic seizures, and hot water-induced seizures.
• Onset before age one year
• Persistence beyond age six years
• Unusual severity (including status epilepticus)
• Occurrence of unprovoked (i.e., afebrile) seizures of any kind
• Onset on or after age six months
• Resolution by age five years
• Fever higher than 38°C (without other evidence of CNS infection)
• No other identifiable cause
• Duration longer than 15 minutes
• Occurrence of more than one seizure within 24 hours
• Presence of any partial (focal) features during the seizure
• Febrile seizure onset before age seven months
• Five or more febrile seizures
• Prolonged seizure(s) lasting more than ten minutes
## Genotype-Phenotype Correlations
Given the variable expressivity of
Pathogenic nonsense variants and missense variants in the voltage sensor or pore region often lead to a more severe phenotype [
Affected individuals with missense variants in the pore-forming region and truncations in the SCN1A protein are more likely to have gait changes [
Variants in
## Nomenclature
Generalized epilepsy with febrile seizures plus has been referred to as GEFS+, type 2 related to
Intractable infantile partial seizures has been referred to as ICE-GTC.
Dravet syndrome is also known as severe myoclonic epilepsy in infancy (SMEI) or polymorphic myoclonic epilepsy in infancy (PMEI). The term "Dravet syndrome" is preferred over the descriptive names because myoclonic seizures can be absent in children whose seizures are otherwise similar.
## Penetrance
Penetrance varies by phenotype. For example,
## Prevalence
## Genetically Related (Allelic) Disorders
Other phenotypes associated with pathogenic variants in
Larger deletions of 2q24.3 are associated with dysmorphic features including microcephaly, ptosis, downslanting palpebral fissures, long eyelashes, micrognathia [
Familial autism [
Rasmussen encephalitis associated with the pathogenic variant p.Arg1575Cys [
• Larger deletions of 2q24.3 are associated with dysmorphic features including microcephaly, ptosis, downslanting palpebral fissures, long eyelashes, micrognathia [
• Familial autism [
• Rasmussen encephalitis associated with the pathogenic variant p.Arg1575Cys [
## Differential Diagnosis
The phenotypes typically seen in individuals with an
It is most important to distinguish
Inborn errors of metabolism, including mitochondrial dysfunction, which may be diagnosed by the presence of abnormal serum concentrations of lactate, ketones, ammonia, amino acids, and/or abnormal concentrations of urine organic acids (See
Hepatic porphyrias, which usually demonstrate photosensitive porphyrins in the urine and reduced monopyrrole porphobilinogen (PBG) deaminase in red cells (See
If the family history is negative or unavailable, sporadic epilepsies (i.e., those without a genetic cause) need to be included in the differential diagnosis, as does any cause of epilepsy with nonspecific imaging findings. Some general categories of injury to consider include the following [
Trauma
Hypoxia
Sequelae of meningitis or hemorrhage
Infectious or autoimmune cerebritis
Vasculitis
Paraneoplastic syndrome
Toxins (including drug withdrawal)
Endocrinopathy
A positive family history for other individuals with epilepsy significantly increases the likelihood of an inherited epilepsy syndrome [
Selected Genes of Interest in the Differential Diagnosis of
ADLTE = autosomal dominant lateral temporal lobe epilepsy; ADNFLE = autosomal dominant nocturnal frontal lobe epilepsy; ADEAF = autosomal dominant partial epilepsy with auditory features; BECTS = benign epilepsy with centrotemporal spikes; BFIE = benign familial infantile epilepsy; BFNE = benign familial neonatal epilepsy; CAE = childhood absence epilepsy; DS = Dravet syndrome; EIEE = early-infantile epileptic encephalopathy; FEB = familial febrile seizures; FLE = frontal lobe epilepsy; GEFS+ = generalized/genetic epilepsy with febrile seizure plus; GTC = generalized tonic-clonic; JAE = juvenile absence epilepsy; JME = juvenile myoclonic epilepsy; MOI = mode of inheritance; MTLS = mesial temporal lobe seizure; NEE = neonatal epileptic encephalopathy; SUDEP = sudden unexpected death in patients with epilepsy; TLE = temporal lobe epilepsy; XL = X-linked
Topic of this
Familial epilepsy syndromes with an unknown molecular basis may also be considered in the differential diagnosis of
Childhood occipital epilepsy, which may be associated with focal seizures that become secondary generalized. Unlike
Epilepsy with photoparoxysmal response. Unlike
To see loci and additional genes associated with the phenotypes in
• Inborn errors of metabolism, including mitochondrial dysfunction, which may be diagnosed by the presence of abnormal serum concentrations of lactate, ketones, ammonia, amino acids, and/or abnormal concentrations of urine organic acids (See
• Hepatic porphyrias, which usually demonstrate photosensitive porphyrins in the urine and reduced monopyrrole porphobilinogen (PBG) deaminase in red cells (See
• Trauma
• Hypoxia
• Sequelae of meningitis or hemorrhage
• Infectious or autoimmune cerebritis
• Vasculitis
• Paraneoplastic syndrome
• Toxins (including drug withdrawal)
• Endocrinopathy
• Childhood occipital epilepsy, which may be associated with focal seizures that become secondary generalized. Unlike
• Epilepsy with photoparoxysmal response. Unlike
•
•
•
•
•
•
## Management
To establish the extent of disease and needs in an individual diagnosed with an
Neurologic examination
Cognitive neuropsychological evaluation
Behavioral neuropsychological evaluation
Electroencephalogram (EEG), including video EEG telemetry where ictal onset or semiology is unclear
Consideration of polysomnography if obstructive or central sleep apnea is suspected
Consultation with a clinical geneticist and/or genetic counselor
Care is best provided by a physician (e.g., pediatric epileptologist) familiar with the pharmacotherapy for this disorder. Seizure control is critical because children with
Pharmacologic treatment focuses on the observations that abnormal SCN1A channels disproportionately affect GABA neurons [
Stiripentol, which acts directly on GABA
Children older than age 12 years may not tolerate stiripentol because of digestive tract side effects and nausea [
Because of the sedating effects of seizure medications and the possibility of respiratory depression (especially with benzodiazepines and barbiturates), parents are advised to take a CPR course. Routine seizure and personal safety counseling is indicated.
Seizures are not always responsive to conventional ASMs. Anecdotal evidence suggests that the following drugs / treatment modalities may be effective for
Ethosuximide and high-dose piracetam for myoclonic seizures
Corticosteroids
Immunoglobulins
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
Placement of an indwelling venous access device
Creating a portable microenvironment
Having a written emergency department protocol
Establishing emergency routines for the family
Assigning a parent on call to lessen the effect on the sibs
Creating personal time to decrease parent stress
Finding respite care
Contacting an internet support group
Individuals experiencing atonic seizures or myoclonic-astatic epilepsy should be advised to wear a protective helmet.
Sleep deprivation and illness can exacerbate
Although immunization may trigger a seizure, it does not affect the natural course of the disorder.
Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration is appropriate.
Clinical examination for scoliosis and impaired gait at each office visit
EEG monitoring is appropriate when new or different seizure types are suspected.
Polysomnography should be considered if obstructive or central sleep apnea is suspected.
Several ASMs that are effective for most forms of epilepsy can worsen
Activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights).
See
In addition to the considerations described in
Risk of major malformations (especially as a result of valproic acid exposure in utero [
Advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily, particularly when women are taking valproic acid or carbamazepine during pregnancy
Effect of in utero exposure to anticonvulsants on future cognitive development [
Effect of anticonvulsants on hormonal methods of birth control
Effects of anticonvulsants on conception; the risk for complications in mothers who are on anticonvulsants
Effect of pregnancy on anticonvulsant metabolism
Effect of pregnancy on maternal seizure control
Pregnancy, family planning, and contraception are issues that should be raised with every female near childbearing age who has epilepsy. These considerations are not unique to or (aside from medication selection) significantly influenced by the presence of an
See
Search
Persons with epilepsy should be made aware of local motor vehicle driving laws and physician reporting laws.
Hippocampal sclerosis can occur as a secondary feature of
• Neurologic examination
• Cognitive neuropsychological evaluation
• Behavioral neuropsychological evaluation
• Electroencephalogram (EEG), including video EEG telemetry where ictal onset or semiology is unclear
• Consideration of polysomnography if obstructive or central sleep apnea is suspected
• Consultation with a clinical geneticist and/or genetic counselor
• Stiripentol, which acts directly on GABA
• Children older than age 12 years may not tolerate stiripentol because of digestive tract side effects and nausea [
• Ethosuximide and high-dose piracetam for myoclonic seizures
• Corticosteroids
• Immunoglobulins
• Placement of an indwelling venous access device
• Creating a portable microenvironment
• Having a written emergency department protocol
• Establishing emergency routines for the family
• Assigning a parent on call to lessen the effect on the sibs
• Creating personal time to decrease parent stress
• Finding respite care
• Contacting an internet support group
• Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration is appropriate.
• Clinical examination for scoliosis and impaired gait at each office visit
• EEG monitoring is appropriate when new or different seizure types are suspected.
• Polysomnography should be considered if obstructive or central sleep apnea is suspected.
• Risk of major malformations (especially as a result of valproic acid exposure in utero [
• Advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily, particularly when women are taking valproic acid or carbamazepine during pregnancy
• Effect of in utero exposure to anticonvulsants on future cognitive development [
• Effect of anticonvulsants on hormonal methods of birth control
• Effects of anticonvulsants on conception; the risk for complications in mothers who are on anticonvulsants
• Effect of pregnancy on anticonvulsant metabolism
• Effect of pregnancy on maternal seizure control
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with an
Neurologic examination
Cognitive neuropsychological evaluation
Behavioral neuropsychological evaluation
Electroencephalogram (EEG), including video EEG telemetry where ictal onset or semiology is unclear
Consideration of polysomnography if obstructive or central sleep apnea is suspected
Consultation with a clinical geneticist and/or genetic counselor
• Neurologic examination
• Cognitive neuropsychological evaluation
• Behavioral neuropsychological evaluation
• Electroencephalogram (EEG), including video EEG telemetry where ictal onset or semiology is unclear
• Consideration of polysomnography if obstructive or central sleep apnea is suspected
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Care is best provided by a physician (e.g., pediatric epileptologist) familiar with the pharmacotherapy for this disorder. Seizure control is critical because children with
Pharmacologic treatment focuses on the observations that abnormal SCN1A channels disproportionately affect GABA neurons [
Stiripentol, which acts directly on GABA
Children older than age 12 years may not tolerate stiripentol because of digestive tract side effects and nausea [
Because of the sedating effects of seizure medications and the possibility of respiratory depression (especially with benzodiazepines and barbiturates), parents are advised to take a CPR course. Routine seizure and personal safety counseling is indicated.
Seizures are not always responsive to conventional ASMs. Anecdotal evidence suggests that the following drugs / treatment modalities may be effective for
Ethosuximide and high-dose piracetam for myoclonic seizures
Corticosteroids
Immunoglobulins
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
Placement of an indwelling venous access device
Creating a portable microenvironment
Having a written emergency department protocol
Establishing emergency routines for the family
Assigning a parent on call to lessen the effect on the sibs
Creating personal time to decrease parent stress
Finding respite care
Contacting an internet support group
• Stiripentol, which acts directly on GABA
• Children older than age 12 years may not tolerate stiripentol because of digestive tract side effects and nausea [
• Ethosuximide and high-dose piracetam for myoclonic seizures
• Corticosteroids
• Immunoglobulins
• Placement of an indwelling venous access device
• Creating a portable microenvironment
• Having a written emergency department protocol
• Establishing emergency routines for the family
• Assigning a parent on call to lessen the effect on the sibs
• Creating personal time to decrease parent stress
• Finding respite care
• Contacting an internet support group
## Prevention of Secondary Complications
Individuals experiencing atonic seizures or myoclonic-astatic epilepsy should be advised to wear a protective helmet.
Sleep deprivation and illness can exacerbate
Although immunization may trigger a seizure, it does not affect the natural course of the disorder.
## Surveillance
Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration is appropriate.
Clinical examination for scoliosis and impaired gait at each office visit
EEG monitoring is appropriate when new or different seizure types are suspected.
Polysomnography should be considered if obstructive or central sleep apnea is suspected.
• Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration is appropriate.
• Clinical examination for scoliosis and impaired gait at each office visit
• EEG monitoring is appropriate when new or different seizure types are suspected.
• Polysomnography should be considered if obstructive or central sleep apnea is suspected.
## Agents/Circumstances to Avoid
Several ASMs that are effective for most forms of epilepsy can worsen
Activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights).
## Evaluation of Relatives at Risk
See
## Pregnancy Management
In addition to the considerations described in
Risk of major malformations (especially as a result of valproic acid exposure in utero [
Advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily, particularly when women are taking valproic acid or carbamazepine during pregnancy
Effect of in utero exposure to anticonvulsants on future cognitive development [
Effect of anticonvulsants on hormonal methods of birth control
Effects of anticonvulsants on conception; the risk for complications in mothers who are on anticonvulsants
Effect of pregnancy on anticonvulsant metabolism
Effect of pregnancy on maternal seizure control
Pregnancy, family planning, and contraception are issues that should be raised with every female near childbearing age who has epilepsy. These considerations are not unique to or (aside from medication selection) significantly influenced by the presence of an
See
• Risk of major malformations (especially as a result of valproic acid exposure in utero [
• Advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily, particularly when women are taking valproic acid or carbamazepine during pregnancy
• Effect of in utero exposure to anticonvulsants on future cognitive development [
• Effect of anticonvulsants on hormonal methods of birth control
• Effects of anticonvulsants on conception; the risk for complications in mothers who are on anticonvulsants
• Effect of pregnancy on anticonvulsant metabolism
• Effect of pregnancy on maternal seizure control
## Therapies Under Investigation
Search
## Other
Persons with epilepsy should be made aware of local motor vehicle driving laws and physician reporting laws.
Hippocampal sclerosis can occur as a secondary feature of
## Genetic Counseling
A proband with an
The proportion of cases caused by a
More than 95% of individuals with GEFS+ have a parent with the same
Most
Testing of parents of children who had Dravet syndrome and a confirmed
Note: In one series, 75% of
Recommendations for the evaluation of parents of a proband with an apparent
If a pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to either parent of having the pathogenic variant is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has been documented [
An apparently negative family history cannot be confirmed until appropriate evaluations have been performed. Although 95% of individuals with
If a parent of the proband has the
The likelihood that a sib who inherits an
Seizure phenotype in sibs who inherit an
If the
If a sib has epilepsy, the sib is presumed to be affected (and therefore to have an
Each child of an individual with an
Penetrance is incomplete (see
The likelihood that a heterozygous child of an individual with an
Individuals with GEFS+ may have offspring who are more severely affected than they are; for example, they may have a child with Dravet syndrome.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• A proband with an
• The proportion of cases caused by a
• More than 95% of individuals with GEFS+ have a parent with the same
• Most
• Testing of parents of children who had Dravet syndrome and a confirmed
• Note: In one series, 75% of
• More than 95% of individuals with GEFS+ have a parent with the same
• Most
• Testing of parents of children who had Dravet syndrome and a confirmed
• Note: In one series, 75% of
• Recommendations for the evaluation of parents of a proband with an apparent
• If a pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to either parent of having the pathogenic variant is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has been documented [
• An apparently negative family history cannot be confirmed until appropriate evaluations have been performed. Although 95% of individuals with
• More than 95% of individuals with GEFS+ have a parent with the same
• Most
• Testing of parents of children who had Dravet syndrome and a confirmed
• Note: In one series, 75% of
• If a parent of the proband has the
• The likelihood that a sib who inherits an
• Seizure phenotype in sibs who inherit an
• The likelihood that a sib who inherits an
• Seizure phenotype in sibs who inherit an
• If the
• If a sib has epilepsy, the sib is presumed to be affected (and therefore to have an
• The likelihood that a sib who inherits an
• Seizure phenotype in sibs who inherit an
• Each child of an individual with an
• Penetrance is incomplete (see
• The likelihood that a heterozygous child of an individual with an
• Individuals with GEFS+ may have offspring who are more severely affected than they are; for example, they may have a child with Dravet syndrome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
## Risk to Family Members
A proband with an
The proportion of cases caused by a
More than 95% of individuals with GEFS+ have a parent with the same
Most
Testing of parents of children who had Dravet syndrome and a confirmed
Note: In one series, 75% of
Recommendations for the evaluation of parents of a proband with an apparent
If a pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to either parent of having the pathogenic variant is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has been documented [
An apparently negative family history cannot be confirmed until appropriate evaluations have been performed. Although 95% of individuals with
If a parent of the proband has the
The likelihood that a sib who inherits an
Seizure phenotype in sibs who inherit an
If the
If a sib has epilepsy, the sib is presumed to be affected (and therefore to have an
Each child of an individual with an
Penetrance is incomplete (see
The likelihood that a heterozygous child of an individual with an
Individuals with GEFS+ may have offspring who are more severely affected than they are; for example, they may have a child with Dravet syndrome.
• A proband with an
• The proportion of cases caused by a
• More than 95% of individuals with GEFS+ have a parent with the same
• Most
• Testing of parents of children who had Dravet syndrome and a confirmed
• Note: In one series, 75% of
• More than 95% of individuals with GEFS+ have a parent with the same
• Most
• Testing of parents of children who had Dravet syndrome and a confirmed
• Note: In one series, 75% of
• Recommendations for the evaluation of parents of a proband with an apparent
• If a pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to either parent of having the pathogenic variant is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has been documented [
• An apparently negative family history cannot be confirmed until appropriate evaluations have been performed. Although 95% of individuals with
• More than 95% of individuals with GEFS+ have a parent with the same
• Most
• Testing of parents of children who had Dravet syndrome and a confirmed
• Note: In one series, 75% of
• If a parent of the proband has the
• The likelihood that a sib who inherits an
• Seizure phenotype in sibs who inherit an
• The likelihood that a sib who inherits an
• Seizure phenotype in sibs who inherit an
• If the
• If a sib has epilepsy, the sib is presumed to be affected (and therefore to have an
• The likelihood that a sib who inherits an
• Seizure phenotype in sibs who inherit an
• Each child of an individual with an
• Penetrance is incomplete (see
• The likelihood that a heterozygous child of an individual with an
• Individuals with GEFS+ may have offspring who are more severely affected than they are; for example, they may have a child with Dravet syndrome.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
•
•
•
•
•
•
•
• Canada
•
•
•
•
•
## Molecular Genetics
SCN1A-Related Seizure Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SCN1A-Related Seizure Disorders (
## Molecular Pathogenesis
## Chapter Notes
17 February 2022 (sw) Revision: clarifications to
18 April 2019 (sw) Comprehensive update posted live
15 May 2014 (me) Comprehensive update posted live
10 November 2011 (me) Comprehensive update posted live
29 November 2007 (me) Review posted live
13 October 2006 (msm) Original submission
• 17 February 2022 (sw) Revision: clarifications to
• 18 April 2019 (sw) Comprehensive update posted live
• 15 May 2014 (me) Comprehensive update posted live
• 10 November 2011 (me) Comprehensive update posted live
• 29 November 2007 (me) Review posted live
• 13 October 2006 (msm) Original submission
## Revision History
17 February 2022 (sw) Revision: clarifications to
18 April 2019 (sw) Comprehensive update posted live
15 May 2014 (me) Comprehensive update posted live
10 November 2011 (me) Comprehensive update posted live
29 November 2007 (me) Review posted live
13 October 2006 (msm) Original submission
• 17 February 2022 (sw) Revision: clarifications to
• 18 April 2019 (sw) Comprehensive update posted live
• 15 May 2014 (me) Comprehensive update posted live
• 10 November 2011 (me) Comprehensive update posted live
• 29 November 2007 (me) Review posted live
• 13 October 2006 (msm) Original submission
## References
## Literature Cited
Findings in a family illustrating variable expressivity among individuals with the same pathogenic variant. The proband, a boy (arrow) with febrile convulsions since age seven months, had frequent, difficult-to-control partial seizures beginning at age three years. His sister had infrequent partial seizures starting early in school age. Their father had a single seizure as a young adult. All three had the same pathogenic variant in the fourth domain fifth segment (D4S5) on the pore region of the SCN1A (Na
Individuals with Dravet syndrome often have an unusual seizure type that frequently will manifest as obtundation status epilepticus. The EEG during these difficult-to-classify seizures shows an alternation of generalized and focal discharges with variable degrees of secondary generalization.
Topologic diagram of Na
|
[
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] |
29/11/2007
|
18/4/2019
|
17/2/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
geleophys-dysp
|
geleophys-dysp
|
[
"ADAMTS-like protein 2",
"Fibrillin-1",
"Latent-transforming growth factor beta-binding protein 3",
"ADAMTSL2",
"FBN1",
"LTBP3",
"Geleophysic Dysplasia"
] |
Geleophysic Dysplasia
|
Pauline Marzin, Valérie Cormier-Daire
|
Summary Geleophysic dysplasia, a progressive condition resembling a lysosomal storage disorder, is characterized by short stature, short hands and feet, progressive joint limitation and contractures, distinctive facial features, progressive cardiac valvular disease, and thickened skin. Intellect is normal. The characteristic clinical findings are likely to be present in the first year of life. Cardiac, airway, and pulmonary involvement result in death before age five years in approximately 33% of individuals. The clinical diagnosis of geleophysic dysplasia can be established in a proband with characteristic clinical and radiographic findings; the molecular diagnosis of geleophysic dysplasia is established in a proband with characteristic clinical and radiographic findings and one of the following on molecular genetic testing: biallelic pathogenic variants in Geleophysic dysplasia caused by biallelic pathogenic variants in Once the geleophysic dysplasia-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
No consensus clinical diagnostic criteria for geleophysic dysplasia have been published.
Geleophysic dysplasia
Proportionate short stature
Very short hands and feet
Progressive joint limitation and contractures
Distinctive facial features: round, full face; small nose with anteverted nares; broad nasal bridge; thin vermilion of the upper lip with a flat philtrum [
Thickened skin
Progressive cardiac valvular disease diagnosed on echocardiography
Normal intellect
Hepatomegaly
Tracheal stenosis
Recurrent respiratory and middle ear infections
Delayed bone age
Broad proximal phalanges
Cone-shaped phalangeal epiphyses
Shortened long tubular bones
Small capital femoral epiphyses
The clinical diagnosis of geleophysic dysplasia
The molecular diagnosis of geleophysic dysplasia
Biallelic pathogenic (or likely pathogenic) variants in
A heterozygous pathogenic (or likely pathogenic) variant in
A heterozygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Perform
If no pathogenic variant is found, perform
If no pathogenic variant is found, perform
For an introduction to multigene panels click
When the diagnosis of geleophysic dysplasia is not considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Geleophysic Dysplasia
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A 30-bp deletion affecting the N glycan-rich module has been described that would likely be identified with sequence analysis [
• Proportionate short stature
• Very short hands and feet
• Progressive joint limitation and contractures
• Distinctive facial features: round, full face; small nose with anteverted nares; broad nasal bridge; thin vermilion of the upper lip with a flat philtrum [
• Thickened skin
• Progressive cardiac valvular disease diagnosed on echocardiography
• Normal intellect
• Hepatomegaly
• Tracheal stenosis
• Recurrent respiratory and middle ear infections
• Delayed bone age
• Broad proximal phalanges
• Cone-shaped phalangeal epiphyses
• Shortened long tubular bones
• Small capital femoral epiphyses
• Biallelic pathogenic (or likely pathogenic) variants in
• A heterozygous pathogenic (or likely pathogenic) variant in
• A heterozygous pathogenic (or likely pathogenic) variant in
• Perform
• If no pathogenic variant is found, perform
• If no pathogenic variant is found, perform
## Suggestive Findings
Geleophysic dysplasia
Proportionate short stature
Very short hands and feet
Progressive joint limitation and contractures
Distinctive facial features: round, full face; small nose with anteverted nares; broad nasal bridge; thin vermilion of the upper lip with a flat philtrum [
Thickened skin
Progressive cardiac valvular disease diagnosed on echocardiography
Normal intellect
Hepatomegaly
Tracheal stenosis
Recurrent respiratory and middle ear infections
Delayed bone age
Broad proximal phalanges
Cone-shaped phalangeal epiphyses
Shortened long tubular bones
Small capital femoral epiphyses
• Proportionate short stature
• Very short hands and feet
• Progressive joint limitation and contractures
• Distinctive facial features: round, full face; small nose with anteverted nares; broad nasal bridge; thin vermilion of the upper lip with a flat philtrum [
• Thickened skin
• Progressive cardiac valvular disease diagnosed on echocardiography
• Normal intellect
• Hepatomegaly
• Tracheal stenosis
• Recurrent respiratory and middle ear infections
• Delayed bone age
• Broad proximal phalanges
• Cone-shaped phalangeal epiphyses
• Shortened long tubular bones
• Small capital femoral epiphyses
## Establishing the Diagnosis
The clinical diagnosis of geleophysic dysplasia
The molecular diagnosis of geleophysic dysplasia
Biallelic pathogenic (or likely pathogenic) variants in
A heterozygous pathogenic (or likely pathogenic) variant in
A heterozygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Perform
If no pathogenic variant is found, perform
If no pathogenic variant is found, perform
For an introduction to multigene panels click
When the diagnosis of geleophysic dysplasia is not considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Geleophysic Dysplasia
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A 30-bp deletion affecting the N glycan-rich module has been described that would likely be identified with sequence analysis [
• Biallelic pathogenic (or likely pathogenic) variants in
• A heterozygous pathogenic (or likely pathogenic) variant in
• A heterozygous pathogenic (or likely pathogenic) variant in
• Perform
• If no pathogenic variant is found, perform
• If no pathogenic variant is found, perform
## Clinical Diagnosis
The clinical diagnosis of geleophysic dysplasia
## Molecular Diagnosis
The molecular diagnosis of geleophysic dysplasia
Biallelic pathogenic (or likely pathogenic) variants in
A heterozygous pathogenic (or likely pathogenic) variant in
A heterozygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Perform
If no pathogenic variant is found, perform
If no pathogenic variant is found, perform
For an introduction to multigene panels click
When the diagnosis of geleophysic dysplasia is not considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Geleophysic Dysplasia
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A 30-bp deletion affecting the N glycan-rich module has been described that would likely be identified with sequence analysis [
• Biallelic pathogenic (or likely pathogenic) variants in
• A heterozygous pathogenic (or likely pathogenic) variant in
• A heterozygous pathogenic (or likely pathogenic) variant in
• Perform
• If no pathogenic variant is found, perform
• If no pathogenic variant is found, perform
##
Perform
If no pathogenic variant is found, perform
If no pathogenic variant is found, perform
For an introduction to multigene panels click
• Perform
• If no pathogenic variant is found, perform
• If no pathogenic variant is found, perform
##
When the diagnosis of geleophysic dysplasia is not considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Geleophysic Dysplasia
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A 30-bp deletion affecting the N glycan-rich module has been described that would likely be identified with sequence analysis [
## Clinical Characteristics
Geleophysic dysplasia is a progressive disorder resembling a lysosomal storage disorder, involving bones and joints, cardiac valves, and skin. To date about 100 individuals have been reported: 51 affected individuals in two large cohorts [
Geleophysic Dysplasia: Frequency of Select Features
The oldest living affected individual is age 62 years. In addition to progressive cardiac valvular thickening, survivors have short stature (height more than three SD below the mean), progressive joint contractures (limited range of motion of the fingers, toes, wrists, and elbows) with toe walking, thickened skin, and intermittent pulmonary hypertension.
The clinical features of
Individuals with
Geleophysic dysplasia is rare; about 100 individuals have been reported to date.
## Clinical Description
Geleophysic dysplasia is a progressive disorder resembling a lysosomal storage disorder, involving bones and joints, cardiac valves, and skin. To date about 100 individuals have been reported: 51 affected individuals in two large cohorts [
Geleophysic Dysplasia: Frequency of Select Features
The oldest living affected individual is age 62 years. In addition to progressive cardiac valvular thickening, survivors have short stature (height more than three SD below the mean), progressive joint contractures (limited range of motion of the fingers, toes, wrists, and elbows) with toe walking, thickened skin, and intermittent pulmonary hypertension.
## Phenotype Correlations by Gene
The clinical features of
Individuals with
## Genotype-Phenotype Correlations
## Prevalence
Geleophysic dysplasia is rare; about 100 individuals have been reported to date.
## Genetically Related (Allelic) Disorders
Other phenotypes associated with pathogenic variants in
Allelic Disorders to Consider in the Differential Diagnosis of Geleophysic Dysplasia
Moderate IUGR
Relative macrocephaly
Short limbs, w/very short hands
Stiff joints
More severe: lethal during neonatal period
Hypertrichosis
Large anterior fontanelle
Short neck
Generalized bone sclerosis
Mild platyspondyly
Short stature
Short hands
Stiff joints
Delayed bone age
Cone-shaped phalangeal epiphyses
Thickened skin
Heart disease
Less severe outcome
Absence of progressive cardiac valvular thickening
Absence of distinctive facial features
Absence of hepatomegaly
See footnote 4.
Microspherophakia (small spherical lens)
Myopia secondary to abnormal shape of the lens
Ectopia lentis (abnormal position of the lens)
Glaucoma (can lead to blindness)
AD = autosomal dominant; AR = autosomal recessive; IUGR = intrauterine growth restriction; MOI = mode of inheritance
Moore-Federman syndrome is probably the same as acromicric dysplasia.
Additional clinical findings in 22 individuals with acromicric dysplasia from 15 families include: frequent ear, tracheal, and respiratory complications; non-progressive heart disease (4/22; 2 with bicuspid aortic valve, 2 with atrial septal defect); and myopia (8/20) [Author, personal observations].
Other Allelic Disorders
• Moderate IUGR
• Relative macrocephaly
• Short limbs, w/very short hands
• Stiff joints
• More severe: lethal during neonatal period
• Hypertrichosis
• Large anterior fontanelle
• Short neck
• Generalized bone sclerosis
• Mild platyspondyly
• Short stature
• Short hands
• Stiff joints
• Delayed bone age
• Cone-shaped phalangeal epiphyses
• Thickened skin
• Heart disease
• Less severe outcome
• Absence of progressive cardiac valvular thickening
• Absence of distinctive facial features
• Absence of hepatomegaly
• See footnote 4.
• Microspherophakia (small spherical lens)
• Myopia secondary to abnormal shape of the lens
• Ectopia lentis (abnormal position of the lens)
• Glaucoma (can lead to blindness)
## Differential Diagnosis
The acromelic dysplasia group includes four rare disorders with striking clinical overlap: geleophysic dysplasia, Weill-Marchesani syndrome, acromicric dysplasia, and Myhre syndrome. Overlapping and distinguishing clinical features are summarized in
Disorders to Consider in the Differential Diagnosis of Geleophysic Dysplasia
IUGR
Short stature
Short hands & feet
Progressive joint limitation & contractures
Thickened skin
Heart involvement
Characteristic facial features w/prognathism
Calvarial thickening
Variable degree of cognitive impairment
Mixed conductive & sensorineural deafness
AD = autosomal dominant; AR = autosomal recessive; IUGR = intrauterine growth restriction; MOI = mode of inheritance
• IUGR
• Short stature
• Short hands & feet
• Progressive joint limitation & contractures
• Thickened skin
• Heart involvement
• Characteristic facial features w/prognathism
• Calvarial thickening
• Variable degree of cognitive impairment
• Mixed conductive & sensorineural deafness
## Management
Clinical practice guidelines have been published (see Supplementary Data in
To establish the extent of disease and needs in an individual diagnosed with geleophysic dysplasia, the evaluations summarized in
Geleophysic Dysplasia: Recommended Evaluations Following Initial Diagnosis
Assessment of growth
Assessment of joint range of motion by an orthopedist/physiotherapist
Radiographs for hip dysplasia
Eye exam for refractive error (incl astigmatism) & corneal thickening
Funduscopic exam for papilledema
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for geleophysic dysplasia. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Geleophysic Dysplasia: Treatment of Manifestations
Cardiac valve replacement in those w/severe stenosis or insufficiency
Mgmt of cardiac septal defect per cardiologist & cardiac surgeon
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Geleophysic Dysplasia: Recommended Surveillance
Assessment of growth & motor & speech development
Assessment for recurrent ear infections, serous otitis media, obstructive sleep apnea, & asthma
Clinical examination incl heart, lungs, & liver size
Age ≤6 mos: monthly
Age 6 mos-2 yrs: every 3 mos
Age 2-3 yrs: every 6 mos
Clinical exam w/clinical geneticist
Genetic counseling incl information re support organizations
Orthopedic/physiotherapy eval for joint limitation
Radiographs for hip dysplasia
Flexible endoscopy (w/rigid endoscopy as needed) to assess for upper airway obstruction & adenoidal hypertrophy
Audiogram for conductive deafness
Ophthalmology exam for refractive error (incl astigmatism) & corneal thickening
Funduscopic exam for papilledema
See
The management of a pregnant woman is complicated due to the small pelvis, cardiac anomalies, and tracheal stenosis. It is recommended that women considering a pregnancy be evaluated prior to pregnancy and followed during pregnancy in a high-risk perinatal center.
Search
• Assessment of growth
• Assessment of joint range of motion by an orthopedist/physiotherapist
• Radiographs for hip dysplasia
• Eye exam for refractive error (incl astigmatism) & corneal thickening
• Funduscopic exam for papilledema
• Community or
• Social work involvement for parental support
• Home nursing referral
• Cardiac valve replacement in those w/severe stenosis or insufficiency
• Mgmt of cardiac septal defect per cardiologist & cardiac surgeon
• Assessment of growth & motor & speech development
• Assessment for recurrent ear infections, serous otitis media, obstructive sleep apnea, & asthma
• Clinical examination incl heart, lungs, & liver size
• Age ≤6 mos: monthly
• Age 6 mos-2 yrs: every 3 mos
• Age 2-3 yrs: every 6 mos
• Clinical exam w/clinical geneticist
• Genetic counseling incl information re support organizations
• Orthopedic/physiotherapy eval for joint limitation
• Radiographs for hip dysplasia
• Flexible endoscopy (w/rigid endoscopy as needed) to assess for upper airway obstruction & adenoidal hypertrophy
• Audiogram for conductive deafness
• Ophthalmology exam for refractive error (incl astigmatism) & corneal thickening
• Funduscopic exam for papilledema
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with geleophysic dysplasia, the evaluations summarized in
Geleophysic Dysplasia: Recommended Evaluations Following Initial Diagnosis
Assessment of growth
Assessment of joint range of motion by an orthopedist/physiotherapist
Radiographs for hip dysplasia
Eye exam for refractive error (incl astigmatism) & corneal thickening
Funduscopic exam for papilledema
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assessment of growth
• Assessment of joint range of motion by an orthopedist/physiotherapist
• Radiographs for hip dysplasia
• Eye exam for refractive error (incl astigmatism) & corneal thickening
• Funduscopic exam for papilledema
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for geleophysic dysplasia. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Geleophysic Dysplasia: Treatment of Manifestations
Cardiac valve replacement in those w/severe stenosis or insufficiency
Mgmt of cardiac septal defect per cardiologist & cardiac surgeon
• Cardiac valve replacement in those w/severe stenosis or insufficiency
• Mgmt of cardiac septal defect per cardiologist & cardiac surgeon
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Geleophysic Dysplasia: Recommended Surveillance
Assessment of growth & motor & speech development
Assessment for recurrent ear infections, serous otitis media, obstructive sleep apnea, & asthma
Clinical examination incl heart, lungs, & liver size
Age ≤6 mos: monthly
Age 6 mos-2 yrs: every 3 mos
Age 2-3 yrs: every 6 mos
Clinical exam w/clinical geneticist
Genetic counseling incl information re support organizations
Orthopedic/physiotherapy eval for joint limitation
Radiographs for hip dysplasia
Flexible endoscopy (w/rigid endoscopy as needed) to assess for upper airway obstruction & adenoidal hypertrophy
Audiogram for conductive deafness
Ophthalmology exam for refractive error (incl astigmatism) & corneal thickening
Funduscopic exam for papilledema
• Assessment of growth & motor & speech development
• Assessment for recurrent ear infections, serous otitis media, obstructive sleep apnea, & asthma
• Clinical examination incl heart, lungs, & liver size
• Age ≤6 mos: monthly
• Age 6 mos-2 yrs: every 3 mos
• Age 2-3 yrs: every 6 mos
• Clinical exam w/clinical geneticist
• Genetic counseling incl information re support organizations
• Orthopedic/physiotherapy eval for joint limitation
• Radiographs for hip dysplasia
• Flexible endoscopy (w/rigid endoscopy as needed) to assess for upper airway obstruction & adenoidal hypertrophy
• Audiogram for conductive deafness
• Ophthalmology exam for refractive error (incl astigmatism) & corneal thickening
• Funduscopic exam for papilledema
## Evaluation of Relatives at Risk
See
## Pregnancy Management
The management of a pregnant woman is complicated due to the small pelvis, cardiac anomalies, and tracheal stenosis. It is recommended that women considering a pregnancy be evaluated prior to pregnancy and followed during pregnancy in a high-risk perinatal center.
## Therapies Under Investigation
Search
## Genetic Counseling
Geleophysic dysplasia caused by biallelic pathogenic variants in
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
All probands reported to date with
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include physical examination for manifestations of geleophysic dysplasia* (e.g., proportionate short stature, joint limitations, short hands and feet, and distinctive facial features) and – if a molecular diagnosis has been established in the proband – molecular genetic testing for the
* Reduced penetrance has not been reported to date in
If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a molecular diagnosis has been established in the proband and the pathogenic variant identified in the proband is not identified in either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [
If the genetic status of the parents is unknown but neither parent has manifestations of geleophysic dysplasia on physical examination, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for geleophysic dysplasia because of the possibility of parental germline mosaicism.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with geleophysic dysplasia or are at risk of being a carrier of an
Once the geleophysic dysplasia-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• All probands reported to date with
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include physical examination for manifestations of geleophysic dysplasia* (e.g., proportionate short stature, joint limitations, short hands and feet, and distinctive facial features) and – if a molecular diagnosis has been established in the proband – molecular genetic testing for the
• * Reduced penetrance has not been reported to date in
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a molecular diagnosis has been established in the proband and the pathogenic variant identified in the proband is not identified in either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [
• If the genetic status of the parents is unknown but neither parent has manifestations of geleophysic dysplasia on physical examination, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for geleophysic dysplasia because of the possibility of parental germline mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with geleophysic dysplasia or are at risk of being a carrier of an
## Mode of Inheritance
Geleophysic dysplasia caused by biallelic pathogenic variants in
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for an
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Autosomal Dominant Inheritance – Risk to Family Members
All probands reported to date with
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include physical examination for manifestations of geleophysic dysplasia* (e.g., proportionate short stature, joint limitations, short hands and feet, and distinctive facial features) and – if a molecular diagnosis has been established in the proband – molecular genetic testing for the
* Reduced penetrance has not been reported to date in
If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a molecular diagnosis has been established in the proband and the pathogenic variant identified in the proband is not identified in either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [
If the genetic status of the parents is unknown but neither parent has manifestations of geleophysic dysplasia on physical examination, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for geleophysic dysplasia because of the possibility of parental germline mosaicism.
• All probands reported to date with
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents of the proband include physical examination for manifestations of geleophysic dysplasia* (e.g., proportionate short stature, joint limitations, short hands and feet, and distinctive facial features) and – if a molecular diagnosis has been established in the proband – molecular genetic testing for the
• * Reduced penetrance has not been reported to date in
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a molecular diagnosis has been established in the proband and the pathogenic variant identified in the proband is not identified in either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [
• If the genetic status of the parents is unknown but neither parent has manifestations of geleophysic dysplasia on physical examination, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for geleophysic dysplasia because of the possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with geleophysic dysplasia or are at risk of being a carrier of an
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with geleophysic dysplasia or are at risk of being a carrier of an
## Prenatal Testing and Preimplantation Genetic Testing
Once the geleophysic dysplasia-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Hôpital Necker-Enfant Malades
France
•
•
•
•
•
• Hôpital Necker-Enfant Malades
• France
•
•
•
## Molecular Genetics
Geleophysic Dysplasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Geleophysic Dysplasia (
The functional consequences of
All
Because
Geleophysic Dysplasia: Mechanism of Disease Causation
Genes from
Geleophysic Dysplasia: Gene-Specific Laboratory Considerations
Genes from
## Molecular Pathogenesis
The functional consequences of
All
Because
Geleophysic Dysplasia: Mechanism of Disease Causation
Genes from
Geleophysic Dysplasia: Gene-Specific Laboratory Considerations
Genes from
## Chapter Notes
Pauline Marzin and Valérie Cormier-Daire (
Contact Pauline Marzin and Valérie Cormier-Daire to inquire about review of
Valérie Cormier-Daire, MD, PhD (2009-present)Carine Le Goff, PhD; Université Paris Descartes (2009-2018)Pauline Marzin, MD (2018-present)
28 March 2024 (sw) Comprehensive update posted live
11 October 2018 (bp) Comprehensive update posted live
19 April 2012 (me) Comprehensive update posted live
22 September 2009 (et) Review posted live
5 June 2009 (vcd) Original submission
• 28 March 2024 (sw) Comprehensive update posted live
• 11 October 2018 (bp) Comprehensive update posted live
• 19 April 2012 (me) Comprehensive update posted live
• 22 September 2009 (et) Review posted live
• 5 June 2009 (vcd) Original submission
## Author Notes
Pauline Marzin and Valérie Cormier-Daire (
Contact Pauline Marzin and Valérie Cormier-Daire to inquire about review of
## Author History
Valérie Cormier-Daire, MD, PhD (2009-present)Carine Le Goff, PhD; Université Paris Descartes (2009-2018)Pauline Marzin, MD (2018-present)
## Revision History
28 March 2024 (sw) Comprehensive update posted live
11 October 2018 (bp) Comprehensive update posted live
19 April 2012 (me) Comprehensive update posted live
22 September 2009 (et) Review posted live
5 June 2009 (vcd) Original submission
• 28 March 2024 (sw) Comprehensive update posted live
• 11 October 2018 (bp) Comprehensive update posted live
• 19 April 2012 (me) Comprehensive update posted live
• 22 September 2009 (et) Review posted live
• 5 June 2009 (vcd) Original submission
## References
## Literature Cited
|
[] |
22/9/2009
|
28/3/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
glc
|
glc
|
[
"Angiopoietin-1 receptor",
"Cytochrome P450 1B1",
"Latent-transforming growth factor beta-binding protein 2",
"CYP1B1",
"LTBP2",
"TEK",
"Primary Congenital Glaucoma"
] |
Primary Congenital Glaucoma
|
Khaled K Abu-Amero, Deepak P Edward
|
Summary Primary congenital glaucoma (PCG) is characterized by elevated intraocular pressure (IOP), enlargement of the globe (buphthalmos), edema, and opacification of the cornea with rupture of Descemet's membrane (Haab's striae), thinning of the anterior sclera and iris atrophy, anomalously deep anterior chamber, and structurally normal posterior segment except for progressive glaucomatous optic atrophy. Symptoms include photophobia, blepharospasm, and excessive tearing. Typically, the diagnosis is made in the first year of life. Depending on when treatment is instituted, visual acuity may be reduced and/or visual fields may be restricted. In untreated individuals, blindness invariably occurs. The diagnosis of PCG is based on clinical criteria including: elevated IOP in a child typically before age one year, enlargement of the globe, increased corneal diameter, cloudy corneas, breaks in Decsemet’s membrane (Haab’s striae) and anomalously deep anterior chamber. Identification of biallelic pathogenic variants in PCG caused by biallelic pathogenic variants in Prenatal testing for a pregnancy at increased risk is possible if the PCG-causing pathogenic variant(s) in the family are known.
|
## Diagnosis
Primary congenital glaucoma (PCG)
Photophobia, blepharospasm, and excessive tearing
Edema and opacification of the cornea with rupture of Descemet's membrane, known as Haab's striae
Thinning of the anterior sclera and atrophy of the iris
Structurally normal posterior segment except for progressive optic atrophy
Absence of structural changes in the anterior chamber that are consistent with a diagnosis of anterior segment dysgenesis or associated systemic disease.
The diagnosis of PCG
Elevated intraocular pressure (IOP) in an infant or child typically (but not always) before age one year. An IOP greater than 21 mm Hg (mercury) in one or both eyes as measured by applanation tonometry, I-care tonometry
Enlargement of the (infantile) globe (buphthalmos)
Increased corneal diameter and cloudy corneas
Breaks in Decsemet’s membrane (Haab’s striae)
Anomalously deep anterior chamber
Bilateral or unilateral findings
Identification of biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular testing approaches can include
Targeted analysis for
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Primary Congenital Glaucoma
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The probability of identifying pathogenic variants in
At least five
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Heterozygous
Two additional loci, GLC3B on 1p36 [
• Photophobia, blepharospasm, and excessive tearing
• Edema and opacification of the cornea with rupture of Descemet's membrane, known as Haab's striae
• Thinning of the anterior sclera and atrophy of the iris
• Structurally normal posterior segment except for progressive optic atrophy
• Absence of structural changes in the anterior chamber that are consistent with a diagnosis of anterior segment dysgenesis or associated systemic disease.
• Elevated intraocular pressure (IOP) in an infant or child typically (but not always) before age one year. An IOP greater than 21 mm Hg (mercury) in one or both eyes as measured by applanation tonometry, I-care tonometry
• Enlargement of the (infantile) globe (buphthalmos)
• Increased corneal diameter and cloudy corneas
• Breaks in Decsemet’s membrane (Haab’s striae)
• Anomalously deep anterior chamber
• Bilateral or unilateral findings
• Targeted analysis for
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Primary congenital glaucoma (PCG)
Photophobia, blepharospasm, and excessive tearing
Edema and opacification of the cornea with rupture of Descemet's membrane, known as Haab's striae
Thinning of the anterior sclera and atrophy of the iris
Structurally normal posterior segment except for progressive optic atrophy
Absence of structural changes in the anterior chamber that are consistent with a diagnosis of anterior segment dysgenesis or associated systemic disease.
• Photophobia, blepharospasm, and excessive tearing
• Edema and opacification of the cornea with rupture of Descemet's membrane, known as Haab's striae
• Thinning of the anterior sclera and atrophy of the iris
• Structurally normal posterior segment except for progressive optic atrophy
• Absence of structural changes in the anterior chamber that are consistent with a diagnosis of anterior segment dysgenesis or associated systemic disease.
## Establishing the Diagnosis
The diagnosis of PCG
Elevated intraocular pressure (IOP) in an infant or child typically (but not always) before age one year. An IOP greater than 21 mm Hg (mercury) in one or both eyes as measured by applanation tonometry, I-care tonometry
Enlargement of the (infantile) globe (buphthalmos)
Increased corneal diameter and cloudy corneas
Breaks in Decsemet’s membrane (Haab’s striae)
Anomalously deep anterior chamber
Bilateral or unilateral findings
Identification of biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular testing approaches can include
Targeted analysis for
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Primary Congenital Glaucoma
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The probability of identifying pathogenic variants in
At least five
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Heterozygous
Two additional loci, GLC3B on 1p36 [
• Elevated intraocular pressure (IOP) in an infant or child typically (but not always) before age one year. An IOP greater than 21 mm Hg (mercury) in one or both eyes as measured by applanation tonometry, I-care tonometry
• Enlargement of the (infantile) globe (buphthalmos)
• Increased corneal diameter and cloudy corneas
• Breaks in Decsemet’s membrane (Haab’s striae)
• Anomalously deep anterior chamber
• Bilateral or unilateral findings
• Targeted analysis for
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Primary congenital glaucoma (PCG) is characterized by developmental defect(s) of the trabecular meshwork and anterior chamber angle that prevent adequate drainage of aqueous humor, resulting in elevated intraocular pressure (IOP) and stretching of the sclera that produces an enlarged globe (buphthalmos).
The following information comes from the detailed clinical papers on PCG of
By definition, congenital glaucoma is present at birth; it is typically diagnosed in the first year of life. PCG is more common in males (65%) and is bilateral in 70% of individuals.
The clinical signs and symptoms depend primarily on the age of onset and the severity of the disease. The classic symptoms include tearing, photophobia, and irritability. Occasionally, parents may notice cloudy and/or unusually large corneas in their child caused by corneal edema; the corneal enlargement generally occurs before age three years.
The most severe clinical features are typically seen in the newborn, who may present with corneal opacity, increased corneal diameter, increased IOP, and an enlarged globe [
Early detection and appropriate treatment of congenital glaucoma can improve visual outcome. In contrast to the permanent optic nerve cupping and visual field loss seen in adults with adult-onset glaucoma, the pressure-induced optic nerve cupping in infants and young children with PCG is reversible, particularly in the early stages of the disease. This favorable outcome is believed to be a result of the highly elastic nature of the tissues of the optic nerves of infants and young children [
The ultimate visual outcome depends on the severity of the disease at diagnosis, the presence of other associated ocular abnormalities, response to surgical treatment, and success in controlling IOP on follow up. The earlier the onset of clinical manifestations of glaucoma, the worse the prognosis.
Despite early treatment and multiple surgical interventions, some individuals with severe disease evident at birth develop significant visual impairment from corneal opacification, advanced glaucomatous damage, or amblyopia, and may eventually become legally blind.
Individuals with milder forms of disease who present later in childhood often do well with a single surgical procedure and have an excellent visual prognosis later in life.
The IOP is a significant prognostic factor for postoperative visual function, with substantially better vision observed in individuals with IOP <19 mm Hg.
Individuals with
Individuals with
Walton and colleagues have shown that the phenotype can vary significantly in the same individual (one eye being more severely affected than the other) [
Some pathogenic variants are more common in specific ethnic groups. For example:
Additional pathogenic variants have been associated (although with lesser frequencies) with other specific ethnic groups [
PCG occurs in all ethnic groups. The birth prevalence, however, varies worldwide:
1:5,000-22,000 in western countries
1:2,500 in the Middle East
1:1,250 in the Rom population of Slovakia [
1:3,300 in the Indian state of Andhra Pradesh, where the disease accounts for approximately 4.2% of all childhood blindness [
In Saudi Arabia and in the Rom population of Slovakia, PCG is the most common cause of childhood blindness [
• 1:5,000-22,000 in western countries
• 1:2,500 in the Middle East
• 1:1,250 in the Rom population of Slovakia [
• 1:3,300 in the Indian state of Andhra Pradesh, where the disease accounts for approximately 4.2% of all childhood blindness [
## Clinical Description
Primary congenital glaucoma (PCG) is characterized by developmental defect(s) of the trabecular meshwork and anterior chamber angle that prevent adequate drainage of aqueous humor, resulting in elevated intraocular pressure (IOP) and stretching of the sclera that produces an enlarged globe (buphthalmos).
The following information comes from the detailed clinical papers on PCG of
By definition, congenital glaucoma is present at birth; it is typically diagnosed in the first year of life. PCG is more common in males (65%) and is bilateral in 70% of individuals.
The clinical signs and symptoms depend primarily on the age of onset and the severity of the disease. The classic symptoms include tearing, photophobia, and irritability. Occasionally, parents may notice cloudy and/or unusually large corneas in their child caused by corneal edema; the corneal enlargement generally occurs before age three years.
The most severe clinical features are typically seen in the newborn, who may present with corneal opacity, increased corneal diameter, increased IOP, and an enlarged globe [
Early detection and appropriate treatment of congenital glaucoma can improve visual outcome. In contrast to the permanent optic nerve cupping and visual field loss seen in adults with adult-onset glaucoma, the pressure-induced optic nerve cupping in infants and young children with PCG is reversible, particularly in the early stages of the disease. This favorable outcome is believed to be a result of the highly elastic nature of the tissues of the optic nerves of infants and young children [
The ultimate visual outcome depends on the severity of the disease at diagnosis, the presence of other associated ocular abnormalities, response to surgical treatment, and success in controlling IOP on follow up. The earlier the onset of clinical manifestations of glaucoma, the worse the prognosis.
Despite early treatment and multiple surgical interventions, some individuals with severe disease evident at birth develop significant visual impairment from corneal opacification, advanced glaucomatous damage, or amblyopia, and may eventually become legally blind.
Individuals with milder forms of disease who present later in childhood often do well with a single surgical procedure and have an excellent visual prognosis later in life.
The IOP is a significant prognostic factor for postoperative visual function, with substantially better vision observed in individuals with IOP <19 mm Hg.
## Phenotype Correlations by Gene
Individuals with
Individuals with
## Genotype-Phenotype Correlations
Walton and colleagues have shown that the phenotype can vary significantly in the same individual (one eye being more severely affected than the other) [
## Prevalence
Some pathogenic variants are more common in specific ethnic groups. For example:
Additional pathogenic variants have been associated (although with lesser frequencies) with other specific ethnic groups [
PCG occurs in all ethnic groups. The birth prevalence, however, varies worldwide:
1:5,000-22,000 in western countries
1:2,500 in the Middle East
1:1,250 in the Rom population of Slovakia [
1:3,300 in the Indian state of Andhra Pradesh, where the disease accounts for approximately 4.2% of all childhood blindness [
In Saudi Arabia and in the Rom population of Slovakia, PCG is the most common cause of childhood blindness [
• 1:5,000-22,000 in western countries
• 1:2,500 in the Middle East
• 1:1,250 in the Rom population of Slovakia [
• 1:3,300 in the Indian state of Andhra Pradesh, where the disease accounts for approximately 4.2% of all childhood blindness [
## Genetically Related (Allelic) Disorders
In the study of
12 of 14 unrelated Saudi Arabians with JOAG had at least one
Eight were homozygous for the p.Gly61Glu pathogenic variant.
Two were compound heterozygous for the p.Gly61Glu and p.Leu432Val variants.
Two were heterozygous for the p.Gly61Glu variant with no other variant identified.
No genotype-phenotype correlation was demonstrated in those with biallelic
Heterozygous
• 12 of 14 unrelated Saudi Arabians with JOAG had at least one
• Eight were homozygous for the p.Gly61Glu pathogenic variant.
• Two were compound heterozygous for the p.Gly61Glu and p.Leu432Val variants.
• Two were heterozygous for the p.Gly61Glu variant with no other variant identified.
##
In the study of
12 of 14 unrelated Saudi Arabians with JOAG had at least one
Eight were homozygous for the p.Gly61Glu pathogenic variant.
Two were compound heterozygous for the p.Gly61Glu and p.Leu432Val variants.
Two were heterozygous for the p.Gly61Glu variant with no other variant identified.
No genotype-phenotype correlation was demonstrated in those with biallelic
• 12 of 14 unrelated Saudi Arabians with JOAG had at least one
• Eight were homozygous for the p.Gly61Glu pathogenic variant.
• Two were compound heterozygous for the p.Gly61Glu and p.Leu432Val variants.
• Two were heterozygous for the p.Gly61Glu variant with no other variant identified.
##
##
Heterozygous
## Differential Diagnosis
A number of congenital ocular conditions can mimic PCG and must be considered by the clinician [
Primary "newborn"-type congenital glaucoma. The most severe type; clinically apparent between birth and age one month
Primary "infantile" glaucoma (or infantile PCG) as described by
"Juvenile" ("late-recognized") primary infantile glaucoma. Onset clinically apparent after age two years
The types do not correlate with a specific genetic cause, although primary "newborn"-type congenital glaucoma is more likely to be caused by mutation of
In the older child with juvenile onset, or in less severely affected individuals, the increase in intraocular pressure (IOP) is gradual; thus, corneal edema and opacity may be less obvious than in the newborn type. Progressive enlargement of the globe or "buphthalmos" usually does not occur after age three to four years [
It is important to establish the diagnosis of an associated syndrome because of the implications for genetic counseling and treatment (see
Conditions/Syndromes Associated with Infantile Glaucoma
Complete or partial iris hypoplasia w/assoc foveal hypoplasia, resulting in ↓ visual acuity & nystagmus
Presents in early infancy
Frequently assoc w/other ocular abnormalities, often of later onset, incl cataract, glaucoma, & corneal opacification& vascularization
Presents w/posterior embryotoxon & (variably) iris strands adherent to Schwalbe's line, iris hypoplasia, focal iris atrophy, & ectropion uveae.
Glaucoma develops in ~50% of persons but is more common in those w/central iris changes & marked anterior iris insertion
Always bilateral, but may be distinctly asymmetric
Corneal diameter <10 mm
Can be assoc w/glaucoma & other ocular anomalies incl congenital cataracts, sclerocornea, & corneal plana
Bilateral corneal opacification
May be difficult to distinguish from microcornea, but corneal diameter & IOP are usually normal in CHED
The primary defect in the corneal endothelium leads to corneal edema & opacification.
CHED & CG are known to coexist; exact incidence unknown
Dense congenital cataracts are found in all affected boys, infantile glaucoma in ~50%
All boys have impaired vision; corrected acuity rarely >20/100
Almost all affected males have some ID
Iris Lisch nodules
CG rarely observed
AD = autosomal dominant; AR = autosomal recessive; CG = congenital glaucoma; ESKD = end-stage kidney disease; ID = intellectual disability; MOI = mode of inheritance; WAGR = Wilms tumor-aniridia-genital anomalies-retardation; XL = X-linked
Pathogenic variants or deletions in
Anterior segment dysgenesis syndromes are a heterogeneous group of disorders that are usually inherited in an autosomal dominant manner with reduced penetrance.
Somatic mosaic pathogenic variants in
• Primary "newborn"-type congenital glaucoma. The most severe type; clinically apparent between birth and age one month
• Primary "infantile" glaucoma (or infantile PCG) as described by
• "Juvenile" ("late-recognized") primary infantile glaucoma. Onset clinically apparent after age two years
• Complete or partial iris hypoplasia w/assoc foveal hypoplasia, resulting in ↓ visual acuity & nystagmus
• Presents in early infancy
• Frequently assoc w/other ocular abnormalities, often of later onset, incl cataract, glaucoma, & corneal opacification& vascularization
• Presents w/posterior embryotoxon & (variably) iris strands adherent to Schwalbe's line, iris hypoplasia, focal iris atrophy, & ectropion uveae.
• Glaucoma develops in ~50% of persons but is more common in those w/central iris changes & marked anterior iris insertion
• Always bilateral, but may be distinctly asymmetric
• Corneal diameter <10 mm
• Can be assoc w/glaucoma & other ocular anomalies incl congenital cataracts, sclerocornea, & corneal plana
• Bilateral corneal opacification
• May be difficult to distinguish from microcornea, but corneal diameter & IOP are usually normal in CHED
• The primary defect in the corneal endothelium leads to corneal edema & opacification.
• CHED & CG are known to coexist; exact incidence unknown
• Dense congenital cataracts are found in all affected boys, infantile glaucoma in ~50%
• All boys have impaired vision; corrected acuity rarely >20/100
• Almost all affected males have some ID
• Iris Lisch nodules
• CG rarely observed
## Management
To establish the extent of disease and needs in an individual diagnosed with primary congenital glaucoma (PCG), examination under anesthesia or sedation is warranted to make a complete assessment of both eyes. The examination includes the following:
Measurement of intraocular pressure (IOP) within the first few minutes of anesthesia
Measurement of corneal diameter
Examination of the anterior segment
Direct gonioscopy to rule out secondary glaucoma
Dilated fundus examination to evaluate for optic nerve damage
If the cornea is opaque, ultrasound biomicroscopy or optical coherence tomography to aid in evaluating the anterior segment structures
Measurement of axial length
If the child is examined under anesthesia, consent may be obtained to perform the appropriate surgical procedure after evaluation under anesthesia.
Consultation with a clinical geneticist and/or genetic counselor is recommended.
The primary goal of treatment is to decrease IOP to prevent vision-threatening complications including corneal opacification and glaucomatous optic atrophy. Early treatment to control IOP will reverse some of these complications in children. A Cochcrane review analyzed the literature that addressed the surgical management of congenital glaucoma but could not draw any conclusions from the analysis [
PCG is almost always managed surgically. The primary goal of surgery is to eliminate the resistance to aqueous outflow caused by the structural abnormalities in the anterior chamber angle. This goal may be accomplished through an internal approach (goniotomy) or an external approach (trabeculotomy or trabeculectomy).
In goniotomy, the surgeon visualizes the anterior chamber structures through a special lens (goniolens) to create openings in the trabecular meshwork. The goal of the procedure is to eliminate any resistance imposed by the abnormal trabecular meshwork. A clear cornea is necessary for direct visualization of the anterior chamber structures during this procedure.
In trabeculotomy, the trabecular meshwork is incised by cannulating Schlemm's canal with a metal probe or suture via an external opening in the sclera.
In trabeculectomy, a section of trabecular meshwork and Schlemm's canal is removed under a partial thickness sclera flap to create a wound fistula [
In deep sclerectomy the dissection of a deep scleral flap, deroofing of Schlemm's canal, and preserving the structural integrity of the trabecular meshwork results in improved aqueous outflow outside the anterior chamber.
Note: In contrast to goniotomy, deep sclerectomy, trabeculotomy, and trabeculectomy can be performed in individuals with advanced glaucoma and cloudy corneas.
Glaucoma drainage implants or cyclodestruction may be used to control IOP when initial surgical procedures have failed.
More than one surgical intervention may be necessary to control IOP; thus, significant morbidity is associated with both PCG and the currently available surgical treatment options. Individuals with milder forms of disease who present later in childhood often do well with a single surgical procedure and have an excellent visual prognosis later in life.
Clarity of the cornea and other ocular media, control of the ocular dimensions (corneal diameters and axial lengths), and optic nerve damage are important indicators of the course of the disease following surgery. Reported success rates for each (initial) procedure are approximately 80%. Infants with elevated IOP and cloudy corneas at birth have the poorest prognosis. The most favorable outcome is seen in infants in whom surgery is performed between the second and eighth month of life. With increasing age, surgery is less effective in preserving vision.
Surgery should not be delayed in an attempt to achieve medical control of IOP.
Medication may be used preoperatively to lower the IOP to prevent optic nerve damage, to reduce the risk of sudden decompression of the globe, and to clear the cornea for better visualization during examination and surgery.
Postoperatively, medication may help control IOP until the success of the surgical procedure is established.
Medical therapy is also used when surgery may be life threatening or has led to incomplete control of the glaucoma [
Medications such as Phospholine Iodide
Lifelong monitoring is necessary to ensure control of IOP to preserve remaining vision and to prevent further loss of vision; the intervals at which monitoring needs to be performed vary depending on the severity of disease and control of IOP.
Once IOP is controlled and the child is visually rehabilitated, follow up is typically every three months to keep IOP at the "target" level, which depends on the severity of the glaucomatous optic nerve damage and the age of the individual. Standard clinical follow-up tests include optic nerve photography and visual field testing. The complete ophthalmic evaluation often requires examination under anesthesia or sedation in infants and in young and uncooperative children. This process may be challenging to the individual, the family, and the treating physician [
Alpha-2 agonists should be avoided in children in the treatment of elevated IOP because of the risk for apnea and bradycardia.
Testing at-risk sibs in the neonatal period may be helpful in establishing the diagnosis of PCG early and in avoiding repeated examinations under anesthesia in at-risk young children.
Molecular genetic testing alone is appropriate in sibs of affected individuals in whom the pathogenic variant(s) have been identified.
If the PCG-related pathogenic variant(s) have not been identified in an affected family member (i.e., no definitive exclusion of the disease is possible by molecular genetic testing), screening including IOP measurements under anesthesia/sedation may be necessary.
Note: The literature is unclear as to timing of the onset of glaucoma, especially in families in whom pathogenic variants have been identified. In this high-risk group, it may be appropriate to perform yearly glaucoma screening into young adulthood.
See
Search
• Measurement of intraocular pressure (IOP) within the first few minutes of anesthesia
• Measurement of corneal diameter
• Examination of the anterior segment
• Direct gonioscopy to rule out secondary glaucoma
• Dilated fundus examination to evaluate for optic nerve damage
• If the cornea is opaque, ultrasound biomicroscopy or optical coherence tomography to aid in evaluating the anterior segment structures
• Measurement of axial length
• Molecular genetic testing alone is appropriate in sibs of affected individuals in whom the pathogenic variant(s) have been identified.
• If the PCG-related pathogenic variant(s) have not been identified in an affected family member (i.e., no definitive exclusion of the disease is possible by molecular genetic testing), screening including IOP measurements under anesthesia/sedation may be necessary.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with primary congenital glaucoma (PCG), examination under anesthesia or sedation is warranted to make a complete assessment of both eyes. The examination includes the following:
Measurement of intraocular pressure (IOP) within the first few minutes of anesthesia
Measurement of corneal diameter
Examination of the anterior segment
Direct gonioscopy to rule out secondary glaucoma
Dilated fundus examination to evaluate for optic nerve damage
If the cornea is opaque, ultrasound biomicroscopy or optical coherence tomography to aid in evaluating the anterior segment structures
Measurement of axial length
If the child is examined under anesthesia, consent may be obtained to perform the appropriate surgical procedure after evaluation under anesthesia.
Consultation with a clinical geneticist and/or genetic counselor is recommended.
• Measurement of intraocular pressure (IOP) within the first few minutes of anesthesia
• Measurement of corneal diameter
• Examination of the anterior segment
• Direct gonioscopy to rule out secondary glaucoma
• Dilated fundus examination to evaluate for optic nerve damage
• If the cornea is opaque, ultrasound biomicroscopy or optical coherence tomography to aid in evaluating the anterior segment structures
• Measurement of axial length
## Treatment of Manifestations
The primary goal of treatment is to decrease IOP to prevent vision-threatening complications including corneal opacification and glaucomatous optic atrophy. Early treatment to control IOP will reverse some of these complications in children. A Cochcrane review analyzed the literature that addressed the surgical management of congenital glaucoma but could not draw any conclusions from the analysis [
PCG is almost always managed surgically. The primary goal of surgery is to eliminate the resistance to aqueous outflow caused by the structural abnormalities in the anterior chamber angle. This goal may be accomplished through an internal approach (goniotomy) or an external approach (trabeculotomy or trabeculectomy).
In goniotomy, the surgeon visualizes the anterior chamber structures through a special lens (goniolens) to create openings in the trabecular meshwork. The goal of the procedure is to eliminate any resistance imposed by the abnormal trabecular meshwork. A clear cornea is necessary for direct visualization of the anterior chamber structures during this procedure.
In trabeculotomy, the trabecular meshwork is incised by cannulating Schlemm's canal with a metal probe or suture via an external opening in the sclera.
In trabeculectomy, a section of trabecular meshwork and Schlemm's canal is removed under a partial thickness sclera flap to create a wound fistula [
In deep sclerectomy the dissection of a deep scleral flap, deroofing of Schlemm's canal, and preserving the structural integrity of the trabecular meshwork results in improved aqueous outflow outside the anterior chamber.
Note: In contrast to goniotomy, deep sclerectomy, trabeculotomy, and trabeculectomy can be performed in individuals with advanced glaucoma and cloudy corneas.
Glaucoma drainage implants or cyclodestruction may be used to control IOP when initial surgical procedures have failed.
More than one surgical intervention may be necessary to control IOP; thus, significant morbidity is associated with both PCG and the currently available surgical treatment options. Individuals with milder forms of disease who present later in childhood often do well with a single surgical procedure and have an excellent visual prognosis later in life.
Clarity of the cornea and other ocular media, control of the ocular dimensions (corneal diameters and axial lengths), and optic nerve damage are important indicators of the course of the disease following surgery. Reported success rates for each (initial) procedure are approximately 80%. Infants with elevated IOP and cloudy corneas at birth have the poorest prognosis. The most favorable outcome is seen in infants in whom surgery is performed between the second and eighth month of life. With increasing age, surgery is less effective in preserving vision.
Surgery should not be delayed in an attempt to achieve medical control of IOP.
Medication may be used preoperatively to lower the IOP to prevent optic nerve damage, to reduce the risk of sudden decompression of the globe, and to clear the cornea for better visualization during examination and surgery.
Postoperatively, medication may help control IOP until the success of the surgical procedure is established.
Medical therapy is also used when surgery may be life threatening or has led to incomplete control of the glaucoma [
## Prevention of Secondary Complications
Medications such as Phospholine Iodide
## Surveillance
Lifelong monitoring is necessary to ensure control of IOP to preserve remaining vision and to prevent further loss of vision; the intervals at which monitoring needs to be performed vary depending on the severity of disease and control of IOP.
Once IOP is controlled and the child is visually rehabilitated, follow up is typically every three months to keep IOP at the "target" level, which depends on the severity of the glaucomatous optic nerve damage and the age of the individual. Standard clinical follow-up tests include optic nerve photography and visual field testing. The complete ophthalmic evaluation often requires examination under anesthesia or sedation in infants and in young and uncooperative children. This process may be challenging to the individual, the family, and the treating physician [
## Agents/Circumstances to Avoid
Alpha-2 agonists should be avoided in children in the treatment of elevated IOP because of the risk for apnea and bradycardia.
## Evaluation of Relatives at Risk
Testing at-risk sibs in the neonatal period may be helpful in establishing the diagnosis of PCG early and in avoiding repeated examinations under anesthesia in at-risk young children.
Molecular genetic testing alone is appropriate in sibs of affected individuals in whom the pathogenic variant(s) have been identified.
If the PCG-related pathogenic variant(s) have not been identified in an affected family member (i.e., no definitive exclusion of the disease is possible by molecular genetic testing), screening including IOP measurements under anesthesia/sedation may be necessary.
Note: The literature is unclear as to timing of the onset of glaucoma, especially in families in whom pathogenic variants have been identified. In this high-risk group, it may be appropriate to perform yearly glaucoma screening into young adulthood.
See
• Molecular genetic testing alone is appropriate in sibs of affected individuals in whom the pathogenic variant(s) have been identified.
• If the PCG-related pathogenic variant(s) have not been identified in an affected family member (i.e., no definitive exclusion of the disease is possible by molecular genetic testing), screening including IOP measurements under anesthesia/sedation may be necessary.
## Therapies Under Investigation
Search
## Genetic Counseling
Primary congenital glaucoma (PCG) caused by pathogenic variants in
PCG caused by a pathogenic variant in
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
All probands with
Recommendations for the evaluation of parents of a proband with an apparent
All affected individuals reported to date have had a
If the
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• All probands with
• Recommendations for the evaluation of parents of a proband with an apparent
• All affected individuals reported to date have had a
• If the
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Primary congenital glaucoma (PCG) caused by pathogenic variants in
PCG caused by a pathogenic variant in
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Autosomal Dominant Inheritance – Risk to Family Members
All probands with
Recommendations for the evaluation of parents of a proband with an apparent
All affected individuals reported to date have had a
If the
• All probands with
• Recommendations for the evaluation of parents of a proband with an apparent
• All affected individuals reported to date have had a
• If the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
•
•
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
Primary Congenital Glaucoma: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Primary Congenital Glaucoma (
Variants listed in the table have been provided by the authors.
See
##
Variants listed in the table have been provided by the authors.
See
##
##
## Chapter Notes
Khaled K Abu-Amero, PhD, FRCPath (2011-present)Bassem A Bejjani, MD, FACMG; Washington State University (2004-2011)Deepak P Edward, MD (2004-present)
17 August 2017 (sw) Comprehensive update posted live
20 March 2014 (me) Comprehensive update posted live
25 August 2011 (cd) Revision: sequence analysis of
21 July 2011 (me) Comprehensive update posted live
3 December 2007 (me) Comprehensive update posted live
30 September 2004 (me) Review posted live
3 June 2004 (bab) Original submission
• 17 August 2017 (sw) Comprehensive update posted live
• 20 March 2014 (me) Comprehensive update posted live
• 25 August 2011 (cd) Revision: sequence analysis of
• 21 July 2011 (me) Comprehensive update posted live
• 3 December 2007 (me) Comprehensive update posted live
• 30 September 2004 (me) Review posted live
• 3 June 2004 (bab) Original submission
## Author History
Khaled K Abu-Amero, PhD, FRCPath (2011-present)Bassem A Bejjani, MD, FACMG; Washington State University (2004-2011)Deepak P Edward, MD (2004-present)
## Revision History
17 August 2017 (sw) Comprehensive update posted live
20 March 2014 (me) Comprehensive update posted live
25 August 2011 (cd) Revision: sequence analysis of
21 July 2011 (me) Comprehensive update posted live
3 December 2007 (me) Comprehensive update posted live
30 September 2004 (me) Review posted live
3 June 2004 (bab) Original submission
• 17 August 2017 (sw) Comprehensive update posted live
• 20 March 2014 (me) Comprehensive update posted live
• 25 August 2011 (cd) Revision: sequence analysis of
• 21 July 2011 (me) Comprehensive update posted live
• 3 December 2007 (me) Comprehensive update posted live
• 30 September 2004 (me) Review posted live
• 3 June 2004 (bab) Original submission
## References
## Literature Cited
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"AO Khan, MA Aldahmesh, FS Alkuraya. Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma: a distinct phenotype caused by recessive LTBP2 mutations.. Mol Vis. 2011;17:2570-9",
"A Kumar, MR Duvvari, VC Prabhakaran, JS Shetty, GJ Murthy, SH Blanton. A homozygous mutation in LTBP2 causes isolated microspherophakia.. Hum Genet. 2010;128:365-71",
"PJ Maris, AK Mandal, PA Netland. Medical therapy of pediatric glaucoma and glaucoma in pregnancy.. Ophthalmol Clin North Am. 2005;18:461-8",
"Y Mashima, Y Suzuki, Y Sergeev, Y Ohtake, T Tanino, I Kimura, H Miyata, M Aihara, H Tanihara, M Inatani, N Azuma, T Iwata, M Araie. Novel cytochrome P4501B1 (CYP1B1) gene mutations in Japanese patients with primary congenital glaucoma.. Invest Ophthalmol Vis Sci 2001;42:2211-6",
"R Melki, E Colomb, N Lefort, AP Brézin, HJ Garchon. CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma.. J Med Genet. 2004;41:647-51",
"S Micheal, H Ayub, SN Zafar, B Bakker, M Ali, F Akhtar, F Islam, MI Khan, R Qamar, AI den Hollander. Identification of novel CYP1B1 gene mutations in patients with primary congenital and primary open-angle glaucoma.. Clin Exp Ophthalmol. 2015;43:31-9",
"S Micheal, SN Siddiqui, SN Zafar, A Iqbal, MI Khan, AI den Hollander. Identification of novel variants in LTBP2 and PXDN using whole-exome sequencing in developmental and congenital glaucoma.. PLoS One. 2016;11",
"J Morales, S Al Shahwan, S Al Odhayb, I Al Jadaan, DP Edward. Current surgical options for the management of pediatric glaucoma.. J Ophthalmol. 2013;2013",
"S Murray, BG Lake, S Gray, AJ Edwards, C Springall, EA Bowey, G Williamson, AR Boobis, NJ Gooderham. Effect of cruciferous vegetable consumption on heterocyclic aromatic amine metabolism in man.. Carcinogenesis. 2001;22:1413-20",
"M Narooie-Nejad, SH Paylakhi, S Shojaee, Z Fazlali, M Rezaei Kanavi, N Nilforushan, S Yazdani, F Babrzadeh, F Suri, M Ronaghi, E Elahi, C Paisán-Ruiz. Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma.. Hum Mol Genet. 2009;18:3969-77",
"SG Panicker, AB Reddy, AK Mandal, N Ahmed, HA Nagarajaram, SE Hasnain, D Balasubramanian. Identification of novel mutations causing familial primary congenital glaucoma in Indian pedigrees.. Invest Ophthalmol Vis Sci 2002;43:1358-66",
"M Papadopoulos, PT Khaw. Advances in the management of paediatric glaucoma.. Eye (Lond) 2007;21:1319-25",
"M Plásilová, E Feráková, L Kádasi, H Poláková, A Gerinec, J Ott, V Ferák. Linkage of autosomal recessive primary congenital glaucoma to the GLC3A locus in Roms (Gypsies) from Slovakia.. Hum Hered. 1998;48:30-3",
"M Plásilová, I Stoilov, M Sarfarazi, L Kádasi, E Feráková, V Ferák. Identification of a single ancestral CYP1B1 mutation in Slovak Gypsies (Roms) affected with primary congenital glaucoma.. J Med Genet. 1999;36:290-4",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"B Ramamurthy, V Sachdeva, AK Mandal, GK Vemuganti, P Garg, VS Sangwan. Coexistent congenital hereditary endothelial dystrophy and congenital glaucoma.. Cornea 2007;26:647-9",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"T Sharaawy, S Bhartiya. Surgical management of glaucoma: evolving paradigms.. Indian J Ophthalmol. 2011;59:S123-30",
"R Sihota, D Tuli, T Dada, V Gupta, MM Sachdeva. Distribution and determinants of intraocular pressure in a normal pediatric population.. J Pediatr Ophthalmol Strabismus. 2006;43:14-8",
"R Sitorus, SM Ardjo, B Lorenz, M Preising. CYP1B1 gene analysis in primary congenital glaucoma in Indonesian and European patients.. J Med Genet. 2003;40",
"T Souma, SW Tompson, BR Thomson, OM Siggs, K Kizhatil, S Yamaguchi, L Feng, V Limviphuvadh, KN Whisenhunt, S Maurer-Stroh, TL Yanovitch, L Kalaydjieva, DN Azmanov, S Finzi, L Mauri, S Javadiyan, E Souzeau, T Zhou, AW Hewitt, B Kloss, KP Burdon, DA Mackey, KF Allen, JB Ruddle, SH Lim, S Rozen, KN Tran-Viet, X Liu, S John, JL Wiggs, F Pasutto, JE Craig, J Jin, SE Quaggin, TL Young. Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.. J Clin Invest. 2016;126:2575-87",
"IR Stoilov, VP Costa, JP Vasconcellos, MB Melo, AJ Betinjane, JC Carani, EV Oltrogge, M Sarfarazi. Molecular genetics of primary congenital glaucoma in Brazil.. Invest Ophthalmol Vis Sci. 2002;43:1820-7",
"AL Vincent, G Billingsley, Y Buys, AV Levin, M Priston, G Trope, D Williams-Lyn, E Heon. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene.. Am J Hum Genet 2002;70:448-60",
"DS Walton, G Katsavounidou. Newborn primary congenital glaucoma: 2005 update.. J Pediatr Ophthalmol Strabismus 2005;42:333-41",
"YH Zhuo, M Wang, YT Wei, YL Huang, J Ge. Analysis of MYOC gene mutation in a Chinese glaucoma family with primary open-angle glaucoma and primary congenital glaucoma.. Chin Med J (Engl) 2006;119:1210-4"
] |
30/9/2004
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17/8/2017
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25/8/2011
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GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
glossary
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glossary
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[] |
## Terms and Definitions
One version of a gene at a given location (locus) along a chromosome
The proportion of individuals in a population who have inherited a specific variant
Presence of different pathogenic variants in the same gene and at the same chromosome locus that cause a single disease phenotype
The situation in which the presumed mother of a particular individual is not the biological mother
The situation in which the presumed father of a particular individual is not the biological father
A chemical substance of interest; a biologic component whose properties (e.g., concentration, presence, absence) can be indicators of human disease; in inherited conditions properties of analytes of interest are often measured in a biochemical/metabolic specialty laboratory to identify abnormalities in a metabolic pathway.
The occurrence of one or more extra or missing chromosomes leading to an unbalanced chromosome complement, or any chromosome number that is not an exact multiple of the haploid number
The tendency in certain genetic disorders for individuals in successive generations to present at an earlier age and/or with more severe manifestations; often observed in disorders resulting from the expression of a nucleotide repeat expansion that tends to increase in size and have a more significant effect when passed from one generation to the next
The Eastern European Jewish population primarily from Germany, Poland, and Russia, in contrast to the Sephardic Jewish population primarily from Spain, parts of France, Italy, and North Africa
Referring to any of the chromosomes other than the sex-determining chromosomes (i.e., the X and Y) or to the genes on these chromosomes
Referring to a trait or disorder in which the phenotype can be expressed in individuals who have one copy of a pathogenic variant at a particular locus (heterozygotes); specifically refers to a gene on one of the 22 pairs of autosomes (non-sex chromosomes)
Referring to a trait or disorder requiring the presence of biallelic pathogenic variants (i.e., homozygous or compound heterozygous variants) at a particular locus in order to express an observable phenotype; specifically refers to genes on one of the 22 pairs of autosomes (non-sex chromosomes)
The proportion of individuals in a given population who are affected with a particular disorder or who have pathogenic variants in a certain gene; often discussed in the genetic counseling process as a comparison to the proband's personal risk given his/her family history or other circumstances
Two nitrogenous bases paired together in double-stranded DNA by weak bonds; specific pairing of these bases (adenine with thymine and guanine with cytosine) facilitates accurate DNA replication; when quantified (e.g., 8 bp), refers to the physical length of a sequence of nucleotides
An alteration in DNA (distinct from the reference sequence) that is not associated with an abnormal phenotype or increased disease risk. A benign variant meets criteria to be classified as benign according to the five-tier system of describing the clinical significance of genetic variants (See related terms).
Referring to both alleles of a gene pair. Biallelic variants may be homozygous or compound heterozygous.
An individual with a recessive pathogenic variant at a particular locus on one chromosome of a pair who is not expected to develop manifestations of the related condition; may also refer to an individual with a balanced chromosome rearrangement. Note regarding autosomal dominant disorders: While the terms "heterozygote" and "carrier" are often used synonymously in the literature,
The proportion of individuals in a population who have a single copy of a recessive variant that is pathogenic for a specific condition
Testing used in the course of reproductive counseling to identify (typically) asymptomatic individuals who are heterozygous for a pathogenic variant associated with a specific autosomal recessive or X-linked disorder
Complementary DNA; the reverse-transcribed mRNA. The cDNA sequence of a gene differs from the genomic sequence of the gene in that it does not include the introns; cDNA does not occur in nature but can be synthesized from mRNA using a series of chemical reactions and may be analyzed to determine mRNA sequence. The nomenclature system used to annotate sequence variants in the context of the coding sequence is based on complementary DNA.
Within a single individual or tissue, two or more genetically distinct cell lineages originating from different zygotes
Term that refers to methods used to detect copy number variants (losses or gains of chromosome material), which may be benign, pathogenic, or of uncertain clinical significance. A far more sensitive method than traditional karyotyping, CMA detects both large and small copy number variants. Depending on the method used, CMA may involve scanning of the whole genome (also referred to as cytogenomic CMA), targeted regions of the genome, or a specific chromosome or chromosome segment. The CMA methods used most commonly in clinical practice include oligo (oligonucleotide) array, SNP (single-nucleotide polymorphism) array, and oligo/SNP combination array.
Physical structure consisting of a large DNA molecule organized into genes and supported by proteins called chromatin
Cytogenetic testing to detect an increased rate of chromosome breakage or rearrangement in metaphase cells by exposing cell cultures to clastogenic agents such as diepoxybutane (DEB) or mitomycin C (MMC); cell cultures not exposed to the DNA clastogenic agent are used as controls to measure the spontaneous rate of chromosome breakage or rearrangement.
DNA sequence that has the potential to be transcribed into RNA and translated into protein; must include a start codon and termination codon
Referring to two phenotypes being expressed at the same time from the same gene; for example, the AB blood groups in humans
Method in which two DNA samples (a control and a test sample), labeled in different fluorescent colors, are hybridized to a single target to assay for relative losses (deletions) or gains (duplications) in the DNA of the test sample compared to the control
Referring to two heterozygous variants each present on opposite homologous chromosomes (alleles) within the same genomic region of interest (typically within the same gene)
Present at birth; not necessarily genetic
Referring to reproductive partners who have a relatively close genetic relationship (e.g., cousins)
See
See
A variant that is present in all somatic and germline cells and thus has the potential to be passed to subsequent generations; may be used synonymously with "germline variant"
Deletion of a chromosome segment that encompasses two or more adjacent genes
A constellation of clinical findings caused by deletion of a chromosome segment that encompasses two or more adjacent genes
Duplication or deletion of a section of DNA. CNVs can be benign (normal), pathogenic, or of uncertain clinical significance. The method used to detect a CNV varies based on its size (see
The specific portion of a chromosome or a gene that, when altered in some way (deleted, duplicated, or otherwise mutated), produces the characteristic set of phenotypic abnormalities associated with a particular syndrome or disorder
Prenatal testing offered to families in which (a) pathogenic variant(s) have been identified in an affected family member in either a research or clinical laboratory; testing is not otherwise clinically available for prenatal diagnosis.
Testing offered to families in which (a) pathogenic variant(s) have been identified in an affected family member in either a research or clinical laboratory; testing is not otherwise clinically available.
Referring to chromosome abnormalities such as aneuploidies, deletions, duplications, and translocations
Referring to a genetic variant that is present for the first time in one family member
Absence of a segment of DNA; may be as small as a single base or as large as one or more genes. The method used to detect a deletion depends on the size of the deletion.
Testing that identifies deletions/duplications not routinely detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes the gene/chromosome segment of interest.
A recognizable phenotype caused by a chromosome deletion that spans one or more genes and may be too small to be detected using conventional cytogenetic methods; the deletion is typically detected by chromosomal microarray (CMA). Depending on the size of the deletion, other techniques including FISH and quantitative PCR can sometimes be employed to identify the deletion.
Referring to expression of a phenotype that requires the presence of pathogenic variants in two different genes
A specific region or amino acid sequence in a protein associated with a particular function or corresponding segment of DNA
Referring to a single, heterozygous pathogenic variant which produces a protein that interferes with (i.e., dimerizes or combines with, or blocks) the normal protein produced by the other allele, adversely affecting protein function. In cases of polymeric molecules, such as collagen, dominant-negative variants are often more deleterious than variants resulting in no gene product (null variants).
The presence in an individual of a heterozygous variant in two different genomic regions of interest (typically, a heterozygous variant in each of two different genes). The clinical consequences of double heterozygosity depend on the related disorder(s) and the mode(s) of inheritance of the disorder(s).
The presence of one or more additional copies of a segment of DNA; may be as small as a single base or as large as one or more genes. The method used to detect a duplication depends on the size of the duplication.
Referring to visible morphologic findings that differ from those commonly seen in the general population or that are expected from the family background
Referring to chemical alterations to DNA nucleotides or proteins that control gene expression but do not alter the DNA sequence
A heritable change in gene activity that is not associated with a DNA variant but rather with gain or loss of DNA methylation or other heritable modifications of chromatin
(Reprinted from
The part of the genome that includes all coding nuclear DNA sequences. The human exome comprises approximately 180,000 exons that are transcribed into mature RNA.
A microarray designed to determine exon-level copy number for as many genes associated with disease as possible regardless of phenotype or clinical features associated with the genes
Sequence analysis of the exons of protein-coding genes in the genome typically performed by target enrichment or capture of exons followed by next-generation sequencing (NGS). Exome sequencing techniques have nonstandardized, highly variable coverage; of particular note are regions of the exome refractory to accurate sequencing by this method (including genes with a pseudogene, highly repetitive coding regions, and large deletions and duplications). Laboratories may also include sequence analysis of some noncoding regions of the genome (e.g., promoters, highly conserved regulatory sequences). Note that the term "exome sequencing" is preferred over the formerly used term "whole-exome sequencing" because coverage of the exome is less than 100%, and thus the "whole" exome is not sequenced.
Coding sequence of DNA present in mature messenger RNA
Referring to a condition or variant that occurs in more than one family member
A parent, full sib, or child of an individual
Fluorescent in situ hybridization; a technique used to identify the presence of specific chromosomes or chromosomal regions through hybridization (attachment) of fluorescently labeled DNA probes to denatured chromosomal DNA. Examination under fluorescent lighting detects the presence of the hybridized fluorescent signal (and hence presence of the chromosome material) or absence of the hybridized fluorescent signal (and hence absence of the chromosome material).
With
With
See
The higher-than-average frequency of a rare allele in a population isolated over time by geography, language, and/or culture, resulting from the presence of the allele in an early member or members ("founders") of that group. For example, a founder effect accounts for the high incidence of Huntington disease in the Lake Maracaibo region of Venezuela.
A pathogenic variant observed in high frequency in a specific population due to the presence of the variant in a single ancestor or small number of ancestors
A deletion, duplication, or insertion within an exon involving a number of base pairs that is not a multiple of three, consequently disrupting the triplet reading frame and usually leading to the creation of a premature termination (stop) codon and subsequent loss of normal protein product
In autosomal dominant, autosomal recessive, and X-linked disorders caused by nucleotide repeat expansion, an abnormally large allele that is associated with disease manifestations
Referring to a gene variant associated with one of the following abnormalities: an increase in one or more functions of the gene product; a novel function of the gene product; a change in timing of gene expression
Genomic DNA. The DNA in a cell that is chromosomal DNA. Genomic DNA does not include mitochondrial DNA.
The basic unit of heredity, consisting of a segment of DNA arranged in a linear manner along a chromosome. A gene codes for a specific protein, a segment of protein, or noncoding RNA.
The transfer of DNA sequences between two very similar genes, most often by unequal crossing over during meiosis; can be a mechanism for mutation if the transfer of material disrupts the coding sequence of the gene or if the transferred material itself contains one or more pathogenic variants
Most genes are transcribed into segments of RNA (ribonucleic acid), which are translated into proteins. Both RNA and proteins are products expressed by the gene.
A microarray designed to determine exon-level copy number for a gene or set of genes associated with a phenotype or specific clinical feature
Treatment of a genetic disorder by replacing or manipulating an abnormal gene
The process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. Genetic counseling deals with risk assessment and the use of family history and testing to clarify genetic status for family members.
Sequence analysis of the genome including coding and noncoding regions typically performed by next-generation sequencing (NGS) of sheared genomic DNA; genome sequencing techniques have nonstandardized, highly variable coverage. Note that "genome sequencing" is preferred over the formerly used term "whole-genome sequencing" because coverage of the genome is less than 100%, and thus the "whole" genome is not sequenced.
Referring to the human genome, which comprises the DNA in all chromosomes and in mitochondria
In
Associations between an individual's genotype and the resulting pattern of clinical findings, or phenotype
Molecular assay designed to detect the presence or absence of a specific variant (or variants) in DNA; variants in DNA not targeted by the assay will not be detected.
The cell line from which egg or sperm cells (gametes) are derived
See
A variant that is presumed to be present in all germ (egg and sperm) cells and somatic cells. Unlike a somatic variant (i.e., a variant that arises spontaneously in a somatic cell), a germline variant can be transmitted to offspring.
Mosaicism confined to or involving gonadal cells
Half the diploid or normal number of chromosomes in a somatic cell; the number of chromosomes in a gamete (egg or sperm) cell, which in humans is 23 chromosomes, one chromosome from each chromosome pair
A cause of disease in which the protein product from a single normal allele is insufficient -- given the presence of a loss-of-function pathogenic variant on the other allele -- to prevent the appearance of an abnormal phenotype
Referring to a gene normally present in only a single copy; usually an X-linked gene in a male
See
The presence within a single cell of both normal and mutated mitochondrial DNA (mtDNA); the proportion of normal to mutated mtDNA (i.e., the mutant load) may vary in different tissues and is a critical factor in the expression and severity of disease caused by mutation of mtDNA.
An individual with two different alleles at a particular locus (one on each chromosome of a pair), one of which is usually pathogenic. The risk that an individual who is heterozygous for a pathogenic variant will have manifestations of the related phenotype depends on the specific disorder and the mode of inheritance of the disorder.
See
A member of the family of proteins (referred to as histones) around which nuclear DNA is wrapped to facilitate condensation into chromosomes and access for transcription. Eight histone proteins form a single histone core.
Characterized by homoplasmy
The presence of identical alleles at all mitochodondrial loci within a single cell or organism
Denoting a variant (distinct from the reference sequence) that is present on both alleles of a given gene
A DNA sequence that is highly susceptible to mutation because of some inherent instability, a tendency toward unequal crossing over, or chemical predisposition to single-nucleotide substitutions; a region where pathogenic variants are observed with greater frequency
Referring to a variant characterized by partial loss of gene activity (including reduction in protein production or function)
Relating to or denoting a disease or condition for which the cause is unknown
See
The process by which maternally and paternally derived chromosomes are uniquely chemically modified (usually by methylation), leading to different expression of a certain gene or genes on those chromosomes depending on their parental origin. Patterns of gene expression and repression vary between imprinted regions.
See
Abbreviation for an insertion (i.e., duplication) or a deletion of nucleotides, typically within a gene or coding region
Referring to a variant (usually a small deletion or insertion) that does not cause a shift in the triplet reading frame. Such variants can be pathogenic when they lead to the synthesis of an abnormal protein product (i.e., one with one or more missing or inserted amino acids).
Presence of extra DNA in a gene or other DNA region; may be as small as a single base or as large as one or more genes; if the insertion occurs in a coding region, it may potentially disrupt gene function. An insertion is considered a duplication when the inserted DNA is a perfect match to the adjacent DNA.
Variability in clinical presentation of a particular disorder among affected individuals from different families
Variability in clinical presentation of a particular disorder among affected individuals within the same immediate or extended family
Noncoding sequence of DNA removed from mature messenger RNA prior to translation
Referring to DNA or variants in DNA within an intron
Method by which proteins migrate in a matrix according to the pH; an amino acid substitution can change the isoelectric point of a protein.
Similar forms of a protein produced by different versions of messenger RNA resulting from use of different promoters, skipping of exons, or differences in splicing; may be tissue specific.
Referring to a finding that occurs in the absence of other systemic involvement
A photographic representation of the chromosomes of a single cell, cut and arranged in pairs based on their size and banding pattern according to a standard classification
Referring to an alteration in a gene (distinct from the reference sequence) that is very unlikely to be associated with an abnormal phenotype or increased disease risk. A likely benign variant meets most, but not all, criteria to be classified as benign according to the five-tier system for describing the clinical significance of genetic variants (see Related terms).
Referring to an alteration in a gene (distinct from the reference sequence) that is likely to be associated with an abnormal phenotype or increased disease risk. A likely pathogenic variant meets most but not all criteria to be classified as pathogenic according to the five-tier system for describing the clinical significance of genetic events. A likely pathogenic variant is considered diagnostic and can be used for clinical decision making (see Related terms).
The physical site or location of a specific gene on a chromosome. OMIM (http://omim.org) is the standard reference used for locus information included in
An informally assigned abbreviation used in the process of mapping to designate a putative gene prior to gene identification; once the gene is identified, the locus name is generally replaced by a formally assigned gene symbol (which often differs from the locus name).
Referring to a variant associated with partial or total loss of the function of a gene product
Loss of one of the two alleles at a locus or at multiple loci leading to a homozygous or hemizygous state. LOH can be caused by a variety of genetic mechanisms including deletion, chromosome loss, and mitotic crossing over.
An individual who has at a particular locus a pathogenic variant on one chromosome and a wild type allele on the other chromosome, and who has findings of the disorder; generally refers to a clinically affected female with a heterozygous pathogenic variant in an X-linked gene. The phenotype is usually less severe than in a hemizygous male with the same pathogenic variant.
The attachment of methyl groups to DNA at cytosine bases; correlated with reduced transcription of the gene and thought to be the principal mechanism in X-chromosome inactivation and imprinting
Testing that evaluates the methylation status of a gene (attachment of methyl groups to DNA cytosine bases). Genes that are methylated are not expressed.
See
A segment of DNA two to five nucleotides in length (di-, tri-, tetra-, or pentanucleotide repeats) typically repeated five to 50 times or more. Microsatellite DNA is dispersed throughout the genome in noncoding regions between genes or within genes (i.e., in introns). Microsatellite DNA is inherently unstable and susceptible to mutation.
Refers to the situation in which a person reported to be the biological father or mother of a child is in fact not the biological parent. Factors that may result in misattributed parentage include assisted reproduction (i.e., use of a donor sperm, donor egg, or donor embryo), undisclosed adoption, and alternate paternity.
The DNA "proofreading" system that identifies, excises, and corrects errors in the pairing of the bases during DNA replication. Mutation of the genes encoding mismatch repair proteins can result in susceptibility to some cancers.
Referring to a single base-pair substitution that results in the translation of a different amino acid at that position; can be pathogenic or benign
Mitochondria - cytoplasmic organelles that produce the energy source ATP for most chemical reactions in the body - contain their own distinct genome; pathogenic variants in mitochondrial genes are responsible for several recognized syndromes and are always maternally inherited because mitochondria are transmitted by the ova, not the sperm.
The manner in which a particular genetic condition is passed from one generation to the next. Autosomal dominant, autosomal recessive, X-linked, multifactorial, and mitochondrial inheritance are examples.
Technique in which fluorescent in situ hybridization (FISH) probes of known sequence are hybridized to uniformly stretched long fragments of DNA to determine content of and distance between targeted sequence with high resolution. Used to assess repetitive regions of DNA not amenable to sequence analysis.
A term widely used in clinical genetics encompassing the diverse techniques used to identify the molecular basis of genetic disease. Examples of molecular genetic tests include: genotyping to detect specific pathogenic variants; sequencing of a gene to detect pathogenic variants; amplification or hybridization methods (e.g., qPCR, array CGH, MLPA) to detect copy number variants involving one or more genes; methylation-specific techniques to detect epigenetic changes that influence gene expression; and exome and genome sequencing.
Referring to one allele of a gene pair, as opposed to biallelic, which refers to both alleles of a gene pair.
The presence of only one chromosome from a pair; partial monosomy refers to the presence of only one copy of a segment of a chromosome
Within a single individual or tissue, the postzygotic occurrence of two or more cell lines with a different genetic or chromosomal composition that are derived from a single fertilized egg. Mosaicism may involve somatic cells, gonadal cells, and/or tumor cells.
Messenger RNA
Referring to the combined contribution of one or more often unspecified genes and environmental factors, often unknown, in the causation of a particular finding
Simultaneous molecular testing of multiple genes associated with the same or similar clinical phenotypes. The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. Methods used may include sequence analysis, deletion/duplication analysis, or other non-sequencing-based tests.
Referring to several different technologies, all of which allow simultaneous sequence analysis of millions of DNA fragments. NGS can detect variations as small as a single-base substitution; depending on the methods used, NGS may detect copy number variants (CNVs). NGS is used primarily for multigene panels and genome, exome, and transcriptome sequencing. NGS may also be used for single-gene testing (e.g., targeting of a single gene on a mult-gene panel or sequencing of a large multiexon gene). Results from NGS may require confirmation by an alternative sequencing method.
The result of a process in which segmental duplications (low copy repeats) flanking a region misalign during meiosis, followed by unequal crossing over between the segmental duplications. The process can produce gametes with the recurrent deletion or the reciprocal recurrent duplication.
Functional RNA (transcribed from a gene) that is not translated into protein
Referring to a variant in which a codon is changed from one that specifies an amino acid to one that specifies a termination (stop)
See
The functional unit of a chromosome, consisting of the length of DNA and the core of histone proteins around which DNA is wrapped. The nucleosome is the building block of the chromosome.
Sequence of n nucleotides repeated a number of times in tandem; can occur within or near a gene. The size of nucleotide repeats varies: smaller numbers of repeats are common and not associated with phenotypic abnormalities; abnormally large numbers of repeats may be associated with phenotypic abnormalities and are classified as (in increasing order): mutable normal alleles, premutations, reduced-penetrance alleles, and full-penetrance alleles.
Referring to a pathogenic variant that results in either no mRNA, no protein, or a nonfunctional protein
An individual who must be heterozygous for a variant based on analysis of the family history; applies to disorders inherited in an autosomal recessive or X-linked manner. The term "obligate heterozygote" can also refer to individuals with an autosomal dominant disorder whose position in a pedigree indicates that they must be heterozygous even though they do not manifest the phenotype.
Referring to a phenotype expressed only in the presence of pathogenic variants in more than one gene; may be referred to (with less precision) as multigenic or polygenic
See
An alteration in a gene (distinct from the reference sequence) that is associated with an abnormal phenotype or increased disease risk. A pathogenic variant meets criteria to be classified as pathogenic according to the five-tier system for describing the clinical significance of genetic variants (see Related terms).
A procedure that produces millions of copies of a short segment of DNA through repeated cycles of: (1) denaturation, (2) annealing, and (3) elongation. PCR is commonly used either: (a) to generate a sufficient quantity of DNA to perform a test (e.g., sequence analysis); or (b) as a test in and of itself (e.g., allele-specific amplification, trinucleotide repeat quantification).
A diagram of the genetic relationships and medical history of a family using standard symbols and terminology
The proportion of individuals with a pathogenic variant causing a particular disorder who exhibit clinical findings of that disorder; most often refers to autosomal dominant conditions.
The observable characteristics of the expression of a gene; the clinical presentation of an individual with a particular genotype
Referring to a condition caused by the additive contributions of variants in multiple genes at different loci
See
A natural variation in a gene, DNA sequence, protein, or chromosome that has no adverse effect on the individual
Referring to a pathogenic variant or abnormality in chromosome replication/segregation/methylation that occurs after fertilization of the ovum by the sperm, often leading to mosaicism (two or more genetically distinct cell lines within the same organism)
See
Genetic testing of one or more cells removed from early embryos conceived by in vitro fertilization and transferring to the mother's uterus only those embryos determined not to have the pathogenic variant(s)/chromosome anomaly(ies) of concern
An allele in which a tandemly repeated nucleotide sequence within or near a gene contains more repeats than a normal allele. A premutation allele can expand into a full-penetrance allele (repeat size associated with disease) when passed through the germline. Although premutation alleles are not typically associated with disease, in rare instances they are; the best example is premutation
See
Testing performed during pregnancy. Prenatal testing may be used to determine if a fetus is affected with a particular disorder. Invasive procedures such as chorionic villus sampling (CVS), amniocentesis, or periumbilical blood sampling (PUBS) are used to obtain a sample for testing; imaging (e.g., ultrasound, MRI) is used to evaluate fetal anatomy.
Referring to a variant that does not have appreciable allele frequency in the general population; a private variant may be benign or pathogenic; historically used to describe a variant thought to occur in a single family
The affected individual through whom a family with a genetic disorder is ascertained; may or may not be the individual presenting for genetic counseling
A region of DNA (just upstream of a gene) that acts as a binding site for transcription factors and RNA polymerase to initiate transcription
An autosomal recessive condition present in individuals in two or more generations of a family, thereby appearing to follow a dominant inheritance pattern; occurs as a result of reproduction between an affected individual and a carrier partner
A copy of a gene that is transcriptionally or translationally inactive due to accumulation of inactivating variants. Pseudogenes are classified as either non-processed (includes introns) or processed (does not include introns).
A form of PCR used to determine the relative amount of DNA or RNA in a sample; commonly used to detect heterozygous deletions and duplications
The exchange of a segment of DNA between two homologous chromosomes during meiosis leading to a novel combination of genetic material in the gamete
The likelihood that a trait or disorder present in one family member will occur again in other family members in the same or subsequent generations
Deletion of a specific size - usually mediated by nonallelic homologous recombination (NAHR) - occurring multiple times in the general population
An alteration in a gene (distinct from the reference sequence) that is associated with an abnormal phenotype or increased disease risk in some (not all) individuals who have the alteration
Presence of two or more cell lines in one individual that have different genetic compositions - one or more cell lines having a germline pathogenic variant and the other(s) derived from spontaneous somatic correction of the germline pathogenic variant to the normal (wild type) state
The joining of two acrocentric chromosomes at the centromeres with loss of their short arms to form a single abnormal chromosome; in acrocentric chromosomes the centromere is located near the end of the chromosome. Acrocentric chromosomes are 13, 14, 15, 21, and 22.
A method of DNA sequencing that uses DNA polymerase to copy single-stranded DNA templates by adding nucleotides to form a complementary strand. Its use is limited to sequence analysis of a single region of DNA (maximum ~1000 bp) - in contrast to massively parallel sequencing, in which millions of fragments of DNA can be sequenced simultaneously.
A relative who shares one quarter of an individual's genes is shared (i.e., grandparent, grandchild, uncle, aunt, nephew, niece, half-sib)
The separation of the homologous chromosomes and their random distribution to the gametes at meiosis
The frequency with which testing yields a positive result when the individual being tested either (a) is actually affected (clinical sensitivity) or (b) has a pathogenic variant detected by molecular genetic testing (analytic sensitivity)
Any alteration in a gene from its natural state; may be benign (may be referred to as a "polymorphism"), pathogenic, or of uncertain significance
Process by which the nucleotide sequence for a segment of DNA is determined
Referring to a single occurrence of a disorder in a family
An alteration in DNA sequence caused by a single-nucleotide base change, insertion, or deletion; can be benign, pathogenic, or of uncertain significance
Exchange of genetic material between the two chromatids of a single chromosome during the cell division process; similar to crossing over (recombination), except that the exchange involves the two sister chromatids of a single chromosome, whereas crossing over refers to exchange of genetic material between the two homologous chromosomes of a chromosome pair
Method used in a given individual to genotype single-nucleotide polymorphisms (SNPs) across the genome to identify: (1) copy number variants; (2) regions of uniparental disomy; (3) evidence of parental consanguinity
Two or more cell lines with a different genetic composition within the cells of an individual (may or may not include the germline cells)
Variant resulting from mutation that occurs during embryonic development (i.e., that is not inherited from a parent)
Technique used to detect differences in the lengths of DNA fragments occurring as a result of a variant or gene rearrangement
The junction between an intron and an exon in a DNA sequence; the site of intron/exon splicing. A variant in the splice site can cause abnormal removal of introns and splicing together of exons such that one or more introns remaining in the mRNA can potentially disrupt generation of the protein product.
The process by which introns (noncoding regions) are excised out of the primary messenger RNA transcript and exons (i.e., coding regions) are joined together to generate mature messenger RNA
Referring to the chance occurrence of a disorder or abnormality that is not expected to recur in a family
In
Testing for specific variants known to cause disease. Examples include: (1) one or more specific pathogenic variants (e.g., Glu6Val for sickle cell anemia, a panel of pathogenic variants for cystic fibrosis); (2) a nucleotide repeat expansion (e.g., the trinucleotide repeat expansion associated with Huntington disease); and (3) common deletions (e.g., population-specific alpha globin gene deletions).
See
A protein that binds to DNA and either activates or represses transcription of one or more genes
A chromosome alteration in which a whole chromosome or segment of a chromosome becomes attached to or interchanged with another whole chromosome or segment
Balanced translocations (in which there is no apparent net loss or gain of chromosome material) are usually not associated with phenotypic abnormalities, although gene disruptions at the breakpoints of the translocation can, in some cases, cause adverse effects, including some known genetic disorders.
Unbalanced translocations (in which there is loss or gain of chromosome material) are nearly always associated with an abnormal phenotype.
Balanced and unbalanced translocations can be visualized by karyotype analysis; chromosomal microarray (CMA) cannot detect balanced translocations.
Referring to expression of a phenotype that requires the presence of pathogenic variants in three different genes
Sequences of three nucleotides repeated a number of times in tandem within a gene
The phenomenon in which a fertilized ovum initially contains 47 chromosomes (i.e., one chromosome is trisomic), but loses one of the trisomic chromosomes in the process of cell division such that the resulting daughter cells and their descendants contain 46 chromosomes, the normal number
A variant of uncertain significance (VOUS, VUS) is an alteration in a gene (distinct from the reference sequence) that may or may not be disease-causing or associated with increased risk of an abnormal phenotype; the identification of a variant of uncertain significance neither confirms nor rules out a diagnosis. A variant of uncertain significance does not meet criteria to be classified as pathogenic or benign according to the five-tier system for describing the clinical significance of genetic variants (see Related terms). Sequence analysis may identify multiple variants of uncertain significance in a given gene or hundreds to thousands in the human exome.
Exchange of DNA during meiosis between improperly aligned segments of DNA that can result in a gain or loss of DNA. Circumstances that predispose to unequal crossing over are misalignment of: (1) highly homologous segment duplications (low copy repeats) referred to as nonallelic homologous recombination which result in recurrent deletions or duplications; and (2) a gene and its pseudogene in tandem on a chromosome (e.g.,
See
The situation in which both copies of a chromosome pair (or chromosome pair segment) are from one parent (i.e., no copy is from the other parent). The individual may have two identical copies of one of the pair of parental chromosomes (termed
The situation in which an individual inherits both copies of a chromosome pair (or chromosome pair segment) from one parent; no copy is inherited from the other parent (compare
The situation in which an individual inherits two identical copies of one of a chromosome pair (or chromosome pair segment) from one parent; no copy is inherited from the other parent (compare
See
Variation in clinical features (type and severity) of a genetic disorder between affected individuals, even within the same family
See
See
Referring to a normal, fully functional gene or allele
In females, the phenomenon by which one X chromosome (either maternally or paternally derived) is randomly inactivated in early embryonic cells, with fixed inactivation in all descendant cells; first described by the geneticist Mary F Lyon, PhD.
Referring to a gene on the X chromosome or to the mode of inheritance in which the causative pathogenic variant is on the X chromosome; hemizygous males will be affected; heterozygous females may or may not be affected depending on the disorder and factors influencing X-chromosome inactivation.
See
See
Alleles may be pathogenic (i.e., known to be associated with disease), benign, or of uncertain significance. The term "mutated allele" implies that the allele is pathogenic.
Maternal allele. Inherited from the mother
Paternal allele. Inherited from the father
Homozygous. Identical wild type or identical pathogenic alleles
Heterozygous. Two different alleles (both wild type, both pathogenic, or one wild type and one pathogenic allele)
Compound heterozygous. Two different pathogenic alleles
Illustrations adapted from Nussbaum RL, McInnes RR, Willard HF, eds:
Example of a normal male karyotype, denoted 46,XY
46 refers to the total number of chromosomes.
XY indicates a male karyotype; XX would indicate a female karyotype.
A normal human karyotype consists of 22 pairs of autosomes and two sex chromosomes. Note the similar size and striped (banding) pattern between each of the pairs. The autosomal chromosome pairs are numbered and arranged from largest to smallest. Bending and curling of the chromosomes are typically observed and do not represent an abnormality.
Reprinted from Nussbaum RL, McInnes RR, Willard HF, eds:
Symbols adapted from Bennett RL, French KS, Resta RG, Doyle DL. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. J Genet Couns. 2008;424-33.
Two genes located on the same chromosome may or may not segregate together. Recombination between homologous chromosomes during meiosis leads to novel combinations of genes in the gamete, and hence offspring.
Through the process of recombination, each chromosome that is transmitted from parent to child contains some segments derived from the child's grandfather and some from the child's grandmother.
Recombination plays an important role in assuring genetic variability between individuals, even within the same family.
The behavior during meiosis of alleles at two loci (1 and 2) on the same chromosome depends on their proximity.
Illustrations adapted from Nussbaum RL, McInnes RR, Willard HF, eds:
In an autosomal recessive disorder:
The parents of an affected individual are carriers.
The unaffected sibs of an affected individual are at a 2/3 risk of being carriers.
The offspring of an affected individual and a non-carrier are carriers.
The offspring of a carrier and a non-carrier are at a 50% risk of being carriers.
Individuals who carry a single recessive pathogenic variant usually cannot be identified by their phenotype (i.e., they are unaffected); carrier frequency can be estimated using the Hardy-Weinberg Law when the disease frequency (i.e., homozygote frequency) is known.
Genetic etiology of sporadic disorders
Uniparental disomy - The affected individual has both chromosomes of one pair from one parent and none from the other, a chance occurrence of a genetic abnormality not likely to recur in other family members.
Sporadic tumors - All cancer is genetic at the cellular level; however, all cancer is NOT hereditary. A single tumor occurring in an older individual is likely to be caused by acquired (not inherited) pathogenic variants in cell regulator genes leading to uncontrolled cell proliferation.
Non-genetic etiology of sporadic disorders
Congenital rubella syndrome in an infant due to maternal rubella infection during pregnancy
Ataxia caused by alcoholism
Autosomal dominant or X-linked disorders that occur in a single individual in a family, often the result of a new pathogenic variant. Because recurrence risk is increased for sibs of the affected individual and is as high as 50% for the offspring of the affected individual, the use of the term "sporadic" is not appropriate. Use of the term "simplex case" is correct.
If a particular condition is truly sporadic, recurrence risk should be the same in families with an affected individual as compared to families with no history of the condition.
Care must be taken to distinguish a true sporadic case from a simplex case (single occurrence of a condition in a family) with recurrence risk implications.
A sporadic case is usually simplex (a single case of a disorder in a family ); a simplex case may or may not be sporadic.
The following are examples by mode of inheritance of simplex cases that are NOT sporadic. All have recurrence risk implications for subsequent offspring of the parents and of the affected individual.
A couple of normal stature has a child with achondroplasia.
A woman mildly affected by myotonic dystrophy type 1 is unaware of the diagnosis until she gives birth to a child with severe congenital myotonic dystrophy.
Carrier testing is traditionally offered to individuals who:
Have family members with a genetic condition;
Have family members who are identified carriers;
Are members of ethnic or racial groups known to have a higher carrier rate for a particular condition.
Common
A trisomic conceptus consisting of a total of 47 chromosomes is usually non-viable; the trisomic chromosomes can be 2 maternal / 1 paternal or 1 maternal / 2 paternal. The outcomes of trisomy rescue (see Table) may be normal or abnormal.
Uniparental disomy (UPD) leads to an abnormal phenotype if the chromosome involved has imprinted gene(s) or if UPD results in homozygosity for a pathogenic variant resulting in an autosomal recessive condition.
If prenatal diagnostic testing via chorionic villus sampling (CVS) reveals a trisomic cell line involving a chromosome known to have imprinted genes, and follow-up amniocentesis reveals normal fetal chromosomes, UPD testing for the trisomic chromosome should be considered to exclude the possibility that trisomy rescue restored the normal karyotype in the fetal cells, but in doing so, led to UPD.
Illustration adapted from Nussbaum RL, McInnes RR, Willard HF, eds:
Members of multigene "families" in which genes share significant homology with one another (e.g., alpha globin gene cluster; red and green visual pigment gene cluster)
A gene and pseudogene in tandem on a chromosome (e.g.,
Similar sequences along the same strand of DNA predisposing to inversions or deletions (e.g.,
Homologous noncoding sequences (e.g., Alu family of repeated DNA sequences interspersed throughout the genome)
Illustrations adapted from Nussbaum RL, McInnes RR, Willard HF, eds:
Nonallelic homologous recombination between segmental duplications/low copy repeats on homologous chromosomes can lead to deletions and duplications associated with different phenotypes (e.g.,
MUPD14 syndrome (maternal UPD14)
Illustrations adapted from Nussbaum RL, McInnes RR, Willard HF, eds:
The method used to detect a deletion or duplication varies by the size of the CNV.
Illustrations adapted from Nussbaum RL, McInnes RR, Willard HF, eds:
First-degree relatives of the person indicated by the arrow are parents, sibs, and children.
An individual shares half of his/her genes with each parent and each child.
An individual shares an on average half of his/her genes with each sib.
Gonadal mosaicism for a specific genetic condition occurs when an individual has two populations of cells in the gonads (testes or ovaries). One population of cells contains only wild type (or normal) alleles. The other population of cells contains a pathogenic variant or a chromosome anomaly. Gonadal mosaicism is the result of sporadic mutation or chromosome alteration in a cell that will give rise to gonadal cells. The pathogenic variant or chromosome anomaly is confined to the individual's germline and is not present in other cells of the body.
Gonadal mosaicism is typically seen in autosomal dominant or X-linked disorders. It becomes evident or suspected when an unaffected parent has two or more children with the same pathogenic variant or chromosome anomaly, which is not present in the leukocyte DNA of either parent.
Molecular genetic testing using blood or tissue samples (other than gonadal tissue) from an individual with gonadal mosaicism will not identify the pathogenic variant or chromosome anomaly that is present in the germline.
The recurrence risk for a genetic condition is proportionate to the number of gamete cells that contain the pathogenic variant or chromosome anomaly. Gonadal mosaicism has been reported in numerous genetic conditions; some genetic conditions are associated with a higher risk for gonadal mosaicism (e.g., Duchenne muscular dystrophy, osteogenesis imperfecta).
Gonadal mosaicism for this fully penetrant autosomal dominant condition is suspected in the father because he has two affected children and is not affected himself.
• Maternal allele. Inherited from the mother
• Paternal allele. Inherited from the father
• Homozygous. Identical wild type or identical pathogenic alleles
• Heterozygous. Two different alleles (both wild type, both pathogenic, or one wild type and one pathogenic allele)
• Compound heterozygous. Two different pathogenic alleles
• 46 refers to the total number of chromosomes.
• XY indicates a male karyotype; XX would indicate a female karyotype.
• Two genes located on the same chromosome may or may not segregate together. Recombination between homologous chromosomes during meiosis leads to novel combinations of genes in the gamete, and hence offspring.
• Through the process of recombination, each chromosome that is transmitted from parent to child contains some segments derived from the child's grandfather and some from the child's grandmother.
• Recombination plays an important role in assuring genetic variability between individuals, even within the same family.
• The parents of an affected individual are carriers.
• The unaffected sibs of an affected individual are at a 2/3 risk of being carriers.
• The offspring of an affected individual and a non-carrier are carriers.
• The offspring of a carrier and a non-carrier are at a 50% risk of being carriers.
• Genetic etiology of sporadic disorders
• Uniparental disomy - The affected individual has both chromosomes of one pair from one parent and none from the other, a chance occurrence of a genetic abnormality not likely to recur in other family members.
• Sporadic tumors - All cancer is genetic at the cellular level; however, all cancer is NOT hereditary. A single tumor occurring in an older individual is likely to be caused by acquired (not inherited) pathogenic variants in cell regulator genes leading to uncontrolled cell proliferation.
• Uniparental disomy - The affected individual has both chromosomes of one pair from one parent and none from the other, a chance occurrence of a genetic abnormality not likely to recur in other family members.
• Sporadic tumors - All cancer is genetic at the cellular level; however, all cancer is NOT hereditary. A single tumor occurring in an older individual is likely to be caused by acquired (not inherited) pathogenic variants in cell regulator genes leading to uncontrolled cell proliferation.
• Non-genetic etiology of sporadic disorders
• Congenital rubella syndrome in an infant due to maternal rubella infection during pregnancy
• Ataxia caused by alcoholism
• Congenital rubella syndrome in an infant due to maternal rubella infection during pregnancy
• Ataxia caused by alcoholism
• Uniparental disomy - The affected individual has both chromosomes of one pair from one parent and none from the other, a chance occurrence of a genetic abnormality not likely to recur in other family members.
• Sporadic tumors - All cancer is genetic at the cellular level; however, all cancer is NOT hereditary. A single tumor occurring in an older individual is likely to be caused by acquired (not inherited) pathogenic variants in cell regulator genes leading to uncontrolled cell proliferation.
• Congenital rubella syndrome in an infant due to maternal rubella infection during pregnancy
• Ataxia caused by alcoholism
• If a particular condition is truly sporadic, recurrence risk should be the same in families with an affected individual as compared to families with no history of the condition.
• Care must be taken to distinguish a true sporadic case from a simplex case (single occurrence of a condition in a family) with recurrence risk implications.
• A sporadic case is usually simplex (a single case of a disorder in a family ); a simplex case may or may not be sporadic.
• The following are examples by mode of inheritance of simplex cases that are NOT sporadic. All have recurrence risk implications for subsequent offspring of the parents and of the affected individual.
• A couple of normal stature has a child with achondroplasia.
• A woman mildly affected by myotonic dystrophy type 1 is unaware of the diagnosis until she gives birth to a child with severe congenital myotonic dystrophy.
• A couple of normal stature has a child with achondroplasia.
• A woman mildly affected by myotonic dystrophy type 1 is unaware of the diagnosis until she gives birth to a child with severe congenital myotonic dystrophy.
• A couple of normal stature has a child with achondroplasia.
• A woman mildly affected by myotonic dystrophy type 1 is unaware of the diagnosis until she gives birth to a child with severe congenital myotonic dystrophy.
• A couple of normal stature has a child with achondroplasia.
• A woman mildly affected by myotonic dystrophy type 1 is unaware of the diagnosis until she gives birth to a child with severe congenital myotonic dystrophy.
• A couple of normal stature has a child with achondroplasia.
• A woman mildly affected by myotonic dystrophy type 1 is unaware of the diagnosis until she gives birth to a child with severe congenital myotonic dystrophy.
• A couple of normal stature has a child with achondroplasia.
• A woman mildly affected by myotonic dystrophy type 1 is unaware of the diagnosis until she gives birth to a child with severe congenital myotonic dystrophy.
• Have family members with a genetic condition;
• Have family members who are identified carriers;
• Are members of ethnic or racial groups known to have a higher carrier rate for a particular condition.
• Uniparental disomy (UPD) leads to an abnormal phenotype if the chromosome involved has imprinted gene(s) or if UPD results in homozygosity for a pathogenic variant resulting in an autosomal recessive condition.
• If prenatal diagnostic testing via chorionic villus sampling (CVS) reveals a trisomic cell line involving a chromosome known to have imprinted genes, and follow-up amniocentesis reveals normal fetal chromosomes, UPD testing for the trisomic chromosome should be considered to exclude the possibility that trisomy rescue restored the normal karyotype in the fetal cells, but in doing so, led to UPD.
• Members of multigene "families" in which genes share significant homology with one another (e.g., alpha globin gene cluster; red and green visual pigment gene cluster)
• A gene and pseudogene in tandem on a chromosome (e.g.,
• Similar sequences along the same strand of DNA predisposing to inversions or deletions (e.g.,
• Homologous noncoding sequences (e.g., Alu family of repeated DNA sequences interspersed throughout the genome)
• MUPD14 syndrome (maternal UPD14)
• An individual shares half of his/her genes with each parent and each child.
• An individual shares an on average half of his/her genes with each sib.
|
[] |
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||||||
glut1
|
glut1
|
[
"De Vivo Disease",
"Glut1 Deficiency Syndrome",
"Glut1DS",
"Glut1-DS",
"De Vivo Disease",
"Glut1 Deficiency Syndrome",
"Glut1DS",
"Glut1-DS",
"Solute carrier family 2, facilitated glucose transporter member 1",
"SLC2A1",
"Glucose Transporter Type 1 Deficiency Syndrome"
] |
Glucose Transporter Type 1 Deficiency Syndrome
|
Dong Wang, Tristan Sands, Maoxue Tang, Umrao Monani, Darryl De Vivo
|
Summary Glucose transporter type 1 deficiency syndrome (Glut1DS) is a disorder of brain energy metabolism. Glucose, the essential metabolic fuel for the brain, is transported into the brain exclusively by the protein glucose transporter type 1 (Glut1) across the endothelial cells forming the blood-brain barrier (BBB). Glut1DS results from the inability of Glut1 to transfer sufficient glucose across the BBB to meet the glucose demands of the brain. The needs of the brain for glucose increase rapidly after birth, peaking in early childhood, remaining high until about age 10 years, then gradually decreasing throughout adolescence and plateauing in early adulthood. When first diagnosed in infancy to early childhood, the predominant clinical findings of Glut1DS are paroxysmal eye-head movements, pharmacoresistant seizures of varying types, deceleration of head growth, and developmental delay. Subsequently children develop complex movement disorders and intellectual disability ranging from mild to severe. Institution of ketogenic diet therapies (KDTs) helps with early neurologic growth and development and seizure control. Typically, the earlier the treatment the better the long-term clinical outcome. When first diagnosed in later childhood to adulthood (occasionally in a parent following the diagnosis of an affected child), the predominant clinical findings of Glut1DS are usually complex paroxysmal movement disorders, spasticity, ataxia, dystonia, speech difficulty, and intellectual disability. The diagnosis of Glut1DS is established in a proband with suggestive clinical findings, hypoglycorrhachia documented by lumbar puncture, and a (usually) heterozygous pathogenic variant in Glut1DS is most commonly caused by a heterozygous Autosomal recessive inheritance has been reported in two families to date. Once the
|
## Diagnosis
An international consensus statement on the standard of care for glucose transporter type 1 deficiency syndrome (Glut1DS) diagnosis and management has been published [
Glut1DS
Generalized seizures more common than focal seizures
Early-onset childhood absence epilepsy (i.e., age <4 years)
Epilepsy with myoclonic-atonic seizures (Doose syndrome)
Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
Glucose Transporter Type 1 Deficiency Syndrome: Laboratory Findings by Clinical Severity
A more severe phenotype (infantile- or childhood-onset Glut1DS) results from greater reductions (perhaps 40%-75%) in Glut1 transporter function [
Most probands have the disorder as the result of a
The diagnosis of Glut1DS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Note: (1) Single-gene testing (sequence analysis of
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in Glucose Transporter Type 1 Deficiency Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis [
• Generalized seizures more common than focal seizures
• Early-onset childhood absence epilepsy (i.e., age <4 years)
• Epilepsy with myoclonic-atonic seizures (Doose syndrome)
• Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
• Generalized seizures more common than focal seizures
• Early-onset childhood absence epilepsy (i.e., age <4 years)
• Epilepsy with myoclonic-atonic seizures (Doose syndrome)
• Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
• Generalized seizures more common than focal seizures
• Early-onset childhood absence epilepsy (i.e., age <4 years)
• Epilepsy with myoclonic-atonic seizures (Doose syndrome)
• Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
•
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Suggestive Findings
Glut1DS
Generalized seizures more common than focal seizures
Early-onset childhood absence epilepsy (i.e., age <4 years)
Epilepsy with myoclonic-atonic seizures (Doose syndrome)
Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
Glucose Transporter Type 1 Deficiency Syndrome: Laboratory Findings by Clinical Severity
A more severe phenotype (infantile- or childhood-onset Glut1DS) results from greater reductions (perhaps 40%-75%) in Glut1 transporter function [
Most probands have the disorder as the result of a
• Generalized seizures more common than focal seizures
• Early-onset childhood absence epilepsy (i.e., age <4 years)
• Epilepsy with myoclonic-atonic seizures (Doose syndrome)
• Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
• Generalized seizures more common than focal seizures
• Early-onset childhood absence epilepsy (i.e., age <4 years)
• Epilepsy with myoclonic-atonic seizures (Doose syndrome)
• Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
• Generalized seizures more common than focal seizures
• Early-onset childhood absence epilepsy (i.e., age <4 years)
• Epilepsy with myoclonic-atonic seizures (Doose syndrome)
• Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
•
## Clinical Features by Age
Generalized seizures more common than focal seizures
Early-onset childhood absence epilepsy (i.e., age <4 years)
Epilepsy with myoclonic-atonic seizures (Doose syndrome)
Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
• Generalized seizures more common than focal seizures
• Early-onset childhood absence epilepsy (i.e., age <4 years)
• Epilepsy with myoclonic-atonic seizures (Doose syndrome)
• Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
• Generalized seizures more common than focal seizures
• Early-onset childhood absence epilepsy (i.e., age <4 years)
• Epilepsy with myoclonic-atonic seizures (Doose syndrome)
• Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
• Generalized seizures more common than focal seizures
• Early-onset childhood absence epilepsy (i.e., age <4 years)
• Epilepsy with myoclonic-atonic seizures (Doose syndrome)
• Any epilepsy associated with movement disorders. Classically, Glut1DS-associated seizures occur in the morning preprandially and disappear postprandially. The EEG pattern correlates with the clinical pattern.
•
## Laboratory Findings at All Ages
Glucose Transporter Type 1 Deficiency Syndrome: Laboratory Findings by Clinical Severity
A more severe phenotype (infantile- or childhood-onset Glut1DS) results from greater reductions (perhaps 40%-75%) in Glut1 transporter function [
## Family History
Most probands have the disorder as the result of a
## Establishing the Diagnosis
The diagnosis of Glut1DS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Note: (1) Single-gene testing (sequence analysis of
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in Glucose Transporter Type 1 Deficiency Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis [
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Clinical Characteristics
Glucose transporter type 1 deficiency syndrome (Glut1DS) is a disorder of brain energy metabolism. Glucose, the essential metabolic fuel for the brain, is transported exclusively by the protein glucose transporter type 1 (Glut1) across the endothelial cells forming the blood-brain barrier (BBB). Glut1DS results from the inability of Glut1 to transfer sufficient glucose across the BBB to meet the glucose demands of the brain. The needs of the brain for glucose increase rapidly after birth, peaking in early childhood, remaining high until about age 10 years, then gradually decreasing throughout adolescence and plateauing in early adulthood [
The cardinal findings of Glut1DS in children are eye-head movement abnormalities, epilepsy, movement disorders, and developmental delay (DD); however, affected children may not have all these early movement abnormalities and/or they are often not identified as such and thus are overlooked. When Glut1DS is diagnosed in infancy to early childhood, the predominant clinical findings are paroxysmal eye-head movements, pharmacoresistant seizures of varying types, deceleration of head growth, and DD. Subsequently these children display complex movement disorders and intellectual disability ranging from mild to severe. Institution of ketogenic diet therapies (KDTs) helps with early neurologic growth and development and seizure control. Typically, the earlier the treatment the better the long-term clinical outcome [
When Glut1DS is first diagnosed in later childhood to adulthood (occasionally in a parent following the diagnosis of an affected child), the predominant clinical findings are usually complex paroxysmal movement disorders, spasticity, ataxia, dystonia, speech difficulty, and intellectual disability.
To date, several hundred individuals have been reported with Glut1DS [
Infants appear normal at birth following an uneventful pregnancy and delivery.
The clinical manifestations in children are often influenced by daily activities such as meal pattern, physical activity, and intercurrent illnesses.
Seizures can be generalized tonic-clonic, focal, myoclonic, atonic, and typical and atypical absence. Typical absence seizures with 3-Hz generalized spike-wave discharges on EEG are characteristic of the early-onset absence epilepsy phenotype.
The frequency, severity, and type of seizures vary among affected individuals. Some individuals experience multiple seizures daily; others have only occasional seizures separated by days, weeks, or months. Seizure frequency may correlate inversely with disease severity; however, further studies are necessary to document this correlation.
Seizures tend to decrease or disappear later in childhood, adolescence, and adulthood.
Seizure control typically improves at any age when treated with KDTs.
Subsequently, young children show delayed neurologic growth and development.
Cognitive impairment ranges from learning disabilities to severe ID. Minimally affected individuals have estimated IQ scores in the low-normal range.
However, features of attention-deficit/hyperactivity disorder (ADHD) are evident in most individuals and occasionally need to be treated with medications.
Although some individuals exhibit autistic features, manifestations of autism spectrum disorder appear to be underrepresented in individuals with Glut1DS. Similarly, mood disturbances are uncommon.
Intellectual disability (ID), speech and language impairment, and neurobehavioral/psychiatric manifestations in later childhood, adolescence, and/or adulthood reflect previous structural damage to the immature brain during early rapid growth and development. Seizures are uncommon after adolescence, whereas complex movement disorders are common.
Gait disturbance (89%), the most frequent being ataxia and spasticity together or ataxia alone
Action limb dystonia (86%)
Mild chorea (75%)
Cerebellar action tremor (70%)
Non-epileptic paroxysmal events (28%)
Dyspraxia (21%)
Myoclonus (16%)
Two families with
Other paroxysmal events have been reported by
Confusion
Lethargy
Somnolence
Recurrent headaches, migraine headaches
Sleep disturbances
Hemiparesis
Total body paralysis
Intermittent ataxia
Writer's cramp
Dystonic tremor (described as the only finding in a mother and daughter [
Parkinsonism
Non-kinesigenic dyskinesias
Note: The sensitivity and specificity of PET in the diagnosis of Glut1DS have not been established.
Milder manifestations (e.g., intermittent epilepsy, dyskinesias, and ataxia) of Glut1DS are associated with 25%-35% reduction in Glut1 transporter function [
Missense variants. Predominantly mild or moderate clinical phenotype
Splice site and nonsense variants and insertions, deletions, and exon deletions. Almost exclusively moderate or severe clinical phenotype
Complete gene deletions. Severe clinical phenotype
Penetrance in Glut1DS inherited in an autosomal dominant manner is complete. If an asymptomatic or minimally symptomatic parent of a fully symptomatic child is identified by genetic testing, one should investigate the possibility that the parent is mosaic for the
The following disorders are now recognized to be part of the Glut1DS phenotypic spectrum [
Paroxysmal exercise-induced dyskinesia and epilepsy (also referred to as PxMD-
Paroxysmal choreoathetosis with spasticity (DYT9)
Early-onset childhood absence epilepsy
Epilepsy with myoclonic-atonic seizures
Cryohydrocytosis (stomatocytosis that leads to hemolytic anemia induced by cold exposure)
The first attempt to estimate birth incidence and point prevalence that was conducted in Australia suggested a prevalence of 1:90,000 [
• Gait disturbance (89%), the most frequent being ataxia and spasticity together or ataxia alone
• Action limb dystonia (86%)
• Mild chorea (75%)
• Cerebellar action tremor (70%)
• Non-epileptic paroxysmal events (28%)
• Dyspraxia (21%)
• Myoclonus (16%)
• Confusion
• Lethargy
• Somnolence
• Recurrent headaches, migraine headaches
• Sleep disturbances
• Hemiparesis
• Total body paralysis
• Intermittent ataxia
• Writer's cramp
• Dystonic tremor (described as the only finding in a mother and daughter [
• Parkinsonism
• Non-kinesigenic dyskinesias
• Missense variants. Predominantly mild or moderate clinical phenotype
• Splice site and nonsense variants and insertions, deletions, and exon deletions. Almost exclusively moderate or severe clinical phenotype
• Complete gene deletions. Severe clinical phenotype
• Paroxysmal exercise-induced dyskinesia and epilepsy (also referred to as PxMD-
• Paroxysmal choreoathetosis with spasticity (DYT9)
• Early-onset childhood absence epilepsy
• Epilepsy with myoclonic-atonic seizures
• Cryohydrocytosis (stomatocytosis that leads to hemolytic anemia induced by cold exposure)
## Clinical Description
Glucose transporter type 1 deficiency syndrome (Glut1DS) is a disorder of brain energy metabolism. Glucose, the essential metabolic fuel for the brain, is transported exclusively by the protein glucose transporter type 1 (Glut1) across the endothelial cells forming the blood-brain barrier (BBB). Glut1DS results from the inability of Glut1 to transfer sufficient glucose across the BBB to meet the glucose demands of the brain. The needs of the brain for glucose increase rapidly after birth, peaking in early childhood, remaining high until about age 10 years, then gradually decreasing throughout adolescence and plateauing in early adulthood [
The cardinal findings of Glut1DS in children are eye-head movement abnormalities, epilepsy, movement disorders, and developmental delay (DD); however, affected children may not have all these early movement abnormalities and/or they are often not identified as such and thus are overlooked. When Glut1DS is diagnosed in infancy to early childhood, the predominant clinical findings are paroxysmal eye-head movements, pharmacoresistant seizures of varying types, deceleration of head growth, and DD. Subsequently these children display complex movement disorders and intellectual disability ranging from mild to severe. Institution of ketogenic diet therapies (KDTs) helps with early neurologic growth and development and seizure control. Typically, the earlier the treatment the better the long-term clinical outcome [
When Glut1DS is first diagnosed in later childhood to adulthood (occasionally in a parent following the diagnosis of an affected child), the predominant clinical findings are usually complex paroxysmal movement disorders, spasticity, ataxia, dystonia, speech difficulty, and intellectual disability.
To date, several hundred individuals have been reported with Glut1DS [
Infants appear normal at birth following an uneventful pregnancy and delivery.
The clinical manifestations in children are often influenced by daily activities such as meal pattern, physical activity, and intercurrent illnesses.
Seizures can be generalized tonic-clonic, focal, myoclonic, atonic, and typical and atypical absence. Typical absence seizures with 3-Hz generalized spike-wave discharges on EEG are characteristic of the early-onset absence epilepsy phenotype.
The frequency, severity, and type of seizures vary among affected individuals. Some individuals experience multiple seizures daily; others have only occasional seizures separated by days, weeks, or months. Seizure frequency may correlate inversely with disease severity; however, further studies are necessary to document this correlation.
Seizures tend to decrease or disappear later in childhood, adolescence, and adulthood.
Seizure control typically improves at any age when treated with KDTs.
Subsequently, young children show delayed neurologic growth and development.
Cognitive impairment ranges from learning disabilities to severe ID. Minimally affected individuals have estimated IQ scores in the low-normal range.
However, features of attention-deficit/hyperactivity disorder (ADHD) are evident in most individuals and occasionally need to be treated with medications.
Although some individuals exhibit autistic features, manifestations of autism spectrum disorder appear to be underrepresented in individuals with Glut1DS. Similarly, mood disturbances are uncommon.
Intellectual disability (ID), speech and language impairment, and neurobehavioral/psychiatric manifestations in later childhood, adolescence, and/or adulthood reflect previous structural damage to the immature brain during early rapid growth and development. Seizures are uncommon after adolescence, whereas complex movement disorders are common.
Gait disturbance (89%), the most frequent being ataxia and spasticity together or ataxia alone
Action limb dystonia (86%)
Mild chorea (75%)
Cerebellar action tremor (70%)
Non-epileptic paroxysmal events (28%)
Dyspraxia (21%)
Myoclonus (16%)
Two families with
Other paroxysmal events have been reported by
Confusion
Lethargy
Somnolence
Recurrent headaches, migraine headaches
Sleep disturbances
Hemiparesis
Total body paralysis
Intermittent ataxia
Writer's cramp
Dystonic tremor (described as the only finding in a mother and daughter [
Parkinsonism
Non-kinesigenic dyskinesias
Note: The sensitivity and specificity of PET in the diagnosis of Glut1DS have not been established.
• Gait disturbance (89%), the most frequent being ataxia and spasticity together or ataxia alone
• Action limb dystonia (86%)
• Mild chorea (75%)
• Cerebellar action tremor (70%)
• Non-epileptic paroxysmal events (28%)
• Dyspraxia (21%)
• Myoclonus (16%)
• Confusion
• Lethargy
• Somnolence
• Recurrent headaches, migraine headaches
• Sleep disturbances
• Hemiparesis
• Total body paralysis
• Intermittent ataxia
• Writer's cramp
• Dystonic tremor (described as the only finding in a mother and daughter [
• Parkinsonism
• Non-kinesigenic dyskinesias
## Manifestations in Infancy to Early Childhood
Infants appear normal at birth following an uneventful pregnancy and delivery.
The clinical manifestations in children are often influenced by daily activities such as meal pattern, physical activity, and intercurrent illnesses.
Seizures can be generalized tonic-clonic, focal, myoclonic, atonic, and typical and atypical absence. Typical absence seizures with 3-Hz generalized spike-wave discharges on EEG are characteristic of the early-onset absence epilepsy phenotype.
The frequency, severity, and type of seizures vary among affected individuals. Some individuals experience multiple seizures daily; others have only occasional seizures separated by days, weeks, or months. Seizure frequency may correlate inversely with disease severity; however, further studies are necessary to document this correlation.
Seizures tend to decrease or disappear later in childhood, adolescence, and adulthood.
Seizure control typically improves at any age when treated with KDTs.
Subsequently, young children show delayed neurologic growth and development.
Cognitive impairment ranges from learning disabilities to severe ID. Minimally affected individuals have estimated IQ scores in the low-normal range.
However, features of attention-deficit/hyperactivity disorder (ADHD) are evident in most individuals and occasionally need to be treated with medications.
Although some individuals exhibit autistic features, manifestations of autism spectrum disorder appear to be underrepresented in individuals with Glut1DS. Similarly, mood disturbances are uncommon.
## Manifestations in Later Childhood to Adulthood
Intellectual disability (ID), speech and language impairment, and neurobehavioral/psychiatric manifestations in later childhood, adolescence, and/or adulthood reflect previous structural damage to the immature brain during early rapid growth and development. Seizures are uncommon after adolescence, whereas complex movement disorders are common.
Gait disturbance (89%), the most frequent being ataxia and spasticity together or ataxia alone
Action limb dystonia (86%)
Mild chorea (75%)
Cerebellar action tremor (70%)
Non-epileptic paroxysmal events (28%)
Dyspraxia (21%)
Myoclonus (16%)
Two families with
Other paroxysmal events have been reported by
Confusion
Lethargy
Somnolence
Recurrent headaches, migraine headaches
Sleep disturbances
Hemiparesis
Total body paralysis
Intermittent ataxia
Writer's cramp
Dystonic tremor (described as the only finding in a mother and daughter [
Parkinsonism
Non-kinesigenic dyskinesias
Note: The sensitivity and specificity of PET in the diagnosis of Glut1DS have not been established.
• Gait disturbance (89%), the most frequent being ataxia and spasticity together or ataxia alone
• Action limb dystonia (86%)
• Mild chorea (75%)
• Cerebellar action tremor (70%)
• Non-epileptic paroxysmal events (28%)
• Dyspraxia (21%)
• Myoclonus (16%)
• Confusion
• Lethargy
• Somnolence
• Recurrent headaches, migraine headaches
• Sleep disturbances
• Hemiparesis
• Total body paralysis
• Intermittent ataxia
• Writer's cramp
• Dystonic tremor (described as the only finding in a mother and daughter [
• Parkinsonism
• Non-kinesigenic dyskinesias
## Genotype-Phenotype Correlations
Milder manifestations (e.g., intermittent epilepsy, dyskinesias, and ataxia) of Glut1DS are associated with 25%-35% reduction in Glut1 transporter function [
Missense variants. Predominantly mild or moderate clinical phenotype
Splice site and nonsense variants and insertions, deletions, and exon deletions. Almost exclusively moderate or severe clinical phenotype
Complete gene deletions. Severe clinical phenotype
• Missense variants. Predominantly mild or moderate clinical phenotype
• Splice site and nonsense variants and insertions, deletions, and exon deletions. Almost exclusively moderate or severe clinical phenotype
• Complete gene deletions. Severe clinical phenotype
## Penetrance
Penetrance in Glut1DS inherited in an autosomal dominant manner is complete. If an asymptomatic or minimally symptomatic parent of a fully symptomatic child is identified by genetic testing, one should investigate the possibility that the parent is mosaic for the
## Nomenclature
The following disorders are now recognized to be part of the Glut1DS phenotypic spectrum [
Paroxysmal exercise-induced dyskinesia and epilepsy (also referred to as PxMD-
Paroxysmal choreoathetosis with spasticity (DYT9)
Early-onset childhood absence epilepsy
Epilepsy with myoclonic-atonic seizures
Cryohydrocytosis (stomatocytosis that leads to hemolytic anemia induced by cold exposure)
• Paroxysmal exercise-induced dyskinesia and epilepsy (also referred to as PxMD-
• Paroxysmal choreoathetosis with spasticity (DYT9)
• Early-onset childhood absence epilepsy
• Epilepsy with myoclonic-atonic seizures
• Cryohydrocytosis (stomatocytosis that leads to hemolytic anemia induced by cold exposure)
## Prevalence
The first attempt to estimate birth incidence and point prevalence that was conducted in Australia suggested a prevalence of 1:90,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
A few individuals have a severe clinical phenotype and laboratory signature of glucose transporter type 1 deficiency syndrome (Glut1DS) – low cerebrospinal fluid glucose and lactate, normal red blood cell glucose uptake assay – but no identifiable pathogenic variants in
The differential diagnosis of Glut1DS includes a range of metabolic and neurologic disorders, including those listed in
Glucose Transporter Type 1 Deficiency Syndrome: Differential Diagnosis
Hexokinase 1 deficiency [
Opsoclonus-myoclonus syndrome [
Neuroblastoma
Autosomal dominant intellectual developmental disorders (OMIM
Autosomal recessive intellectual developmental disorders (OMIM
All causes of neonatal seizures & acquired microcephaly; in particular, early presentations of
Developmental and epileptic encephalopathy (OMIM
Familial epilepsies w/autosomal dominant transmission
Episodic paroxysmal neurologic dysfunction responsive to or preventable by carbohydrate intake, esp when assoc w/seizures, alternating hemiparesis, ataxia, or cognitive dysfunction (confusion or intellectual disability)
Levodopa-responsive
CSF = cerebrospinal fluid; Glut1DS = glucose transporter type 1 deficiency syndrome
• Hexokinase 1 deficiency [
• Opsoclonus-myoclonus syndrome [
• Neuroblastoma
• Autosomal dominant intellectual developmental disorders (OMIM
• Autosomal recessive intellectual developmental disorders (OMIM
• All causes of neonatal seizures & acquired microcephaly; in particular, early presentations of
• Developmental and epileptic encephalopathy (OMIM
• Familial epilepsies w/autosomal dominant transmission
• Episodic paroxysmal neurologic dysfunction responsive to or preventable by carbohydrate intake, esp when assoc w/seizures, alternating hemiparesis, ataxia, or cognitive dysfunction (confusion or intellectual disability)
• Levodopa-responsive
## Management
An international consensus statement on the standard of care for glucose transporter type 1 deficiency syndrome (Glut1DS) diagnosis and management has been published [
To establish the extent of disease and needs in an individual diagnosed with Glut1DS, the evaluations summarized in
Glucose Transporter Type 1 Deficiency Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl brain MRI if not performed at time of diagnosis
Consider FDG-PET in select persons; typically used in research settings, but has distinctive findings.
Eval for movement disorders incl ataxia, dystonia, choreoathetosis, paroxysmal dyskinesias
Preprandial & postprandial EEG to characterize seizure types & distinguish seizures from non-seizure paroxysmal behaviors
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech-language eval
For preschool-age children: eval for early intervention
For school-age children: assess need for IEP services or a 504 plan.
Community or
Social work involvement for parental support
Home nursing referral
ASD = autism spectrum disorder; ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; IEP = individualized education plan; FDG-PET = fluorodeoxyglucose positron emission tomography; Glut1DS = glucose transporter type 1 deficiency syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for Glut1DS.
Experience over the past three decades indicates that KDTs are well tolerated in most individuals and are highly effective in controlling seizures and improving gait disturbance [
For those who are treated with KDTs, the following are important:
Dietary supplementation with 50 mg/kg/day of L-carnitine is recommended because the ketogenic diet is deficient in L-carnitine, a cofactor essential for the metabolism of fats [
Proper hydration and avoidance of carbonic anhydrase inhibitors such as acetazolamide is recommended to minimize the likelihood of kidney stones.
Avoidance of carbohydrate-containing foods, intravenous fluids, and medications that will interrupt the state of ketosis is recommended. Family care providers often need to serve as the "watchdogs" to intercept these indiscretions.
Avoidance of valproic acid treatment is recommended, as it may be dangerous in individuals on KDTs because it increases the risk of a Reye-like illness [
In the authors' experience, the neurologic outcome is influenced by the age at which treatment is initiated. Individuals treated effectively at a younger age have a better outcome [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Avoidance of
Glucose Transporter Type 1 Deficiency Syndrome: Treatment of Manifestations
Develop plan for transition from pediatric to adult care.
See American Epilepsy Society clinical practice tools for transitioning from pediatric to adult epilepsy care:
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
AAC = augmentative and alternative communication
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Glucose Transporter Type 1 Deficiency Syndrome: Recommended Surveillance
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, or movement disorders.
OT = occupational therapy/therapist; PT = physical therapy/therapist
A blood beta-hydroxybutyrate concentration of 3-5 mmol/L is recommended to insure a proper ketotic state.
Urinary measurement of ketonuria, which is only qualitative, may be falsely reassuring, as a strongly positive urine test for ketones may correlate with hypoketonemia.
It is appropriate to evaluate at-risk newborns, infants, and other relatives to identify as early as possible those who would benefit from initiation of treatment and preventive measures; early initiation of KDTs, ideally in infancy, results in better seizure control and improves long-term neurologic outcome.
Molecular genetic testing can be used to clarify the genetic status of at-risk relatives if the
If the
See
Experience with KDTs during pregnancy is limited. One mildly affected woman with Glut1DS tolerated KDT well during pregnancy. KDT was continued postnatally in her infant, who inherited the mother's pathogenic variant [
Genetic elements within or outside the
To further develop Glut1 gene therapy for clinical use, AAV9-Glut1 was delivered through the cisterna magna to a porcine model. High levels of virally delivered Glut1 in brain endothelia and, to a lesser extent, in the neuropil were reported [
Notwithstanding the caveat identified above, gene therapy studies for Glut1DS provide important proof-of-concept data of the therapeutic effects of restoring Glut1 protein function early in the life of individuals with Glut1DS and represent an important step toward finding a disease-modifying treatment for the human disease. These findings also indicate the need for newborn screening to facilitate identification and treatment of individuals with genetically confirmed Glut1DS presymptomatically in early infancy.
Search
• To incl brain MRI if not performed at time of diagnosis
• Consider FDG-PET in select persons; typically used in research settings, but has distinctive findings.
• Eval for movement disorders incl ataxia, dystonia, choreoathetosis, paroxysmal dyskinesias
• Preprandial & postprandial EEG to characterize seizure types & distinguish seizures from non-seizure paroxysmal behaviors
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech-language eval
• For preschool-age children: eval for early intervention
• For school-age children: assess need for IEP services or a 504 plan.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Dietary supplementation with 50 mg/kg/day of L-carnitine is recommended because the ketogenic diet is deficient in L-carnitine, a cofactor essential for the metabolism of fats [
• Proper hydration and avoidance of carbonic anhydrase inhibitors such as acetazolamide is recommended to minimize the likelihood of kidney stones.
• Avoidance of carbohydrate-containing foods, intravenous fluids, and medications that will interrupt the state of ketosis is recommended. Family care providers often need to serve as the "watchdogs" to intercept these indiscretions.
• Avoidance of valproic acid treatment is recommended, as it may be dangerous in individuals on KDTs because it increases the risk of a Reye-like illness [
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, or movement disorders.
• Molecular genetic testing can be used to clarify the genetic status of at-risk relatives if the
• If the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Glut1DS, the evaluations summarized in
Glucose Transporter Type 1 Deficiency Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl brain MRI if not performed at time of diagnosis
Consider FDG-PET in select persons; typically used in research settings, but has distinctive findings.
Eval for movement disorders incl ataxia, dystonia, choreoathetosis, paroxysmal dyskinesias
Preprandial & postprandial EEG to characterize seizure types & distinguish seizures from non-seizure paroxysmal behaviors
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech-language eval
For preschool-age children: eval for early intervention
For school-age children: assess need for IEP services or a 504 plan.
Community or
Social work involvement for parental support
Home nursing referral
ASD = autism spectrum disorder; ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; IEP = individualized education plan; FDG-PET = fluorodeoxyglucose positron emission tomography; Glut1DS = glucose transporter type 1 deficiency syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To incl brain MRI if not performed at time of diagnosis
• Consider FDG-PET in select persons; typically used in research settings, but has distinctive findings.
• Eval for movement disorders incl ataxia, dystonia, choreoathetosis, paroxysmal dyskinesias
• Preprandial & postprandial EEG to characterize seizure types & distinguish seizures from non-seizure paroxysmal behaviors
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech-language eval
• For preschool-age children: eval for early intervention
• For school-age children: assess need for IEP services or a 504 plan.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for Glut1DS.
Experience over the past three decades indicates that KDTs are well tolerated in most individuals and are highly effective in controlling seizures and improving gait disturbance [
For those who are treated with KDTs, the following are important:
Dietary supplementation with 50 mg/kg/day of L-carnitine is recommended because the ketogenic diet is deficient in L-carnitine, a cofactor essential for the metabolism of fats [
Proper hydration and avoidance of carbonic anhydrase inhibitors such as acetazolamide is recommended to minimize the likelihood of kidney stones.
Avoidance of carbohydrate-containing foods, intravenous fluids, and medications that will interrupt the state of ketosis is recommended. Family care providers often need to serve as the "watchdogs" to intercept these indiscretions.
Avoidance of valproic acid treatment is recommended, as it may be dangerous in individuals on KDTs because it increases the risk of a Reye-like illness [
In the authors' experience, the neurologic outcome is influenced by the age at which treatment is initiated. Individuals treated effectively at a younger age have a better outcome [
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Avoidance of
Glucose Transporter Type 1 Deficiency Syndrome: Treatment of Manifestations
Develop plan for transition from pediatric to adult care.
See American Epilepsy Society clinical practice tools for transitioning from pediatric to adult epilepsy care:
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
AAC = augmentative and alternative communication
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
• Dietary supplementation with 50 mg/kg/day of L-carnitine is recommended because the ketogenic diet is deficient in L-carnitine, a cofactor essential for the metabolism of fats [
• Proper hydration and avoidance of carbonic anhydrase inhibitors such as acetazolamide is recommended to minimize the likelihood of kidney stones.
• Avoidance of carbohydrate-containing foods, intravenous fluids, and medications that will interrupt the state of ketosis is recommended. Family care providers often need to serve as the "watchdogs" to intercept these indiscretions.
• Avoidance of valproic acid treatment is recommended, as it may be dangerous in individuals on KDTs because it increases the risk of a Reye-like illness [
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Targeted Therapy
Experience over the past three decades indicates that KDTs are well tolerated in most individuals and are highly effective in controlling seizures and improving gait disturbance [
For those who are treated with KDTs, the following are important:
Dietary supplementation with 50 mg/kg/day of L-carnitine is recommended because the ketogenic diet is deficient in L-carnitine, a cofactor essential for the metabolism of fats [
Proper hydration and avoidance of carbonic anhydrase inhibitors such as acetazolamide is recommended to minimize the likelihood of kidney stones.
Avoidance of carbohydrate-containing foods, intravenous fluids, and medications that will interrupt the state of ketosis is recommended. Family care providers often need to serve as the "watchdogs" to intercept these indiscretions.
Avoidance of valproic acid treatment is recommended, as it may be dangerous in individuals on KDTs because it increases the risk of a Reye-like illness [
In the authors' experience, the neurologic outcome is influenced by the age at which treatment is initiated. Individuals treated effectively at a younger age have a better outcome [
• Dietary supplementation with 50 mg/kg/day of L-carnitine is recommended because the ketogenic diet is deficient in L-carnitine, a cofactor essential for the metabolism of fats [
• Proper hydration and avoidance of carbonic anhydrase inhibitors such as acetazolamide is recommended to minimize the likelihood of kidney stones.
• Avoidance of carbohydrate-containing foods, intravenous fluids, and medications that will interrupt the state of ketosis is recommended. Family care providers often need to serve as the "watchdogs" to intercept these indiscretions.
• Avoidance of valproic acid treatment is recommended, as it may be dangerous in individuals on KDTs because it increases the risk of a Reye-like illness [
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Avoidance of
Glucose Transporter Type 1 Deficiency Syndrome: Treatment of Manifestations
Develop plan for transition from pediatric to adult care.
See American Epilepsy Society clinical practice tools for transitioning from pediatric to adult epilepsy care:
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
AAC = augmentative and alternative communication
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
##
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
##
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Glucose Transporter Type 1 Deficiency Syndrome: Recommended Surveillance
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, or movement disorders.
OT = occupational therapy/therapist; PT = physical therapy/therapist
A blood beta-hydroxybutyrate concentration of 3-5 mmol/L is recommended to insure a proper ketotic state.
Urinary measurement of ketonuria, which is only qualitative, may be falsely reassuring, as a strongly positive urine test for ketones may correlate with hypoketonemia.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, or movement disorders.
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
It is appropriate to evaluate at-risk newborns, infants, and other relatives to identify as early as possible those who would benefit from initiation of treatment and preventive measures; early initiation of KDTs, ideally in infancy, results in better seizure control and improves long-term neurologic outcome.
Molecular genetic testing can be used to clarify the genetic status of at-risk relatives if the
If the
See
• Molecular genetic testing can be used to clarify the genetic status of at-risk relatives if the
• If the
## Pregnancy Management
Experience with KDTs during pregnancy is limited. One mildly affected woman with Glut1DS tolerated KDT well during pregnancy. KDT was continued postnatally in her infant, who inherited the mother's pathogenic variant [
## Therapies Under Investigation
Genetic elements within or outside the
To further develop Glut1 gene therapy for clinical use, AAV9-Glut1 was delivered through the cisterna magna to a porcine model. High levels of virally delivered Glut1 in brain endothelia and, to a lesser extent, in the neuropil were reported [
Notwithstanding the caveat identified above, gene therapy studies for Glut1DS provide important proof-of-concept data of the therapeutic effects of restoring Glut1 protein function early in the life of individuals with Glut1DS and represent an important step toward finding a disease-modifying treatment for the human disease. These findings also indicate the need for newborn screening to facilitate identification and treatment of individuals with genetically confirmed Glut1DS presymptomatically in early infancy.
Search
## Genetic Counseling
Glucose transporter type 1 deficiency syndrome (Glut1DS) is most commonly caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner.
Autosomal recessive inheritance has been reported in two families to date:
A consanguineous family [
A family in which a severely affected child had an
In families with autosomal recessive Glut1DS, heterozygous individuals are asymptomatic [
About 10% of individuals diagnosed with Glut1DS have the disorder as the result of an
About 90% of individuals with Glut1DS have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment include:
Molecular genetic testing if a molecular diagnosis has been established in the proband;
Comparison of erythrocyte glucose uptake with control values if a molecular diagnosis has not been established in the proband.
Note: The family history of some individuals diagnosed with Glut1DS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore,
If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and gonadal mosaicism for an
If a parent of the proband is affected and/or is known to have an
If a molecular diagnosis has been established in the proband and the
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent [
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• A consanguineous family [
• A family in which a severely affected child had an
• About 10% of individuals diagnosed with Glut1DS have the disorder as the result of an
• About 90% of individuals with Glut1DS have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment include:
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• Comparison of erythrocyte glucose uptake with control values if a molecular diagnosis has not been established in the proband.
• Note: The family history of some individuals diagnosed with Glut1DS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore,
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• Comparison of erythrocyte glucose uptake with control values if a molecular diagnosis has not been established in the proband.
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• Comparison of erythrocyte glucose uptake with control values if a molecular diagnosis has not been established in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• If a parent of the proband is affected and/or is known to have an
• If a molecular diagnosis has been established in the proband and the
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Glucose transporter type 1 deficiency syndrome (Glut1DS) is most commonly caused by a heterozygous pathogenic variant and inherited in an autosomal dominant manner.
Autosomal recessive inheritance has been reported in two families to date:
A consanguineous family [
A family in which a severely affected child had an
In families with autosomal recessive Glut1DS, heterozygous individuals are asymptomatic [
• A consanguineous family [
• A family in which a severely affected child had an
## Risk to Family Members (Autosomal Dominant Inheritance)
About 10% of individuals diagnosed with Glut1DS have the disorder as the result of an
About 90% of individuals with Glut1DS have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment include:
Molecular genetic testing if a molecular diagnosis has been established in the proband;
Comparison of erythrocyte glucose uptake with control values if a molecular diagnosis has not been established in the proband.
Note: The family history of some individuals diagnosed with Glut1DS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore,
If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and gonadal mosaicism for an
If a parent of the proband is affected and/or is known to have an
If a molecular diagnosis has been established in the proband and the
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent [
• About 10% of individuals diagnosed with Glut1DS have the disorder as the result of an
• About 90% of individuals with Glut1DS have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment include:
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• Comparison of erythrocyte glucose uptake with control values if a molecular diagnosis has not been established in the proband.
• Note: The family history of some individuals diagnosed with Glut1DS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore,
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• Comparison of erythrocyte glucose uptake with control values if a molecular diagnosis has not been established in the proband.
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• Comparison of erythrocyte glucose uptake with control values if a molecular diagnosis has not been established in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for an
• If a parent of the proband is affected and/or is known to have an
• If a molecular diagnosis has been established in the proband and the
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent [
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
UT Southwestern Medical Center
•
•
•
•
•
•
•
•
•
• UT Southwestern Medical Center
## Molecular Genetics
Glucose Transporter Type 1 Deficiency Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Glucose Transporter Type 1 Deficiency Syndrome (
Glucose is the essential metabolic fuel for the brain. Glucose transport across the endothelial cells forming the blood-brain barrier (BBB) and astrocyte plasma membrane is exclusively facilitated by the protein glucose transporter type 1 (Glut1; also called solute carrier family 2, facilitated glucose transporter member 1) encoded by
The cerebral metabolic rate for glucose (which is low during fetal development) increases linearly after birth, peaks around age three years, remains high for the remainder of the first decade of life, and declines gradually during the second decade of life to the rate of glucose utilization seen in early adulthood. It thus appears that the risk for clinical manifestations during fetal development is low and then rises throughout infancy and early childhood.
Human and animal data suggest that the margin of safety for glucose transport across the BBB to meet the needs of brain metabolism and cerebral function is narrow.
A milder clinical phenotype with intermittent manifestations (epilepsy, dyskinesias, and ataxia) may be predicted with 25%-35% reduction in Glut1 transporter function [
The erythrocyte glucose uptake assay is a functional surrogate measure of residual Glut1 transporter function. Individuals with classic Glut1DS have on average a 50% uptake assay, resulting from pathogenic loss-of-function variants that result in 50% reduction in Glut1 activity. (See
A significant fraction (5/21) of known pathogenic variants is in a vulnerable region of the Glut1 protein that involves the fourth transmembrane domain encoded by exon 4, suggesting a critical functional disturbance associated with structural alterations in this region of the protein [
## Molecular Pathogenesis
Glucose is the essential metabolic fuel for the brain. Glucose transport across the endothelial cells forming the blood-brain barrier (BBB) and astrocyte plasma membrane is exclusively facilitated by the protein glucose transporter type 1 (Glut1; also called solute carrier family 2, facilitated glucose transporter member 1) encoded by
The cerebral metabolic rate for glucose (which is low during fetal development) increases linearly after birth, peaks around age three years, remains high for the remainder of the first decade of life, and declines gradually during the second decade of life to the rate of glucose utilization seen in early adulthood. It thus appears that the risk for clinical manifestations during fetal development is low and then rises throughout infancy and early childhood.
Human and animal data suggest that the margin of safety for glucose transport across the BBB to meet the needs of brain metabolism and cerebral function is narrow.
A milder clinical phenotype with intermittent manifestations (epilepsy, dyskinesias, and ataxia) may be predicted with 25%-35% reduction in Glut1 transporter function [
The erythrocyte glucose uptake assay is a functional surrogate measure of residual Glut1 transporter function. Individuals with classic Glut1DS have on average a 50% uptake assay, resulting from pathogenic loss-of-function variants that result in 50% reduction in Glut1 activity. (See
A significant fraction (5/21) of known pathogenic variants is in a vulnerable region of the Glut1 protein that involves the fourth transmembrane domain encoded by exon 4, suggesting a critical functional disturbance associated with structural alterations in this region of the protein [
## Chapter Notes
Decreased 3-O-methyl-D-glucose uptake in erythrocytes confirms the diagnosis of
Molecular genetic testing detects a pathogenic variant in more than 95% of people with abnormally low uptake assay.
Of note, approximately 3% of persons with Glut1DS have a normal uptake assay that is performed at 4 °C, a finding that correlates with the presence of an
In one of the two families reported to date with autosomal recessive inheritance of Glut1DS, the 3-O-methyl-D-glucose uptake assay was useful in determining the molecular pathogenesis and the mode of inheritance. A severely affected child in whom the erythrocyte glucose uptake assay was markedly abnormal (only 37% uptake) had one
The authors are also interested in hearing from clinicians treating patients affected by a neurologic syndrome associated with hypoglycorrhachia in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Drs Umrao Monani and Maoxue Tang to inquire about review of
The authors thank all who have been involved in this work since the original description of Glut1DS in 1991 including the patients and their families, philanthropic donors, clinical and laboratory colleagues, and administrative assistants. We also acknowledge the Glut1 Deficiency Foundation, Hope for Children Research Foundation, and individual donors for their generous and continuous support and encouragement.
Darryl De Vivo, MD (2002-present)Umrao Monani, PhD (2025-present)Juan M Pascual, MD, PhD; University of Texas Southwestern Medical Center (2002-2025)Tristan Sands, MD, PhD (2025-present)Maoxue Tang, PhD (2025-present)Dong Wang, MD (2002-present)
6 March 2025 (bp) Comprehensive update posted live
1 March 2018 (ha) Comprehensive update posted live
22 January 2015 (me) Comprehensive update posted live
9 August 2012 (me) Comprehensive update posted live
7 July 2009 (me) Comprehensive update posted live
6 December 2006 (me) Comprehensive update posted live
16 July 2004 (me) Comprehensive update posted live
30 July 2002 (me) Review posted live
21 February 2002 (jp) Original submission
• Decreased 3-O-methyl-D-glucose uptake in erythrocytes confirms the diagnosis of
• Molecular genetic testing detects a pathogenic variant in more than 95% of people with abnormally low uptake assay.
• 6 March 2025 (bp) Comprehensive update posted live
• 1 March 2018 (ha) Comprehensive update posted live
• 22 January 2015 (me) Comprehensive update posted live
• 9 August 2012 (me) Comprehensive update posted live
• 7 July 2009 (me) Comprehensive update posted live
• 6 December 2006 (me) Comprehensive update posted live
• 16 July 2004 (me) Comprehensive update posted live
• 30 July 2002 (me) Review posted live
• 21 February 2002 (jp) Original submission
## Author Notes
Decreased 3-O-methyl-D-glucose uptake in erythrocytes confirms the diagnosis of
Molecular genetic testing detects a pathogenic variant in more than 95% of people with abnormally low uptake assay.
Of note, approximately 3% of persons with Glut1DS have a normal uptake assay that is performed at 4 °C, a finding that correlates with the presence of an
In one of the two families reported to date with autosomal recessive inheritance of Glut1DS, the 3-O-methyl-D-glucose uptake assay was useful in determining the molecular pathogenesis and the mode of inheritance. A severely affected child in whom the erythrocyte glucose uptake assay was markedly abnormal (only 37% uptake) had one
The authors are also interested in hearing from clinicians treating patients affected by a neurologic syndrome associated with hypoglycorrhachia in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Drs Umrao Monani and Maoxue Tang to inquire about review of
• Decreased 3-O-methyl-D-glucose uptake in erythrocytes confirms the diagnosis of
• Molecular genetic testing detects a pathogenic variant in more than 95% of people with abnormally low uptake assay.
## Acknowledgments
The authors thank all who have been involved in this work since the original description of Glut1DS in 1991 including the patients and their families, philanthropic donors, clinical and laboratory colleagues, and administrative assistants. We also acknowledge the Glut1 Deficiency Foundation, Hope for Children Research Foundation, and individual donors for their generous and continuous support and encouragement.
## Author History
Darryl De Vivo, MD (2002-present)Umrao Monani, PhD (2025-present)Juan M Pascual, MD, PhD; University of Texas Southwestern Medical Center (2002-2025)Tristan Sands, MD, PhD (2025-present)Maoxue Tang, PhD (2025-present)Dong Wang, MD (2002-present)
## Revision History
6 March 2025 (bp) Comprehensive update posted live
1 March 2018 (ha) Comprehensive update posted live
22 January 2015 (me) Comprehensive update posted live
9 August 2012 (me) Comprehensive update posted live
7 July 2009 (me) Comprehensive update posted live
6 December 2006 (me) Comprehensive update posted live
16 July 2004 (me) Comprehensive update posted live
30 July 2002 (me) Review posted live
21 February 2002 (jp) Original submission
• 6 March 2025 (bp) Comprehensive update posted live
• 1 March 2018 (ha) Comprehensive update posted live
• 22 January 2015 (me) Comprehensive update posted live
• 9 August 2012 (me) Comprehensive update posted live
• 7 July 2009 (me) Comprehensive update posted live
• 6 December 2006 (me) Comprehensive update posted live
• 16 July 2004 (me) Comprehensive update posted live
• 30 July 2002 (me) Review posted live
• 21 February 2002 (jp) Original submission
## Key Sections in This
## References
## Literature Cited
|
[] |
30/7/2002
|
6/3/2025
|
9/9/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
glutaric-a1
|
glutaric-a1
|
[
"GA-1",
"GCDH Deficiency",
"Glutaric Aciduria Type 1",
"Glutaryl-CoA Dehydrogenase Deficiency",
"GA-1",
"GCDH Deficiency",
"Glutaric Aciduria Type 1",
"Glutaryl-CoA Dehydrogenase Deficiency",
"Glutaryl-CoA dehydrogenase, mitochondrial",
"GCDH",
"Glutaric Acidemia Type 1"
] |
Glutaric Acidemia Type 1
|
Austin Larson, Steve Goodman
|
Summary The phenotypic spectrum of untreated glutaric acidemia type 1 (GA-1) ranges from the more common form (infantile-onset disease) to the less common form (later-onset disease – i.e., after age 6 years). Of note, the GA-1 phenotype can vary widely between untreated family members with the same genotype, primarily as a function of the age at which the first acute encephalopathic crisis occurred: three months to six years in infantile-onset GA-1 and after age six years in later-onset GA-1. Characteristically these crises result in acute bilateral striatal injury and subsequent complex movement disorders. In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed manifestations of either infantile-onset or later-onset GA-1 remain asymptomatic; however, they may be at increased risk for other manifestations (e.g., renal disease) that are becoming apparent as the understanding of the natural history of treated GA-1 continues to evolve. Because the early initiation of treatment dramatically improved the outcome for persons with GA-1, an international guideline group has recommended NBS. The diagnosis of GA-1 in a proband with a positive NBS result or suggestive biochemical and/or clinical findings is confirmed by identification of biallelic pathogenic variants in GA-1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the
|
## Diagnosis
Guidelines for diagnosis and management of glutaric acidemia type 1 (GA-1) due to deficiency or absence of functional glutaryl-CoA dehydrogenase were developed in 2007 and recently revised [
GA-1
For more information on false positive and false negative results for NBS for glutaric acidemia type 1 click
GA-1
Progressive macrocephaly is observed in 75% of affected individuals and may be present prenatally [
Untreated infantile-onset GA-1 (resulting from
Untreated late-onset GA-1 may manifest as other nonspecific neurologic abnormalities including headaches, vertigo, dementia, and ataxia [
Open opercula (n=15)
Widening of CSF spaces / ventriculomegaly (9)
Attenuated signal from basal ganglia (8)
White matter abnormalities (5)
Subdural hemorrhage (SDH), probably due to stretching of bridging veins in the enlarged extra-axial fluid spaces (1). SDH is typically associated with frontotemporal hypoplasia.
Glutaric acid
3-hydroxyglutaric acid
Glutarylcarnitine (C5DC)
Glutaconic acid
Note: Because elevations of these metabolites individually are not specific to GA-1, additional testing is required to establish the diagnosis of GA-1 (see
The diagnosis of GA-1 in a proband with suggestive biochemical and/or clinical findings
Molecular genetic testing approaches can include
Infants with positive newborn screening and follow-up testing (see
Symptomatic individuals with nonspecific clinical and imaging findings in whom the diagnosis of GA-1 has not been considered (see
When NBS results and other laboratory findings suggest the diagnosis of GA-1, the recommended molecular genetic testing approach is
When the diagnosis of GA-1 has not been considered, either a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glutaric Acidemia Type 1
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
While no data on detection rate of gene-targeted deletion/duplication analysis are available, the authors estimate this number to be extremely low based on extensive sequencing of
Shortcomings of enzymatic testing on fibroblast cultures or leukocytes include the following:
Difficulty distinguishing carriers (i.e., heterozygotes for one
The relatively large blood volumes (3-5 mL) required to reliably perform the leukocyte assay
The limited number of clinical laboratories offering enzymatic testing on leukocytes
• Progressive macrocephaly is observed in 75% of affected individuals and may be present prenatally [
• Untreated infantile-onset GA-1 (resulting from
• Untreated late-onset GA-1 may manifest as other nonspecific neurologic abnormalities including headaches, vertigo, dementia, and ataxia [
• Open opercula (n=15)
• Widening of CSF spaces / ventriculomegaly (9)
• Attenuated signal from basal ganglia (8)
• White matter abnormalities (5)
• Subdural hemorrhage (SDH), probably due to stretching of bridging veins in the enlarged extra-axial fluid spaces (1). SDH is typically associated with frontotemporal hypoplasia.
• Glutaric acid
• 3-hydroxyglutaric acid
• Glutarylcarnitine (C5DC)
• Glutaconic acid
• Infants with positive newborn screening and follow-up testing (see
• Symptomatic individuals with nonspecific clinical and imaging findings in whom the diagnosis of GA-1 has not been considered (see
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• Difficulty distinguishing carriers (i.e., heterozygotes for one
• The relatively large blood volumes (3-5 mL) required to reliably perform the leukocyte assay
• The limited number of clinical laboratories offering enzymatic testing on leukocytes
## Suggestive Findings
GA-1
For more information on false positive and false negative results for NBS for glutaric acidemia type 1 click
GA-1
Progressive macrocephaly is observed in 75% of affected individuals and may be present prenatally [
Untreated infantile-onset GA-1 (resulting from
Untreated late-onset GA-1 may manifest as other nonspecific neurologic abnormalities including headaches, vertigo, dementia, and ataxia [
Open opercula (n=15)
Widening of CSF spaces / ventriculomegaly (9)
Attenuated signal from basal ganglia (8)
White matter abnormalities (5)
Subdural hemorrhage (SDH), probably due to stretching of bridging veins in the enlarged extra-axial fluid spaces (1). SDH is typically associated with frontotemporal hypoplasia.
Glutaric acid
3-hydroxyglutaric acid
Glutarylcarnitine (C5DC)
Glutaconic acid
Note: Because elevations of these metabolites individually are not specific to GA-1, additional testing is required to establish the diagnosis of GA-1 (see
• Progressive macrocephaly is observed in 75% of affected individuals and may be present prenatally [
• Untreated infantile-onset GA-1 (resulting from
• Untreated late-onset GA-1 may manifest as other nonspecific neurologic abnormalities including headaches, vertigo, dementia, and ataxia [
• Open opercula (n=15)
• Widening of CSF spaces / ventriculomegaly (9)
• Attenuated signal from basal ganglia (8)
• White matter abnormalities (5)
• Subdural hemorrhage (SDH), probably due to stretching of bridging veins in the enlarged extra-axial fluid spaces (1). SDH is typically associated with frontotemporal hypoplasia.
• Glutaric acid
• 3-hydroxyglutaric acid
• Glutarylcarnitine (C5DC)
• Glutaconic acid
## Scenario 1: Positive Newborn Screening (NBS)
GA-1
For more information on false positive and false negative results for NBS for glutaric acidemia type 1 click
## Scenario 2: Symptomatic Individuals
GA-1
Progressive macrocephaly is observed in 75% of affected individuals and may be present prenatally [
Untreated infantile-onset GA-1 (resulting from
Untreated late-onset GA-1 may manifest as other nonspecific neurologic abnormalities including headaches, vertigo, dementia, and ataxia [
Open opercula (n=15)
Widening of CSF spaces / ventriculomegaly (9)
Attenuated signal from basal ganglia (8)
White matter abnormalities (5)
Subdural hemorrhage (SDH), probably due to stretching of bridging veins in the enlarged extra-axial fluid spaces (1). SDH is typically associated with frontotemporal hypoplasia.
Glutaric acid
3-hydroxyglutaric acid
Glutarylcarnitine (C5DC)
Glutaconic acid
Note: Because elevations of these metabolites individually are not specific to GA-1, additional testing is required to establish the diagnosis of GA-1 (see
• Progressive macrocephaly is observed in 75% of affected individuals and may be present prenatally [
• Untreated infantile-onset GA-1 (resulting from
• Untreated late-onset GA-1 may manifest as other nonspecific neurologic abnormalities including headaches, vertigo, dementia, and ataxia [
• Open opercula (n=15)
• Widening of CSF spaces / ventriculomegaly (9)
• Attenuated signal from basal ganglia (8)
• White matter abnormalities (5)
• Subdural hemorrhage (SDH), probably due to stretching of bridging veins in the enlarged extra-axial fluid spaces (1). SDH is typically associated with frontotemporal hypoplasia.
• Glutaric acid
• 3-hydroxyglutaric acid
• Glutarylcarnitine (C5DC)
• Glutaconic acid
## Establishing the Diagnosis
The diagnosis of GA-1 in a proband with suggestive biochemical and/or clinical findings
Molecular genetic testing approaches can include
Infants with positive newborn screening and follow-up testing (see
Symptomatic individuals with nonspecific clinical and imaging findings in whom the diagnosis of GA-1 has not been considered (see
When NBS results and other laboratory findings suggest the diagnosis of GA-1, the recommended molecular genetic testing approach is
When the diagnosis of GA-1 has not been considered, either a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glutaric Acidemia Type 1
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
While no data on detection rate of gene-targeted deletion/duplication analysis are available, the authors estimate this number to be extremely low based on extensive sequencing of
Shortcomings of enzymatic testing on fibroblast cultures or leukocytes include the following:
Difficulty distinguishing carriers (i.e., heterozygotes for one
The relatively large blood volumes (3-5 mL) required to reliably perform the leukocyte assay
The limited number of clinical laboratories offering enzymatic testing on leukocytes
• Infants with positive newborn screening and follow-up testing (see
• Symptomatic individuals with nonspecific clinical and imaging findings in whom the diagnosis of GA-1 has not been considered (see
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• Difficulty distinguishing carriers (i.e., heterozygotes for one
• The relatively large blood volumes (3-5 mL) required to reliably perform the leukocyte assay
• The limited number of clinical laboratories offering enzymatic testing on leukocytes
## Scenario 1
When NBS results and other laboratory findings suggest the diagnosis of GA-1, the recommended molecular genetic testing approach is
## Scenario 2
When the diagnosis of GA-1 has not been considered, either a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glutaric Acidemia Type 1
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
While no data on detection rate of gene-targeted deletion/duplication analysis are available, the authors estimate this number to be extremely low based on extensive sequencing of
Shortcomings of enzymatic testing on fibroblast cultures or leukocytes include the following:
Difficulty distinguishing carriers (i.e., heterozygotes for one
The relatively large blood volumes (3-5 mL) required to reliably perform the leukocyte assay
The limited number of clinical laboratories offering enzymatic testing on leukocytes
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• Difficulty distinguishing carriers (i.e., heterozygotes for one
• The relatively large blood volumes (3-5 mL) required to reliably perform the leukocyte assay
• The limited number of clinical laboratories offering enzymatic testing on leukocytes
## Clinical Characteristics
The phenotypic spectrum of untreated glutaric acidemia type 1 (GA-1) ranges from the more common form (infantile-onset disease) to the less common form (later-onset disease after age 6 years). Of note, the GA-1 phenotype can vary widely among untreated family members with the same genotype, primarily as a function of the age at which the first acute encephalopathic crisis occurred: three months to three years in infantile-onset GA-1 and after age six years in later-onset GA-1 [
In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed manifestations of either infantile-onset or later-onset GA-1 remain asymptomatic.
Dietary treatment and intense emergency treatment during intercurrent illness (see
Subdural hemorrhages, a rare manifestation of GA-1, may develop even in individuals diagnosed on NBS, managed appropriately, and without macrocephaly [
Seizures are reported in 7% of individuals with GA-1 [
When GA-1 is diagnosed after the onset of neurologic manifestations, outcome is poor and the therapeutic effect of the usual interventions is more limited [
With early diagnosis and adherence to treatment, 80%-90% of individuals with GA-1 remain largely asymptomatic [
Insidious onset of manifestations was previously seen in an estimated 10%-20% of symptomatic individuals [
Individuals who adhere to maintenance and emergency treatments rarely develop dystonia; those who do not are at high risk of developing a movement disorder [
Other reported manifestations of late-onset GA-1 include the following:
Peripheral neuropathy (1 adult) [
Brain neoplasms (in several adults and children) [
Most
High excreters have no or very low glutaryl-CoA dehydrogenase activity (0%-3%) [
Low excreters have up to 30% residual glutaryl-CoA dehydrogenase activity [
Well over 500 individuals with GA-1 have been reported to date [
Details on founder variants reported in Ojibway-Cree First Nation Canadians of Manitoba and Ontario, South African Xhosa peoples, Pennsylvania Amish, Lumbee Native Americans of North Carolina, and Irish Traveler communities in the Republic of Ireland are included in
• Peripheral neuropathy (1 adult) [
• Brain neoplasms (in several adults and children) [
• High excreters have no or very low glutaryl-CoA dehydrogenase activity (0%-3%) [
• Low excreters have up to 30% residual glutaryl-CoA dehydrogenase activity [
## Clinical Description
The phenotypic spectrum of untreated glutaric acidemia type 1 (GA-1) ranges from the more common form (infantile-onset disease) to the less common form (later-onset disease after age 6 years). Of note, the GA-1 phenotype can vary widely among untreated family members with the same genotype, primarily as a function of the age at which the first acute encephalopathic crisis occurred: three months to three years in infantile-onset GA-1 and after age six years in later-onset GA-1 [
In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed manifestations of either infantile-onset or later-onset GA-1 remain asymptomatic.
Dietary treatment and intense emergency treatment during intercurrent illness (see
Subdural hemorrhages, a rare manifestation of GA-1, may develop even in individuals diagnosed on NBS, managed appropriately, and without macrocephaly [
Seizures are reported in 7% of individuals with GA-1 [
When GA-1 is diagnosed after the onset of neurologic manifestations, outcome is poor and the therapeutic effect of the usual interventions is more limited [
With early diagnosis and adherence to treatment, 80%-90% of individuals with GA-1 remain largely asymptomatic [
Insidious onset of manifestations was previously seen in an estimated 10%-20% of symptomatic individuals [
Individuals who adhere to maintenance and emergency treatments rarely develop dystonia; those who do not are at high risk of developing a movement disorder [
Other reported manifestations of late-onset GA-1 include the following:
Peripheral neuropathy (1 adult) [
Brain neoplasms (in several adults and children) [
• Peripheral neuropathy (1 adult) [
• Brain neoplasms (in several adults and children) [
## Genotype-Phenotype Correlations
Most
High excreters have no or very low glutaryl-CoA dehydrogenase activity (0%-3%) [
Low excreters have up to 30% residual glutaryl-CoA dehydrogenase activity [
• High excreters have no or very low glutaryl-CoA dehydrogenase activity (0%-3%) [
• Low excreters have up to 30% residual glutaryl-CoA dehydrogenase activity [
## Prevalence
Well over 500 individuals with GA-1 have been reported to date [
Details on founder variants reported in Ojibway-Cree First Nation Canadians of Manitoba and Ontario, South African Xhosa peoples, Pennsylvania Amish, Lumbee Native Americans of North Carolina, and Irish Traveler communities in the Republic of Ireland are included in
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Other Genes of Interest in the Differential Diagnosis of Glutaric Acidemia Type 1 (GA-1)
Hypotonia
Liver dysfunction
Muscle weakness
Cardiomyopathy
May result in suspected GA-1 from NBS result
↑ plasma GA, 3-OH-GA, & C5DC acylcarnitine as well as many other acylcarnitine species
↑ ethylmalonic acid
↑ suberylglycine, hexanoylglycine, isovalerylglycine, isobutyrylglycine
Neuronal migration defects & leukodystrophy on MRI
Key diagnostic marker: massively ↑ GA/3-OH-GA ratio (not seen in GA-1)
↑ plasma GA
Normal or minimally ↑ 3-OH-GA & C5DC acylcarnitine
May be only a biochemical phenotype
Hypotonia
DD & regression
Seizures
Optic atrophy
N-acetyl aspartate in urine
Leukodystrophy on MRI
Regression w/illness
Progressive course
↑ lactic acid in CSF or blood
↑ alanine
Metabolic "stroke" &/or basal ganglia injury
Possible white matter abnormality on MRI
Abnormal signal of the brain stem & dentate nuclei
Decompensation w/illness
DD
Cardiomyopathy
Renal failure
Pancreatitis
Bone marrow suppression
Optic atrophy
Ketoacidosis
Diagnostic urine organic acid testing
↑ methylmalonic acid
Metabolic "stroke" &/or basal ganglia injury
Possible white matter abnormality on MRI
3-OH-GA = 3-hydroxyglutaric acid; AR = autosomal recessive; C5DC = glutarylcarnitine; DD = developmental delay; DiffDx = differential diagnosis; GA = glutaric acid; Mat = maternal; MOI = mode of inheritance; mt = mitochondrial; NBS = newborn screening; XL = X-linked
In children with
• Hypotonia
• Liver dysfunction
• Muscle weakness
• Cardiomyopathy
• May result in suspected GA-1 from NBS result
• ↑ plasma GA, 3-OH-GA, & C5DC acylcarnitine as well as many other acylcarnitine species
• ↑ ethylmalonic acid
• ↑ suberylglycine, hexanoylglycine, isovalerylglycine, isobutyrylglycine
• Neuronal migration defects & leukodystrophy on MRI
• Key diagnostic marker: massively ↑ GA/3-OH-GA ratio (not seen in GA-1)
• ↑ plasma GA
• Normal or minimally ↑ 3-OH-GA & C5DC acylcarnitine
• May be only a biochemical phenotype
• Hypotonia
• DD & regression
• Seizures
• Optic atrophy
• N-acetyl aspartate in urine
• Leukodystrophy on MRI
• Regression w/illness
• Progressive course
• ↑ lactic acid in CSF or blood
• ↑ alanine
• Metabolic "stroke" &/or basal ganglia injury
• Possible white matter abnormality on MRI
• Abnormal signal of the brain stem & dentate nuclei
• Decompensation w/illness
• DD
• Cardiomyopathy
• Renal failure
• Pancreatitis
• Bone marrow suppression
• Optic atrophy
• Ketoacidosis
• Diagnostic urine organic acid testing
• ↑ methylmalonic acid
• Metabolic "stroke" &/or basal ganglia injury
• Possible white matter abnormality on MRI
## Management
When glutaric acidemia type 1 (GA-1) is suspected during the diagnostic evaluation (i.e., due to elevated concentration of 3-OH-GA in plasma or urine), metabolic treatment should be initiated immediately.
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach to care including multiple subspecialists, with oversight and expertise from a specialized metabolic center.
The second revision of consensus clinical practice guidelines for the treatment of individuals with GA-1 have recently been published [
To establish the extent of disease and needs in an individual following diagnosis of GA-1, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of GA-1
Transfer to specialist center w/experience in management of inherited metabolic diseases is strongly recommended.
Consider short hospitalization at center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises) for caregivers.
OT = occupational therapist; PT = physical therapist
After a new diagnosis of GA-1 in a child, the closest hospital and local pediatrician should also be informed.
All children with GA-1 and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing diet in GA-1. German (D)-Austrian (A)-Swiss (CH) (DACH) recommendations have been used in several clinical trials and have resulted in positive outcomes [
The main principles of treatment are to reduce lysine oxidation and enhance physiologic detoxification of glutaryl-CoA. Combined metabolic therapy includes the following [
Low-lysine diet
Carnitine supplementation
Emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts
Routine Daily Treatment in Individuals with Glutaric Aciduria Type 1
Low-Lys diet
Direct calculation of Lys intake (vs total natural protein intake) is more precise & reduces long-term day-to-day variability of Lys intake.
Lys-free, Trp-reduced amino acid formulas
Age 0-6 mos: ~100 mg/kg/day
Age 6-12 mos: ~90 mg/kg/day) (See
Breastfeeding should be encouraged.
Lys content in breast milk is ~86 mg/100 mL.
Daily Lys intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable.
Controlled protein intake of natural protein w/low Lys content & avoidance of Lys-rich foods advised even after age 6 yrs (See
Diet should follow an age-adapted, protein-controlled protocol w/no requirement for Lys-free, Trp-restricted formula, but w/avoidance or very careful apportioning of Lys-rich natural protein food sources.
Formulas should be Trp-reduced but not completely deficient in Trp.
Depletion may cause severe neurologic deficits.
Quantification of Trp in plasma is technically challenging.
Initial oral dosage of 100 mg L-carnitine/kg per day divided into 3-4 doses is typical.
Dose is adjusted on an individual basis to maintain plasma free L-carnitine concentration w/in normal age-appropriate reference range.
Lifelong carnitine supplementation is generally recommended.
L-carnitine supplementation is considered to contribute to ↓ risk for striatal injury in persons diagnosed early
Physical therapy
Aggressive rehabilitation therapy
EAA = essential amino acid; Lys = lysine; Trp = tryptophan
The Lys content in natural protein sources in food varies considerably – e.g., 2%-4% (lysine/protein) in cereals and 9% (lysine/protein) in fish.
High-lysine foods include poultry, fish, shrimp, shellfish, pork, beef, soy, nuts, seeds, eggs, beans, and lentils.
Consensus recommendations at present state that there is currently insufficient evidence to support routine high-dose arginine (Arg) supplementation orally in addition to (or as a substitute for) the use of a Lys-free, Trp-reduced, Arg-containing amino acid formula as an adjunct to a prescribed daily quantity of natural protein.
Data are extremely limited on optimal Lys intake and protein/calorie requirements in premature infants [Goodman & Baker, personal communication].
Older children need proportionately less Lys per unit body weight than infants due to decelerating nutritional requirements and growth velocities.
Long-term outcome in individuals with GA-1 in this age group as a function of dietary management has not been well characterized.
Tryptophan content in natural protein is only 0.6%-2%, depending on source.
Foods rich in Trp include poultry, fish, legumes, and dairy products.
Dose reduction may be necessary due to adverse effects, such as diarrhea and a fishy body odor, which can be socially stigmatizing.
Such demands may stem from movement disorders (dystonia, orofacial dyskinesia).
Notes: (1) Riboflavin supplementation is not recommended currently as standard therapy for GA-1 [
Nutritional Requirements for L-lysine, L-Carnitine, Calories, and Natural Protein for Infants and Children with GA-1
Adapted from
If normal growth and development are not achieved, these recommendations should be modified according to individual need.
Lysine content in natural sources of protein varies significantly; thus, natural protein requirements will vary considerably according to the natural protein source used (e.g., higher natural protein intake will be required if sources have a very low lysine content). High-lysine foods include poultry, fish, shrimp, shellfish, pork, beef, soy, nuts, seeds, eggs, beans, and lentils.
Lys-free, Trp-reduced amino acid formulas specifically produced for individuals with GA1 should be supplemented with minerals and micronutrients as needed to maintain normal levels. Adequate intake of essential amino acids is provided from natural protein and Lys-free, Trp-reduced amino acid formula.
If an affected individual is clinically well despite an intercurrent infectious illness or febrile reaction to vaccinations, emergency outpatient management may be considered (see
Emergency Outpatient Treatment in Individuals with Glutaric Aciduria Type 1
Carbohydrate supplementation orally or via tube feed
↓ natural protein intake
↑ carnitine supplementation
Trial of outpatient treatment at home for ≤12 hrs
Reassessment (every ~2 hrs) for clinical changes
Administration of antipyretics (acetaminophen, ibuprofen) if temperature rises >38.5°C
Antiemetics
Fever <38.5 °C (101 °F); enteral or gastrostomy tube feeding is tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability, hypotonia, dystonia)
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting; some centers recommend frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment.
Some centers advocate additional steps such as reducing natural protein intake to zero or to 50% of the normal prescribed regimen for short periods (<24 hours) in the outpatient setting during intercurrent illness.
Temporarily increasing L-carnitine doses (e.g., to 200 mg/kg/day in infants) is recommended [
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma), often occurring in the setting of intercurrent illness and/or inadequate caloric intake, should be managed symptomatically and with generous caloric support in a hospital setting, with aggressive treatment and supportive care of any identified or clinically suspected acute conditions (see
Acute In-Patient Treatment in Individuals with Glutaric Aciduria Type 1
Administer high-energy fluids &, if needed, insulin.
Intravenous lipid emulsion
↓ or omit natural protein for 24 hrs.
↑ L-carnitine supplementation.
Address electrolytes & pH imbalances w/intravenous fluid mgmt.
Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine profiling, & urine pH/ketone screening may all be useful in guiding mgmt.
Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
Inadequate or delayed start of emergency treatment → high risk of striatal injury, dystonia, & consequent long-term disability.
No evidence supports use of arginine therapy during acute illness.
In children >6 yrs, adolescents, & adults: consider emergency treatment adapted from protocols for younger children during periods of severe illness or prolonged fasting, though risks of encephalopathic illness & striatal injury are probably ↓ in these age groups.
Initiate the treatment listed above for ↑ catabolism.
Neurologic consultation, ASM if needed
MRI of the brain
In-patient emergency treatment should: (1) take place at the closest medical facility, (2) be started without delay, and (3) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.
ASM = anti-seizure medication; CK = creatine kinase; IV = intravenous
Intravenous glucose solutions should provide 12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children 12 months - 6 years.
Use of insulin if hyperglycemia emerges; intravenous insulin given at a starting dose of 0.025 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma, or glucosuria).
Natural protein can be gradually reintroduced, with continuation of enteral Lys-free, Trp-reduced GA-1-specific amino acid formula as tolerated.
L-carnitine (with options to increase the dose) can be given intravenously, which enhances bioavailability.
To date only case reports on emergency treatment in adolescents and adults have been published [
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with GA-1 together with pediatric metabolic experts, dietitians, psychologists, and social workers.
In puberty and early adulthood, deficits in adherence to treatment may occur due to deteriorating compliance or other unknown factors, resulting in negative impact on outcomes [
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
Dietary restriction of lysine intake remains the cornerstone of GA-1 treatment. Although management of any given affected individual is nuanced and managed on a case-by-case basis, minor illnesses, where caloric needs are increased or provision of adequate calories is compromised, should be observed closely and promptly treated with a low threshold for hospital admission (see
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also
Prevention of Secondary Manifestations in Individuals with Glutaric Aciduria Type 1
Intense & ongoing education of affected individuals & caregivers about worrisome symptoms, natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while on vacation
Medical alert bracelets/pendants or car seat stickers
Always maintain at home: adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); Lys-free, Trp-reduced amino acid formula; medication required for maintenance & emergency treatment (carnitine, antipyretics).
Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers / pediatricians, & to teachers & school staff.
Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for GA-1 & containing contact information for the primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative management w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
Essential information including written treatment protocols should be provided in anticipation of the possible need for in-patient emergency treatment.
Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5°C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur.
Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for affected individuals deemed to be at high risk for perioperative complications.
Regular evaluations by a metabolic specialist and metabolic dietician are appropriate. See
Recommended Surveillance for Individuals with Glutaric Aciduria Type 1
1st year of life: at least every 3 mos
Ages 1-6 yrs: every 6 mos
>6 yrs of age: annually
ALT = alanine transaminase; AST = aspartate transaminase
Correlations between plasma lysine concentration and dietary lysine intake are often poor [
Physicians and specialist metabolic dieticians should be alert to changes in growth velocity, or development of new symptoms that may suggest specific micronutrient or amino acid deficiencies.
These studies are likely to be normal in an affected individual who is in good compliance with prescribed diet and treatment [
Chronic renal insufficiency may be more common than previously appreciated in adults with GA-1 [
Rapid evolution of macrocephaly may suggest development of subdural fluid collections or hemorrhages, and should be imaged appropriately.
Head imaging may have utility in tracking the progression of subependymal mass lesions in individuals with late-onset GA-1 [
Note:
Because C5DC acylcarnitine values are likely to reflect carnitine concentrations in plasma and not dietary lysine intake, they have no role in biochemical surveillance or ongoing care of persons with GA-1 [
Because urinary or plasma concentrations of GA or 3-OH-GA do not correlate with clinical parameters or outcomes [
Avoid the following:
Excessive dietary protein or protein malnutrition inducing catabolic state
Prolonged fasting
Catabolic illness (intercurrent infection; brief febrile illness post-vaccination)
Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
Although there are no data on which to base such a recommendation, given the increased risk of subdural hemorrhage in individuals with GA-1, avoidance or extreme caution with contact sports and physical activities that involve high risk for minor head injuries would appear to be a sensible precaution.
Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment. For at-risk newborn sibs when prenatal testing was not performed: in parallel with NBS, either test for the familial
See
Although there are no formal published recommendations for dietary or medical management for pregnant women with GA-1, it is recommended that care be provided by a multidisciplinary team including the treating obstetrician, a metabolic physician, and a specialist metabolic dietician. Because the perinatal period is a time of high catabolic stress for women with GA-1, most metabolic physicians would agree that emergency management and close observation are required; however, evidence and/or sufficient clinical data regarding efficacy or necessity of emergency treatment for GA-1 during the peripartum period are not available. Uneventful clinical courses for affected mothers (and their babies) has been reported for women receiving emergency treatment during the peripartum period [
While to date no specific guidelines are available for surgical procedures and other perinatal stressors, usual perioperative/perianesthetic precautions are likely to be clinically relevant (see
Search
• Transfer to specialist center w/experience in management of inherited metabolic diseases is strongly recommended.
• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises) for caregivers.
• Low-lysine diet
• Carnitine supplementation
• Emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts
• Low-Lys diet
• Direct calculation of Lys intake (vs total natural protein intake) is more precise & reduces long-term day-to-day variability of Lys intake.
• Lys-free, Trp-reduced amino acid formulas
• Age 0-6 mos: ~100 mg/kg/day
• Age 6-12 mos: ~90 mg/kg/day) (See
• Breastfeeding should be encouraged.
• Lys content in breast milk is ~86 mg/100 mL.
• Daily Lys intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable.
• Controlled protein intake of natural protein w/low Lys content & avoidance of Lys-rich foods advised even after age 6 yrs (See
• Diet should follow an age-adapted, protein-controlled protocol w/no requirement for Lys-free, Trp-restricted formula, but w/avoidance or very careful apportioning of Lys-rich natural protein food sources.
• Depletion may cause severe neurologic deficits.
• Quantification of Trp in plasma is technically challenging.
• Initial oral dosage of 100 mg L-carnitine/kg per day divided into 3-4 doses is typical.
• Dose is adjusted on an individual basis to maintain plasma free L-carnitine concentration w/in normal age-appropriate reference range.
• Lifelong carnitine supplementation is generally recommended.
• L-carnitine supplementation is considered to contribute to ↓ risk for striatal injury in persons diagnosed early
• Physical therapy
• Aggressive rehabilitation therapy
• Carbohydrate supplementation orally or via tube feed
• ↓ natural protein intake
• ↑ carnitine supplementation
• Trial of outpatient treatment at home for ≤12 hrs
• Reassessment (every ~2 hrs) for clinical changes
• Administer high-energy fluids &, if needed, insulin.
• Intravenous lipid emulsion
• ↓ or omit natural protein for 24 hrs.
• ↑ L-carnitine supplementation.
• Address electrolytes & pH imbalances w/intravenous fluid mgmt.
• Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine profiling, & urine pH/ketone screening may all be useful in guiding mgmt.
• Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
• Inadequate or delayed start of emergency treatment → high risk of striatal injury, dystonia, & consequent long-term disability.
• No evidence supports use of arginine therapy during acute illness.
• In children >6 yrs, adolescents, & adults: consider emergency treatment adapted from protocols for younger children during periods of severe illness or prolonged fasting, though risks of encephalopathic illness & striatal injury are probably ↓ in these age groups.
• Initiate the treatment listed above for ↑ catabolism.
• Neurologic consultation, ASM if needed
• MRI of the brain
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with GA-1 together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• In puberty and early adulthood, deficits in adherence to treatment may occur due to deteriorating compliance or other unknown factors, resulting in negative impact on outcomes [
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
• Intense & ongoing education of affected individuals & caregivers about worrisome symptoms, natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while on vacation
• Medical alert bracelets/pendants or car seat stickers
• Always maintain at home: adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); Lys-free, Trp-reduced amino acid formula; medication required for maintenance & emergency treatment (carnitine, antipyretics).
• Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers / pediatricians, & to teachers & school staff.
• Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for GA-1 & containing contact information for the primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative management w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
• 1st year of life: at least every 3 mos
• Ages 1-6 yrs: every 6 mos
• >6 yrs of age: annually
• Because C5DC acylcarnitine values are likely to reflect carnitine concentrations in plasma and not dietary lysine intake, they have no role in biochemical surveillance or ongoing care of persons with GA-1 [
• Because urinary or plasma concentrations of GA or 3-OH-GA do not correlate with clinical parameters or outcomes [
• Excessive dietary protein or protein malnutrition inducing catabolic state
• Prolonged fasting
• Catabolic illness (intercurrent infection; brief febrile illness post-vaccination)
• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual following diagnosis of GA-1, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of GA-1
Transfer to specialist center w/experience in management of inherited metabolic diseases is strongly recommended.
Consider short hospitalization at center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises) for caregivers.
OT = occupational therapist; PT = physical therapist
After a new diagnosis of GA-1 in a child, the closest hospital and local pediatrician should also be informed.
• Transfer to specialist center w/experience in management of inherited metabolic diseases is strongly recommended.
• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises) for caregivers.
## Treatment of Manifestations
All children with GA-1 and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing diet in GA-1. German (D)-Austrian (A)-Swiss (CH) (DACH) recommendations have been used in several clinical trials and have resulted in positive outcomes [
The main principles of treatment are to reduce lysine oxidation and enhance physiologic detoxification of glutaryl-CoA. Combined metabolic therapy includes the following [
Low-lysine diet
Carnitine supplementation
Emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts
Routine Daily Treatment in Individuals with Glutaric Aciduria Type 1
Low-Lys diet
Direct calculation of Lys intake (vs total natural protein intake) is more precise & reduces long-term day-to-day variability of Lys intake.
Lys-free, Trp-reduced amino acid formulas
Age 0-6 mos: ~100 mg/kg/day
Age 6-12 mos: ~90 mg/kg/day) (See
Breastfeeding should be encouraged.
Lys content in breast milk is ~86 mg/100 mL.
Daily Lys intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable.
Controlled protein intake of natural protein w/low Lys content & avoidance of Lys-rich foods advised even after age 6 yrs (See
Diet should follow an age-adapted, protein-controlled protocol w/no requirement for Lys-free, Trp-restricted formula, but w/avoidance or very careful apportioning of Lys-rich natural protein food sources.
Formulas should be Trp-reduced but not completely deficient in Trp.
Depletion may cause severe neurologic deficits.
Quantification of Trp in plasma is technically challenging.
Initial oral dosage of 100 mg L-carnitine/kg per day divided into 3-4 doses is typical.
Dose is adjusted on an individual basis to maintain plasma free L-carnitine concentration w/in normal age-appropriate reference range.
Lifelong carnitine supplementation is generally recommended.
L-carnitine supplementation is considered to contribute to ↓ risk for striatal injury in persons diagnosed early
Physical therapy
Aggressive rehabilitation therapy
EAA = essential amino acid; Lys = lysine; Trp = tryptophan
The Lys content in natural protein sources in food varies considerably – e.g., 2%-4% (lysine/protein) in cereals and 9% (lysine/protein) in fish.
High-lysine foods include poultry, fish, shrimp, shellfish, pork, beef, soy, nuts, seeds, eggs, beans, and lentils.
Consensus recommendations at present state that there is currently insufficient evidence to support routine high-dose arginine (Arg) supplementation orally in addition to (or as a substitute for) the use of a Lys-free, Trp-reduced, Arg-containing amino acid formula as an adjunct to a prescribed daily quantity of natural protein.
Data are extremely limited on optimal Lys intake and protein/calorie requirements in premature infants [Goodman & Baker, personal communication].
Older children need proportionately less Lys per unit body weight than infants due to decelerating nutritional requirements and growth velocities.
Long-term outcome in individuals with GA-1 in this age group as a function of dietary management has not been well characterized.
Tryptophan content in natural protein is only 0.6%-2%, depending on source.
Foods rich in Trp include poultry, fish, legumes, and dairy products.
Dose reduction may be necessary due to adverse effects, such as diarrhea and a fishy body odor, which can be socially stigmatizing.
Such demands may stem from movement disorders (dystonia, orofacial dyskinesia).
Notes: (1) Riboflavin supplementation is not recommended currently as standard therapy for GA-1 [
Nutritional Requirements for L-lysine, L-Carnitine, Calories, and Natural Protein for Infants and Children with GA-1
Adapted from
If normal growth and development are not achieved, these recommendations should be modified according to individual need.
Lysine content in natural sources of protein varies significantly; thus, natural protein requirements will vary considerably according to the natural protein source used (e.g., higher natural protein intake will be required if sources have a very low lysine content). High-lysine foods include poultry, fish, shrimp, shellfish, pork, beef, soy, nuts, seeds, eggs, beans, and lentils.
Lys-free, Trp-reduced amino acid formulas specifically produced for individuals with GA1 should be supplemented with minerals and micronutrients as needed to maintain normal levels. Adequate intake of essential amino acids is provided from natural protein and Lys-free, Trp-reduced amino acid formula.
If an affected individual is clinically well despite an intercurrent infectious illness or febrile reaction to vaccinations, emergency outpatient management may be considered (see
Emergency Outpatient Treatment in Individuals with Glutaric Aciduria Type 1
Carbohydrate supplementation orally or via tube feed
↓ natural protein intake
↑ carnitine supplementation
Trial of outpatient treatment at home for ≤12 hrs
Reassessment (every ~2 hrs) for clinical changes
Administration of antipyretics (acetaminophen, ibuprofen) if temperature rises >38.5°C
Antiemetics
Fever <38.5 °C (101 °F); enteral or gastrostomy tube feeding is tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability, hypotonia, dystonia)
Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting; some centers recommend frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment.
Some centers advocate additional steps such as reducing natural protein intake to zero or to 50% of the normal prescribed regimen for short periods (<24 hours) in the outpatient setting during intercurrent illness.
Temporarily increasing L-carnitine doses (e.g., to 200 mg/kg/day in infants) is recommended [
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma), often occurring in the setting of intercurrent illness and/or inadequate caloric intake, should be managed symptomatically and with generous caloric support in a hospital setting, with aggressive treatment and supportive care of any identified or clinically suspected acute conditions (see
Acute In-Patient Treatment in Individuals with Glutaric Aciduria Type 1
Administer high-energy fluids &, if needed, insulin.
Intravenous lipid emulsion
↓ or omit natural protein for 24 hrs.
↑ L-carnitine supplementation.
Address electrolytes & pH imbalances w/intravenous fluid mgmt.
Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine profiling, & urine pH/ketone screening may all be useful in guiding mgmt.
Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
Inadequate or delayed start of emergency treatment → high risk of striatal injury, dystonia, & consequent long-term disability.
No evidence supports use of arginine therapy during acute illness.
In children >6 yrs, adolescents, & adults: consider emergency treatment adapted from protocols for younger children during periods of severe illness or prolonged fasting, though risks of encephalopathic illness & striatal injury are probably ↓ in these age groups.
Initiate the treatment listed above for ↑ catabolism.
Neurologic consultation, ASM if needed
MRI of the brain
In-patient emergency treatment should: (1) take place at the closest medical facility, (2) be started without delay, and (3) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.
ASM = anti-seizure medication; CK = creatine kinase; IV = intravenous
Intravenous glucose solutions should provide 12-15 g/kg/day glucose for infants and 10-12 g/kg/day for children 12 months - 6 years.
Use of insulin if hyperglycemia emerges; intravenous insulin given at a starting dose of 0.025 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma, or glucosuria).
Natural protein can be gradually reintroduced, with continuation of enteral Lys-free, Trp-reduced GA-1-specific amino acid formula as tolerated.
L-carnitine (with options to increase the dose) can be given intravenously, which enhances bioavailability.
To date only case reports on emergency treatment in adolescents and adults have been published [
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with GA-1 together with pediatric metabolic experts, dietitians, psychologists, and social workers.
In puberty and early adulthood, deficits in adherence to treatment may occur due to deteriorating compliance or other unknown factors, resulting in negative impact on outcomes [
As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
• Low-lysine diet
• Carnitine supplementation
• Emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts
• Low-Lys diet
• Direct calculation of Lys intake (vs total natural protein intake) is more precise & reduces long-term day-to-day variability of Lys intake.
• Lys-free, Trp-reduced amino acid formulas
• Age 0-6 mos: ~100 mg/kg/day
• Age 6-12 mos: ~90 mg/kg/day) (See
• Breastfeeding should be encouraged.
• Lys content in breast milk is ~86 mg/100 mL.
• Daily Lys intake can be calculated when breast milk is the only natural protein source & breast milk intake is calculated & stable.
• Controlled protein intake of natural protein w/low Lys content & avoidance of Lys-rich foods advised even after age 6 yrs (See
• Diet should follow an age-adapted, protein-controlled protocol w/no requirement for Lys-free, Trp-restricted formula, but w/avoidance or very careful apportioning of Lys-rich natural protein food sources.
• Depletion may cause severe neurologic deficits.
• Quantification of Trp in plasma is technically challenging.
• Initial oral dosage of 100 mg L-carnitine/kg per day divided into 3-4 doses is typical.
• Dose is adjusted on an individual basis to maintain plasma free L-carnitine concentration w/in normal age-appropriate reference range.
• Lifelong carnitine supplementation is generally recommended.
• L-carnitine supplementation is considered to contribute to ↓ risk for striatal injury in persons diagnosed early
• Physical therapy
• Aggressive rehabilitation therapy
• Carbohydrate supplementation orally or via tube feed
• ↓ natural protein intake
• ↑ carnitine supplementation
• Trial of outpatient treatment at home for ≤12 hrs
• Reassessment (every ~2 hrs) for clinical changes
• Administer high-energy fluids &, if needed, insulin.
• Intravenous lipid emulsion
• ↓ or omit natural protein for 24 hrs.
• ↑ L-carnitine supplementation.
• Address electrolytes & pH imbalances w/intravenous fluid mgmt.
• Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine profiling, & urine pH/ketone screening may all be useful in guiding mgmt.
• Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
• Inadequate or delayed start of emergency treatment → high risk of striatal injury, dystonia, & consequent long-term disability.
• No evidence supports use of arginine therapy during acute illness.
• In children >6 yrs, adolescents, & adults: consider emergency treatment adapted from protocols for younger children during periods of severe illness or prolonged fasting, though risks of encephalopathic illness & striatal injury are probably ↓ in these age groups.
• Initiate the treatment listed above for ↑ catabolism.
• Neurologic consultation, ASM if needed
• MRI of the brain
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with GA-1 together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• In puberty and early adulthood, deficits in adherence to treatment may occur due to deteriorating compliance or other unknown factors, resulting in negative impact on outcomes [
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.
## Prevention of Primary Manifestations
Dietary restriction of lysine intake remains the cornerstone of GA-1 treatment. Although management of any given affected individual is nuanced and managed on a case-by-case basis, minor illnesses, where caloric needs are increased or provision of adequate calories is compromised, should be observed closely and promptly treated with a low threshold for hospital admission (see
## Prevention of Secondary Complications
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also
Prevention of Secondary Manifestations in Individuals with Glutaric Aciduria Type 1
Intense & ongoing education of affected individuals & caregivers about worrisome symptoms, natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while on vacation
Medical alert bracelets/pendants or car seat stickers
Always maintain at home: adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); Lys-free, Trp-reduced amino acid formula; medication required for maintenance & emergency treatment (carnitine, antipyretics).
Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers / pediatricians, & to teachers & school staff.
Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for GA-1 & containing contact information for the primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative management w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
Essential information including written treatment protocols should be provided in anticipation of the possible need for in-patient emergency treatment.
Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5°C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur.
Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for affected individuals deemed to be at high risk for perioperative complications.
• Intense & ongoing education of affected individuals & caregivers about worrisome symptoms, natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while on vacation
• Medical alert bracelets/pendants or car seat stickers
• Always maintain at home: adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources); Lys-free, Trp-reduced amino acid formula; medication required for maintenance & emergency treatment (carnitine, antipyretics).
• Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers / pediatricians, & to teachers & school staff.
• Emergency letters/cards should be provided summarizing key information & principles of emergency treatment for GA-1 & containing contact information for the primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near the destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative management w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional management).
## Surveillance
Regular evaluations by a metabolic specialist and metabolic dietician are appropriate. See
Recommended Surveillance for Individuals with Glutaric Aciduria Type 1
1st year of life: at least every 3 mos
Ages 1-6 yrs: every 6 mos
>6 yrs of age: annually
ALT = alanine transaminase; AST = aspartate transaminase
Correlations between plasma lysine concentration and dietary lysine intake are often poor [
Physicians and specialist metabolic dieticians should be alert to changes in growth velocity, or development of new symptoms that may suggest specific micronutrient or amino acid deficiencies.
These studies are likely to be normal in an affected individual who is in good compliance with prescribed diet and treatment [
Chronic renal insufficiency may be more common than previously appreciated in adults with GA-1 [
Rapid evolution of macrocephaly may suggest development of subdural fluid collections or hemorrhages, and should be imaged appropriately.
Head imaging may have utility in tracking the progression of subependymal mass lesions in individuals with late-onset GA-1 [
Note:
Because C5DC acylcarnitine values are likely to reflect carnitine concentrations in plasma and not dietary lysine intake, they have no role in biochemical surveillance or ongoing care of persons with GA-1 [
Because urinary or plasma concentrations of GA or 3-OH-GA do not correlate with clinical parameters or outcomes [
• 1st year of life: at least every 3 mos
• Ages 1-6 yrs: every 6 mos
• >6 yrs of age: annually
• Because C5DC acylcarnitine values are likely to reflect carnitine concentrations in plasma and not dietary lysine intake, they have no role in biochemical surveillance or ongoing care of persons with GA-1 [
• Because urinary or plasma concentrations of GA or 3-OH-GA do not correlate with clinical parameters or outcomes [
## Agents/Circumstances to Avoid
Avoid the following:
Excessive dietary protein or protein malnutrition inducing catabolic state
Prolonged fasting
Catabolic illness (intercurrent infection; brief febrile illness post-vaccination)
Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
Although there are no data on which to base such a recommendation, given the increased risk of subdural hemorrhage in individuals with GA-1, avoidance or extreme caution with contact sports and physical activities that involve high risk for minor head injuries would appear to be a sensible precaution.
• Excessive dietary protein or protein malnutrition inducing catabolic state
• Prolonged fasting
• Catabolic illness (intercurrent infection; brief febrile illness post-vaccination)
• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)
## Evaluation of Relatives at Risk
Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment. For at-risk newborn sibs when prenatal testing was not performed: in parallel with NBS, either test for the familial
See
## Pregnancy Management
Although there are no formal published recommendations for dietary or medical management for pregnant women with GA-1, it is recommended that care be provided by a multidisciplinary team including the treating obstetrician, a metabolic physician, and a specialist metabolic dietician. Because the perinatal period is a time of high catabolic stress for women with GA-1, most metabolic physicians would agree that emergency management and close observation are required; however, evidence and/or sufficient clinical data regarding efficacy or necessity of emergency treatment for GA-1 during the peripartum period are not available. Uneventful clinical courses for affected mothers (and their babies) has been reported for women receiving emergency treatment during the peripartum period [
While to date no specific guidelines are available for surgical procedures and other perinatal stressors, usual perioperative/perianesthetic precautions are likely to be clinically relevant (see
## Therapies Under Investigation
Search
## Genetic Counseling
Glutaric acidemia type 1 (GA-1) is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical features of the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: Phenotype of GA-1 can vary widely among untreated family members who have the same genotype.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the clinical features of the disorder.
Carrier testing for at-risk relatives requires prior identification of the
Carriers are asymptomatic and are not at risk of developing clinical features of the disorder.
Quantification of glutaryl-CoA dehydrogenase enzyme activity in fibroblasts or leukocytes is not useful in determining carrier status.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical features of the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: Phenotype of GA-1 can vary widely among untreated family members who have the same genotype.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the clinical features of the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Glutaric acidemia type 1 (GA-1) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical features of the disorder.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical features of the disorder.
## Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: Phenotype of GA-1 can vary widely among untreated family members who have the same genotype.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the clinical features of the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: Phenotype of GA-1 can vary widely among untreated family members who have the same genotype.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the clinical features of the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
Carriers are asymptomatic and are not at risk of developing clinical features of the disorder.
Quantification of glutaryl-CoA dehydrogenase enzyme activity in fibroblasts or leukocytes is not useful in determining carrier status.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
TEMPLE (Tools Enabling Metabolic Parents LEarning)
United Kingdom
Health Resources & Services Administration
•
• TEMPLE (Tools Enabling Metabolic Parents LEarning)
• United Kingdom
•
•
•
•
• Health Resources & Services Administration
•
•
•
•
•
## Molecular Genetics
Glutaric Acidemia Type I: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Glutaric Acidemia Type I (
Glutaryl-CoA dehydrogenase (GCDH) plays an integral role in degradative metabolism of L-lysine, L-hydroxylysine, and L-tryptophan [
Accumulation of glutaric acid and 3-OH-glutaric acid causes neurotoxicity (especially striatal injury).
Of note, c.91+5G>T (the Ojibway-Cree First Nation founder variant) as well as p.Arg227Pro, p.Val400Met, and p.Met405Val are associated with a low-excreter phenotype and may be more difficult to detect conclusively with biochemical testing (and on NBS utilizing C5DC acylcarnitine). Homozygous p.Arg227Pro and p.Val400Met are both associated with 8%-10% residual enzyme activity [
The c.553_570del18 (p.Gly185_Ser190del) deletion, a suspected dominant-negative allele, is associated with enzyme activity much lower than 50% [
Notable
Low-excreter; 8%-10% residual activity [
A
Low-excreter [
A
Variants listed in the table have been provided by the authors.
GPC = genotype-phenotype correlation
Glutaric acid probably derives from hydrolysis of the accumulated enzyme substrate (glutaryl-CoA), but the origin of 3-hydroxyglutaric acid remains unknown. These putative toxins do not cross the blood-brain barrier and thus are probably synthesized within the brain from accumulated glutaryl-CoA, but the reasons why one or both of them preferentially affect the striatum and why there is a period of heightened striatal vulnerability in infancy and early childhood remain a mystery.
• Low-excreter; 8%-10% residual activity [
• A
• Low-excreter [
• A
## Molecular Pathogenesis
Glutaryl-CoA dehydrogenase (GCDH) plays an integral role in degradative metabolism of L-lysine, L-hydroxylysine, and L-tryptophan [
Accumulation of glutaric acid and 3-OH-glutaric acid causes neurotoxicity (especially striatal injury).
Of note, c.91+5G>T (the Ojibway-Cree First Nation founder variant) as well as p.Arg227Pro, p.Val400Met, and p.Met405Val are associated with a low-excreter phenotype and may be more difficult to detect conclusively with biochemical testing (and on NBS utilizing C5DC acylcarnitine). Homozygous p.Arg227Pro and p.Val400Met are both associated with 8%-10% residual enzyme activity [
The c.553_570del18 (p.Gly185_Ser190del) deletion, a suspected dominant-negative allele, is associated with enzyme activity much lower than 50% [
Notable
Low-excreter; 8%-10% residual activity [
A
Low-excreter [
A
Variants listed in the table have been provided by the authors.
GPC = genotype-phenotype correlation
Glutaric acid probably derives from hydrolysis of the accumulated enzyme substrate (glutaryl-CoA), but the origin of 3-hydroxyglutaric acid remains unknown. These putative toxins do not cross the blood-brain barrier and thus are probably synthesized within the brain from accumulated glutaryl-CoA, but the reasons why one or both of them preferentially affect the striatum and why there is a period of heightened striatal vulnerability in infancy and early childhood remain a mystery.
• Low-excreter; 8%-10% residual activity [
• A
• Low-excreter [
• A
## Chapter Notes
Austin Larson, MD (2019-present)Steve Goodman, MD, FACMG (2019-present)James Weisfeld-Adams, MB ChB, FAAP, FACMG (See
Dr James Weisfeld-Adams contributed extensively to the early drafts of this
19 September 2019 (bp) Review posted live
16 October 2017 (jwa/al) Original submission
• 19 September 2019 (bp) Review posted live
• 16 October 2017 (jwa/al) Original submission
## Author History
Austin Larson, MD (2019-present)Steve Goodman, MD, FACMG (2019-present)James Weisfeld-Adams, MB ChB, FAAP, FACMG (See
## Author Notes
Dr James Weisfeld-Adams contributed extensively to the early drafts of this
## Revision History
19 September 2019 (bp) Review posted live
16 October 2017 (jwa/al) Original submission
• 19 September 2019 (bp) Review posted live
• 16 October 2017 (jwa/al) Original submission
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"CS Lee, YH Chien, SF Peng, PW Cheng, LM Chang, AC Huang, WL Hwu, NC Lee. Promising outcomes in glutaric aciduria type I patients detected by newborn screening.. Metab Brain Dis 2013;28:61-7",
"M Lindner, S Kölker, A Schulze, E Christensen, CR Greenberg, GF Hoffmann. Neonatal screening for glutaryl-CoA dehydrogenase deficiency.. J Inherit Metab Dis 2004;27:851-9",
"XM Liu, R Li, SZ Chen, Y Sang, J Chen, CH Fan. Screening of inherited metabolic disorders in infants with infantile spasms.. Cell Biochem Biophys. 2015;72:61-5",
"E López-Laso, J García-Villoria, E Martín, P Duque, A Cano, A Ribes. Classic and late-onset neurological disease in two siblings with glutaryl-CoA dehydrogenase deficiency.. J Inherit Metab Dis. 2007;30:979",
"JF Marti-Masso, J Ruiz-Martínez, V Makarov, A López de Munain, A Gorostidi, A Bergareche, S Yoon, JD Buxbaum, C Paisán-Ruiz. Exome sequencing identifies GCDH (glutaryl-CoA dehydrogenase) mutations as a cause of a progressive form of early-onset generalized dystonia.. Hum Genet. 2012;131:435-42",
"VM McClelland, DB Bakalinova, C Hendriksz, RP Singh. Glutaric aciduria type1 presenting with epilepsy.. Dev Med Child Neurol 2009;51:235-9",
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"E Müller, S Kölker. Reduction of lysine intake while avoiding malnutrition–major goals and major problems in dietary treatment of glutaryl-CoA dehydrogenase deficiency.. J Inherit Metab Dis. 2004;27:903-10",
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"LA Schillaci, CL Greene, E Strovel, J Rispoli-Joines, E Spector, M Woontner, G Scharer, GM Enns, R Gallagher, AB Zinn, SE McCandless, CL Hoppel, SI Goodman, JK Bedoyan. The M405V allele of the glutaryl-CoA dehydrogenase gene is an important marker for glutaric aciduria type I (GA-I) low excreters.. Mol Genet Metab 2016;119:50-6",
"J Schmiesing, B Lohmöller, M Schweizer, H Tidow, SW Gersting, AC Muntau, T Braulke, C Mühlhausen. Disease causing mutations affecting surface residues of mitochondrial glutaryl-CoA dehydrogenase impair stability, heteromeric complex formation and mitochondria architecture.. Hum Mol Genet. 2017;26:538-51",
"M Schwartz, E Christensen, A Superti-Furga, NJ Brandt. The human glutaryl-CoA dehydrogenase gene: report of intronic sequences and of 13 novel mutations causing glutaric aciduria type I.. Hum Genet. 1998;102:452-8",
"A Serrano Russi, S Donoghue, A Boneh, R Manara, AB Burlina, AP Burlina. Malignant brain tumors in patients with glutaric aciduria type I.. Mol Genet Metab. 2018;125:276-80",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"PD Stenson, M Mort, EV Ball, K Shaw, AD Phillips, DN Cooper. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine.. Hum Genet. 2014;133:1-9",
"KA Strauss, J Brumbaugh, A Duffy, B Wardley, D Robinson, C Hendrickson, S Tortorelli, AB Moser, EG Puffenberger, NL Rider, DH Morton. Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency: focus on cerebral amino acid influx.. Mol Genet Metab 2011;104:93-106",
"KA Strauss, J Lazovic, M Wintermark, DH Morton. Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency.. Brain. 2007;130:1905-20",
"KV Tp, S Muntaj, KS Devaraju, M Kamate, AB Vedamurthy. Genetic screening of selected disease-causing mutations in glutaryl-CoA dehydrogenase gene among Indian patients with glutaric aciduria yype I.. J Pediatr Genet 2017;6:142-8",
"FC Tsai, HJ Lee, AG Wang, SC Hsieh, YH Lu, MC Lee, JS Pai, TH Chu, CF Yang, TR Hsu, CJ Lai, MT Tsai, PH Ho, MC Lin, LY Cheng, YC Chuang, DM Niu. Experiences during newborn screening for glutaric aciduria type 1: diagnosis, treatment, genotype, phenotype, and outcomes.. J Chin Med Assoc 2017;80:253-61",
"G van der Watt, EP Owen, P Berman, S Meldau, N Watermeyer, SE Olpin, NJ Manning, I Baumgarten, F Leisegang, H Henderson. Glutaric aciduria type 1 in South Africa-high incidence of glutaryl-CoA dehydrogenase deficiency in black South Africans.. Mol Genet Metab 2010;101:178-82",
"ME Vester, RA Bilo, WA Karst, JG Daams, WL Duijst, RR van Rijn. Subdural hematomas: glutaric aciduria type 1 or abusive head trauma? A systematic review.. Forensic Sci Med Pathol 2015;11:405-15",
"ME Vester, G Visser, F Wijburg, FJ van Spronsen, M Williams, RR van Rijn. Occurrence of subdural hematomas in Dutch glutaric aciduria type 1 patients.. Eur J Pediatr 2016;175:1001-6",
"K Viau, SL Ernst, RJ Vanzo, LD Botto, M Pasquali, N Longo. Glutaric acidemia type 1: outcomes before and after expanded newborn screening.. Mol Genet Metab 2012;106:430-8",
"Q Wang, X Li, Y Ding, Y Liu, J Song, Y Yang. Clinical and mutational spectra of 23 Chinese patients with glutaric aciduria type 1.. Brain Dev 2014;36:813-22",
"AR Watson. Non-complicance and transfer from paediatric to adult transplant unit.. Pediatr Nephrol. 2000;14:469-72",
"S Yannicelli, F Rohr, ML Warman. Nutrition support for glutaric acidemia type I.. J Am Diet Assoc. 1994;94:183-8,191",
"N Young-Lin, S Shalev, OA Glenn, M Gardner, C Lee, A Wynshaw-Boris, AA Gelfand. Teaching neuroimages: infant with glutaric aciduria type 1 presenting with infantile spasms and hypsarrhythmia.. Neurology 2013;81:e182-3",
"X Zhang, Q Luo. Clinical and laboratory analysis of late-onset glutaric aciduria type I (GA-I) in Uighur: a report of two cases.. Exp Ther Med 2017;13:560-6",
"M Zielonka, K Braun, A Bengel, A Seitz, S Kölker, N Boy. Severe acute subdural hemorrhage in a patient with glutaric aciduria type I after minor head trauma: a case report.. J Child Neurol 2015;30:1065-9",
"J Zschocke, E Quak, P Guldberg, GF Hoffmann. Mutation analysis in glutaric aciduria type I.. J Med Genet. 2000;37:177-81"
] |
19/9/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
glyt1-dis
|
glyt1-dis
|
[
"Sodium- and chloride-dependent glycine transporter 1",
"SLC6A9",
"GLYT1 Encephalopathy"
] |
GLYT1 Encephalopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Alina Kurolap, Tova Hershkovitz, Hagit N Baris
|
Summary GLYT1 encephalopathy is characterized in neonates by severe hypotonia, respiratory failure requiring mechanical ventilation, and absent neonatal reflexes; encephalopathy, including impaired consciousness and unresponsiveness, may be present. Arthrogryposis or joint laxity can be observed. Generalized hypotonia develops later into axial hypotonia with limb hypertonicity and a startle-like response to vocal and visual stimuli which should not be confused with seizures. To date, three of the six affected children reported from three families died between ages two days and seven months; the oldest reported living child is severely globally impaired at age three years. Because of the limited number of affected individuals reported to date, the phenotype has not yet been completely described. The diagnosis of GLYT1 encephalopathy is established in a proband with mildly elevated cerebrospinal fluid glycine levels, normal or slightly elevated serum or plasma glycine levels, and biallelic pathogenic variants in Developmental status Respiratory function Neurologic status Musculoskeletal involvement Nutritional status and feeding Monitor as needed: blood pressure, renal function, vision, hearing. GLYT1 encephalopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the
|
## Diagnosis
GLYT1 encephalopathy
Early respiratory insufficiency
Hypotonia later transitioning to hypertonicity of the extremities
Startle response provoked by sudden loud sounds and tactile stimulation (which may be confused with myoclonic seizures)
Encephalopathy (present in some)
Arthrogryposis multiplex congenita or joint laxity
Dysmorphic features that may include trigonocephaly or dolichocephaly, low-set ears, long myopathic face, broad forehead, broad or sparse eyebrows, long eyelashes, esotropia, ptosis, depressed nasal bridge, short nose, upturned nasal tip, prominent philtrum, tented vermilion of the upper lip, and retrognathia (
Microcephaly and failure to thrive
Cerebrospinal fluid (CSF) glycine levels*: mildly elevated (21-33 µmol/L) (normal 3.8-8 µmol/L) [
Blood (serum or plasma) glycine levels*: normal. Note: Normal values vary by age.
Glycine CSF-to-plasma ratio: abnormal (>0.04)
* Amino acid concentrations should be measured simultaneously in CSF and blood.
The diagnosis of GLYT1 encephalopathy
Molecular genetic testing approaches to be considered include
For an introduction to multigene panels click
Molecular Genetic Testing Used in GLYT1 Encephalopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Three families with GLYT1 encephalopathy have been described to date, all harboring pathogenic homozygous variants in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Early respiratory insufficiency
• Hypotonia later transitioning to hypertonicity of the extremities
• Startle response provoked by sudden loud sounds and tactile stimulation (which may be confused with myoclonic seizures)
• Encephalopathy (present in some)
• Arthrogryposis multiplex congenita or joint laxity
• Dysmorphic features that may include trigonocephaly or dolichocephaly, low-set ears, long myopathic face, broad forehead, broad or sparse eyebrows, long eyelashes, esotropia, ptosis, depressed nasal bridge, short nose, upturned nasal tip, prominent philtrum, tented vermilion of the upper lip, and retrognathia (
• Microcephaly and failure to thrive
• Cerebrospinal fluid (CSF) glycine levels*: mildly elevated (21-33 µmol/L) (normal 3.8-8 µmol/L) [
• Blood (serum or plasma) glycine levels*: normal. Note: Normal values vary by age.
• Glycine CSF-to-plasma ratio: abnormal (>0.04)
• For an introduction to multigene panels click
## Suggestive Findings
GLYT1 encephalopathy
Early respiratory insufficiency
Hypotonia later transitioning to hypertonicity of the extremities
Startle response provoked by sudden loud sounds and tactile stimulation (which may be confused with myoclonic seizures)
Encephalopathy (present in some)
Arthrogryposis multiplex congenita or joint laxity
Dysmorphic features that may include trigonocephaly or dolichocephaly, low-set ears, long myopathic face, broad forehead, broad or sparse eyebrows, long eyelashes, esotropia, ptosis, depressed nasal bridge, short nose, upturned nasal tip, prominent philtrum, tented vermilion of the upper lip, and retrognathia (
Microcephaly and failure to thrive
Cerebrospinal fluid (CSF) glycine levels*: mildly elevated (21-33 µmol/L) (normal 3.8-8 µmol/L) [
Blood (serum or plasma) glycine levels*: normal. Note: Normal values vary by age.
Glycine CSF-to-plasma ratio: abnormal (>0.04)
* Amino acid concentrations should be measured simultaneously in CSF and blood.
• Early respiratory insufficiency
• Hypotonia later transitioning to hypertonicity of the extremities
• Startle response provoked by sudden loud sounds and tactile stimulation (which may be confused with myoclonic seizures)
• Encephalopathy (present in some)
• Arthrogryposis multiplex congenita or joint laxity
• Dysmorphic features that may include trigonocephaly or dolichocephaly, low-set ears, long myopathic face, broad forehead, broad or sparse eyebrows, long eyelashes, esotropia, ptosis, depressed nasal bridge, short nose, upturned nasal tip, prominent philtrum, tented vermilion of the upper lip, and retrognathia (
• Microcephaly and failure to thrive
• Cerebrospinal fluid (CSF) glycine levels*: mildly elevated (21-33 µmol/L) (normal 3.8-8 µmol/L) [
• Blood (serum or plasma) glycine levels*: normal. Note: Normal values vary by age.
• Glycine CSF-to-plasma ratio: abnormal (>0.04)
## Establishing the Diagnosis
The diagnosis of GLYT1 encephalopathy
Molecular genetic testing approaches to be considered include
For an introduction to multigene panels click
Molecular Genetic Testing Used in GLYT1 Encephalopathy
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Three families with GLYT1 encephalopathy have been described to date, all harboring pathogenic homozygous variants in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
## Clinical Characteristics
GLYT1 encephalopathy is characterized in neonates by severe hypotonia, respiratory failure requiring mechanical ventilation, and absent neonatal reflexes; encephalopathy, including impaired consciousness and unresponsiveness, may be present. Arthrogryposis or joint laxity may be observed. Generalized hypotonia later develops into axial hypotonia with limb hypertonicity and a startle-like response provoked by vocal and visual stimuli as well as sudden loud sounds and tactile stimulation and not to be confused with seizures. To date, six affected individuals from three families have been reported [
Arthrogryposis multiplex congenita with club feet, hyperextension of knees, bilateral hip dislocation, contractures of the elbows, wrists, and hips, and overriding toes and fingers was described in children from two of the three families reported.
Absent patellae were observed in one child.
Joint laxity with bilateral club feet was documented in the third family.
All affected children showed startle-like clonus with a normal electroencephalogram (EEG). The startle-like response may resolve over time.
All had severe global developmental delay. Developmental information, available for one child at age three years, revealed that the child had not reached any motor or speech milestones.
Disease complications include feeding difficulties requiring insertion of a gastrostomy tube.
Brain imaging (CT or MRI) findings may include ventriculomegaly, optic nerve atrophy, thin or normal corpus callosum, atrophy in the caudate nucleus, and white matter abnormalities. In addition, MRI in a child age two years (proband of Family 1 [
Abnormal visual evoked potentials and brain stem evoked response audiometry as well as motor and sensory polyneuropathy were reported in one child [
Hypertension with elevated urinary catecholamines was described in one child.
Children from two families had hydronephrosis.
One child had atrial septal defect, cryptorchidism, and inguinal hernia.
Given the small number of individuals reported to date, no genotype-phenotype correlations can be drawn.
Collectively, neurologic disorders caused by disturbance of glycine metabolism and transport are termed
Disorders of glycine metabolism that are caused by deficient activity of the glycine cleavage enzyme system (GCS) are called nonketotic hyperglycinemia (NKH).
Classic NKH is caused by biallelic pathogenic variants in one of the two genes encoding components of the GCS (
Variant nonketotic hyperglycinemia (NKH) refers to a glycine encephalopathy phenotype with elevated glycine levels and deficient GCS enzyme activity, but no pathogenic variants observed in
Disorders of glycine transport include GLYT1 encephalopathy, the subject of this
GLYT1 encephalopathy is rare; to date, only three families have been described, all of Muslim Arab origin. Two families reside in Israel; one family resides in Saudi Arabia [
• Hypertension with elevated urinary catecholamines was described in one child.
• Children from two families had hydronephrosis.
• One child had atrial septal defect, cryptorchidism, and inguinal hernia.
• Disorders of glycine metabolism that are caused by deficient activity of the glycine cleavage enzyme system (GCS) are called nonketotic hyperglycinemia (NKH).
• Classic NKH is caused by biallelic pathogenic variants in one of the two genes encoding components of the GCS (
• Variant nonketotic hyperglycinemia (NKH) refers to a glycine encephalopathy phenotype with elevated glycine levels and deficient GCS enzyme activity, but no pathogenic variants observed in
• Classic NKH is caused by biallelic pathogenic variants in one of the two genes encoding components of the GCS (
• Variant nonketotic hyperglycinemia (NKH) refers to a glycine encephalopathy phenotype with elevated glycine levels and deficient GCS enzyme activity, but no pathogenic variants observed in
• Disorders of glycine transport include GLYT1 encephalopathy, the subject of this
• Classic NKH is caused by biallelic pathogenic variants in one of the two genes encoding components of the GCS (
• Variant nonketotic hyperglycinemia (NKH) refers to a glycine encephalopathy phenotype with elevated glycine levels and deficient GCS enzyme activity, but no pathogenic variants observed in
## Clinical Description
GLYT1 encephalopathy is characterized in neonates by severe hypotonia, respiratory failure requiring mechanical ventilation, and absent neonatal reflexes; encephalopathy, including impaired consciousness and unresponsiveness, may be present. Arthrogryposis or joint laxity may be observed. Generalized hypotonia later develops into axial hypotonia with limb hypertonicity and a startle-like response provoked by vocal and visual stimuli as well as sudden loud sounds and tactile stimulation and not to be confused with seizures. To date, six affected individuals from three families have been reported [
Arthrogryposis multiplex congenita with club feet, hyperextension of knees, bilateral hip dislocation, contractures of the elbows, wrists, and hips, and overriding toes and fingers was described in children from two of the three families reported.
Absent patellae were observed in one child.
Joint laxity with bilateral club feet was documented in the third family.
All affected children showed startle-like clonus with a normal electroencephalogram (EEG). The startle-like response may resolve over time.
All had severe global developmental delay. Developmental information, available for one child at age three years, revealed that the child had not reached any motor or speech milestones.
Disease complications include feeding difficulties requiring insertion of a gastrostomy tube.
Brain imaging (CT or MRI) findings may include ventriculomegaly, optic nerve atrophy, thin or normal corpus callosum, atrophy in the caudate nucleus, and white matter abnormalities. In addition, MRI in a child age two years (proband of Family 1 [
Abnormal visual evoked potentials and brain stem evoked response audiometry as well as motor and sensory polyneuropathy were reported in one child [
Hypertension with elevated urinary catecholamines was described in one child.
Children from two families had hydronephrosis.
One child had atrial septal defect, cryptorchidism, and inguinal hernia.
• Hypertension with elevated urinary catecholamines was described in one child.
• Children from two families had hydronephrosis.
• One child had atrial septal defect, cryptorchidism, and inguinal hernia.
## Genotype-Phenotype Correlations
Given the small number of individuals reported to date, no genotype-phenotype correlations can be drawn.
## Nomenclature
Collectively, neurologic disorders caused by disturbance of glycine metabolism and transport are termed
Disorders of glycine metabolism that are caused by deficient activity of the glycine cleavage enzyme system (GCS) are called nonketotic hyperglycinemia (NKH).
Classic NKH is caused by biallelic pathogenic variants in one of the two genes encoding components of the GCS (
Variant nonketotic hyperglycinemia (NKH) refers to a glycine encephalopathy phenotype with elevated glycine levels and deficient GCS enzyme activity, but no pathogenic variants observed in
Disorders of glycine transport include GLYT1 encephalopathy, the subject of this
• Disorders of glycine metabolism that are caused by deficient activity of the glycine cleavage enzyme system (GCS) are called nonketotic hyperglycinemia (NKH).
• Classic NKH is caused by biallelic pathogenic variants in one of the two genes encoding components of the GCS (
• Variant nonketotic hyperglycinemia (NKH) refers to a glycine encephalopathy phenotype with elevated glycine levels and deficient GCS enzyme activity, but no pathogenic variants observed in
• Classic NKH is caused by biallelic pathogenic variants in one of the two genes encoding components of the GCS (
• Variant nonketotic hyperglycinemia (NKH) refers to a glycine encephalopathy phenotype with elevated glycine levels and deficient GCS enzyme activity, but no pathogenic variants observed in
• Disorders of glycine transport include GLYT1 encephalopathy, the subject of this
• Classic NKH is caused by biallelic pathogenic variants in one of the two genes encoding components of the GCS (
• Variant nonketotic hyperglycinemia (NKH) refers to a glycine encephalopathy phenotype with elevated glycine levels and deficient GCS enzyme activity, but no pathogenic variants observed in
## Prevalence
GLYT1 encephalopathy is rare; to date, only three families have been described, all of Muslim Arab origin. Two families reside in Israel; one family resides in Saudi Arabia [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The following disorders with features overlapping with GLYT1 encephalopathy should be considered in the differential diagnosis.
The major differences between classic NKH and GLYT1 encephalopathy are:
In classic NKH, glycine concentration is usually high in both CSF and serum. Nevertheless, classic NKH can present with normal serum glycine. (Note that the glycine CSF-to-plasma ratio is abnormal [>0.04] in both disorders.)
Children with GLYT1 encephalopathy show a startle-like response with a normal EEG whereas those with classic NKH have seizures (with an abnormal EEG) requiring treatment with antiepileptic drugs.
Brain MRI in neonates and infants with classic NKH shows a pattern of diffusion restriction involving the corticospinal tracts in the posterior part of the internal capsule (PLIC), the brain stem and central tegmental tracts in the brain stem, and the white matter of the cerebellum. After age three months, this recedes in the brain stem and becomes more prominent between the subperirolandic cortex and the PLIC. Data are limited in GLYT1 encephalopathy: diffusion restriction brain MRI in one child showed a focal area of restriction diffusion in one cerebellar hemisphere (proband of Family 1 [
Although no effective treatment is available for either disorder, children with classic NKH may respond to sodium benzoate (which reduces serum glycine concentrations) and an NMDA receptor blocker (e.g., ketamine or dextromethorphan), whereas those with GLYT1 encephalopathy do not.
• In classic NKH, glycine concentration is usually high in both CSF and serum. Nevertheless, classic NKH can present with normal serum glycine. (Note that the glycine CSF-to-plasma ratio is abnormal [>0.04] in both disorders.)
• Children with GLYT1 encephalopathy show a startle-like response with a normal EEG whereas those with classic NKH have seizures (with an abnormal EEG) requiring treatment with antiepileptic drugs.
• Brain MRI in neonates and infants with classic NKH shows a pattern of diffusion restriction involving the corticospinal tracts in the posterior part of the internal capsule (PLIC), the brain stem and central tegmental tracts in the brain stem, and the white matter of the cerebellum. After age three months, this recedes in the brain stem and becomes more prominent between the subperirolandic cortex and the PLIC. Data are limited in GLYT1 encephalopathy: diffusion restriction brain MRI in one child showed a focal area of restriction diffusion in one cerebellar hemisphere (proband of Family 1 [
• Although no effective treatment is available for either disorder, children with classic NKH may respond to sodium benzoate (which reduces serum glycine concentrations) and an NMDA receptor blocker (e.g., ketamine or dextromethorphan), whereas those with GLYT1 encephalopathy do not.
## Management
To establish the extent of disease and needs in an individual diagnosed with GLYT1 encephalopathy, the following evaluations are recommended if they have not already been completed:
Metabolic evaluation including blood and CSF amino acid profile
Neurologic assessment including EEG to distinguish seizures from a startle response. Brain imaging and physiologic tests, such as visual evoked potentials, brain stem evoked response audiometry, and evaluation of motor and sensory nerves, may be performed to better understand the extent of the clinical involvement.
Consultation with a clinical geneticist and/or genetic counselor
To date, no treatment has been effective in mitigating the manifestations of GLYT1 encephalopathy.
The core management of GLYT1 encephalopathy is supportive care provided by a multidisciplinary team including specialists from clinical genetics, pediatric neurology and child development, pulmonology, orthopedics, physiotherapy, nutrition, and others depending on clinical findings (e.g., pediatric nephrology if hypertension is observed).
The management of GLYT1 encephalopathy includes the following:
Address global developmental delay.
While benzodiazepines or antiepileptic drugs are used to control the startle response in
Mechanical ventilation is indicated when first signs of respiratory failure appear. If successful weaning off ventilation is achieved, supplemental oxygen may be required.
Gastrostomy should be considered to assure adequate nutrition and to prevent microaspiration.
Physiotherapy should be considered to preserve range of motion and prevent contractures.
If hypertension is present, refer to pediatric nephrologist for appropriate treatment.
Note: Treatment with sodium benzoate and an NMDA receptor antagonist (e.g., ketamine or dextromethorphan), as customary in classic
The following should be routinely monitored:
Developmental status
Neurologic status
Respiratory function
Nutritional status and feeding
Musculoskeletal involvement
Sensory organ involvement (vision, hearing)
Monitor as needed:
Blood pressure
Renal function
Although no specific agents/circumstances are known to exacerbate disease manifestations, valproate – which is contraindicated in classic NKH – should be avoided as it increases the concentration of blood and CSF glycine [
See
Search
• Metabolic evaluation including blood and CSF amino acid profile
• Neurologic assessment including EEG to distinguish seizures from a startle response. Brain imaging and physiologic tests, such as visual evoked potentials, brain stem evoked response audiometry, and evaluation of motor and sensory nerves, may be performed to better understand the extent of the clinical involvement.
• Consultation with a clinical geneticist and/or genetic counselor
• Address global developmental delay.
• While benzodiazepines or antiepileptic drugs are used to control the startle response in
• Mechanical ventilation is indicated when first signs of respiratory failure appear. If successful weaning off ventilation is achieved, supplemental oxygen may be required.
• Gastrostomy should be considered to assure adequate nutrition and to prevent microaspiration.
• Physiotherapy should be considered to preserve range of motion and prevent contractures.
• If hypertension is present, refer to pediatric nephrologist for appropriate treatment.
• Developmental status
• Neurologic status
• Respiratory function
• Nutritional status and feeding
• Musculoskeletal involvement
• Sensory organ involvement (vision, hearing)
• Blood pressure
• Renal function
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with GLYT1 encephalopathy, the following evaluations are recommended if they have not already been completed:
Metabolic evaluation including blood and CSF amino acid profile
Neurologic assessment including EEG to distinguish seizures from a startle response. Brain imaging and physiologic tests, such as visual evoked potentials, brain stem evoked response audiometry, and evaluation of motor and sensory nerves, may be performed to better understand the extent of the clinical involvement.
Consultation with a clinical geneticist and/or genetic counselor
• Metabolic evaluation including blood and CSF amino acid profile
• Neurologic assessment including EEG to distinguish seizures from a startle response. Brain imaging and physiologic tests, such as visual evoked potentials, brain stem evoked response audiometry, and evaluation of motor and sensory nerves, may be performed to better understand the extent of the clinical involvement.
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
To date, no treatment has been effective in mitigating the manifestations of GLYT1 encephalopathy.
The core management of GLYT1 encephalopathy is supportive care provided by a multidisciplinary team including specialists from clinical genetics, pediatric neurology and child development, pulmonology, orthopedics, physiotherapy, nutrition, and others depending on clinical findings (e.g., pediatric nephrology if hypertension is observed).
The management of GLYT1 encephalopathy includes the following:
Address global developmental delay.
While benzodiazepines or antiepileptic drugs are used to control the startle response in
Mechanical ventilation is indicated when first signs of respiratory failure appear. If successful weaning off ventilation is achieved, supplemental oxygen may be required.
Gastrostomy should be considered to assure adequate nutrition and to prevent microaspiration.
Physiotherapy should be considered to preserve range of motion and prevent contractures.
If hypertension is present, refer to pediatric nephrologist for appropriate treatment.
Note: Treatment with sodium benzoate and an NMDA receptor antagonist (e.g., ketamine or dextromethorphan), as customary in classic
• Address global developmental delay.
• While benzodiazepines or antiepileptic drugs are used to control the startle response in
• Mechanical ventilation is indicated when first signs of respiratory failure appear. If successful weaning off ventilation is achieved, supplemental oxygen may be required.
• Gastrostomy should be considered to assure adequate nutrition and to prevent microaspiration.
• Physiotherapy should be considered to preserve range of motion and prevent contractures.
• If hypertension is present, refer to pediatric nephrologist for appropriate treatment.
## Surveillance
The following should be routinely monitored:
Developmental status
Neurologic status
Respiratory function
Nutritional status and feeding
Musculoskeletal involvement
Sensory organ involvement (vision, hearing)
Monitor as needed:
Blood pressure
Renal function
• Developmental status
• Neurologic status
• Respiratory function
• Nutritional status and feeding
• Musculoskeletal involvement
• Sensory organ involvement (vision, hearing)
• Blood pressure
• Renal function
## Agents/Circumstances to Avoid
Although no specific agents/circumstances are known to exacerbate disease manifestations, valproate – which is contraindicated in classic NKH – should be avoided as it increases the concentration of blood and CSF glycine [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
GLYT1 encephalopathy is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
GLYT1 encephalopathy is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
• United Kingdom
•
## Molecular Genetics
GLYT1 Encephalopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GLYT1 Encephalopathy (
GLYT1 encephalopathy is a glycinopathy caused by dysfunction of the sodium- and chloride-dependent glycine transporter 1 (also known as glial glycine transporter 1) (GLYT1) [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
GLYT1 encephalopathy is a glycinopathy caused by dysfunction of the sodium- and chloride-dependent glycine transporter 1 (also known as glial glycine transporter 1) (GLYT1) [
Variants listed in the table have been provided by the authors.
## Chapter Notes
26 June 2025 (ma) Chapter retired: extremely rare disorder
30 November 2017 (bp) Review posted live
15 June 2017 (hnb) Original submission
• 26 June 2025 (ma) Chapter retired: extremely rare disorder
• 30 November 2017 (bp) Review posted live
• 15 June 2017 (hnb) Original submission
## Revision History
26 June 2025 (ma) Chapter retired: extremely rare disorder
30 November 2017 (bp) Review posted live
15 June 2017 (hnb) Original submission
• 26 June 2025 (ma) Chapter retired: extremely rare disorder
• 30 November 2017 (bp) Review posted live
• 15 June 2017 (hnb) Original submission
## References
## Literature Cited
A girl age six months with GLYT1 encephalopathy. Note facial dysmorphism including trigonocephaly, long myopathic facies, broad forehead, broad eyebrows, long eyelashes, esotropia, ptosis, depressed nasal bridge, short nose, upturned nasal tip, prominent philtrum, tented vermilion of the upper lip, and retrognathia.
|
[] |
30/11/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
gm1-ganglio
|
gm1-ganglio
|
[
"Mucopolysaccharidosis Type IVB (Morquio B Disease)",
"GM1 Gangliosidosis",
"Beta-galactosidase",
"GLB1",
"GLB1-Related Disorders"
] |
Debra S Regier, Cynthia J Tifft, Caroline E Rothermel
|
Summary The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop. The diagnosis of a
|
GM1 gangliosidosis
Type I (infantile)
Type II (late infantile and juvenile)
Type III (chronic/adult)
Mucopolysaccharidosis type IVB (Morquio B disease)
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• GM1 gangliosidosis
• Type I (infantile)
• Type II (late infantile and juvenile)
• Type III (chronic/adult)
• Type I (infantile)
• Type II (late infantile and juvenile)
• Type III (chronic/adult)
• Mucopolysaccharidosis type IVB (Morquio B disease)
• Type I (infantile)
• Type II (late infantile and juvenile)
• Type III (chronic/adult)
## Diagnosis
Macular cherry-red spots
Developmental delay
Developmental regression generally observed by age six months
Hepatosplenomegaly
Hypertrophic or dilated cardiomyopathy
Coarse facial features
Generalized skeletal dysplasia of varying severity
Congenital dermal melanocytosis (Mongolian spots)
Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
Vacuolated lymphocytes and abnormally granulated eosinophils in peripheral blood smear
Late infantile (onset age 1-3 years)
Developmental arrest followed by regression
Corneal clouding (
Motor abnormalities
Progressive and diffuse atrophy on brain imaging
Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
Juvenile (onset age 3-10 years)
Ataxia and progressive impairment of gross and fine motor skills
Progressive dysarthria
Brain MRI findings of progressive atrophy
Dystonia leading to gait and speech/swallowing difficulty
Cognitive/intellectual impairment, behavioral/psychiatric disorders, short stature, and below-normal weight [
Auditory startle (rare clinical finding; may or may not be present) [
Corneal clouding (rare)
Cardiac valvular disease
Severe skeletal abnormalities
Short stature
Normal developmental milestones, cognitive function, and neurologic function
Abnormal pulmonary function, including obstructive or restrictive lung disease
Odontoid hypoplasia with subsequent risk for cervical instability
Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture)
Gibbus (structural kyphosis due to wedging of one or more adjacent vertebrae)
Scoliosis
Pectus carinatum or excavatum
Note: (1) Based on wide variations and subtleties of the radiographic findings in MPS IV, multiple body regions should be evaluated. (2) While the radiographic findings in MPS IVA (caused by biallelic
Elevated glycan biomarkers may be detectable via MS/MS in dried blood spots of newborns with GM1 gangliosidosis [
Note: A glycosaminoglycan screen can be falsely negative; thus, negative results should not deter the clinician from additional testing in an individual with a suspected diagnosis of a
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The definitive diagnosis of a
The diagnosis of MPS IVB can be confirmed by the combination of keratan sulfate in the urine and decreased enzyme activity for beta-galactosidase enzyme activity in peripheral blood leukocytes or fibroblasts in the absence of intellectual disability.
Beta-Galactosidase Enzyme Activity in
Relative values (% of normal activity)
Although the percent of residual enzyme activity correlates generally with phenotype, it cannot predict the type of GM1 gangliosidosis. The lack of direct correlation between enzyme activity and disease severity may be due to the use of artificial substrates in the in vitro enzyme assay, which may not exactly replicate in vivo enzyme activity with natural substrates. Modifier genes could theoretically alter enzyme activity and thus, disease severity.
• Macular cherry-red spots
• Developmental delay
• Developmental regression generally observed by age six months
• Hepatosplenomegaly
• Hypertrophic or dilated cardiomyopathy
• Coarse facial features
• Generalized skeletal dysplasia of varying severity
• Congenital dermal melanocytosis (Mongolian spots)
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Vacuolated lymphocytes and abnormally granulated eosinophils in peripheral blood smear
• Late infantile (onset age 1-3 years)
• Developmental arrest followed by regression
• Corneal clouding (
• Motor abnormalities
• Progressive and diffuse atrophy on brain imaging
• Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Developmental arrest followed by regression
• Corneal clouding (
• Motor abnormalities
• Progressive and diffuse atrophy on brain imaging
• Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Juvenile (onset age 3-10 years)
• Ataxia and progressive impairment of gross and fine motor skills
• Progressive dysarthria
• Brain MRI findings of progressive atrophy
• Ataxia and progressive impairment of gross and fine motor skills
• Progressive dysarthria
• Brain MRI findings of progressive atrophy
• Developmental arrest followed by regression
• Corneal clouding (
• Motor abnormalities
• Progressive and diffuse atrophy on brain imaging
• Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Ataxia and progressive impairment of gross and fine motor skills
• Progressive dysarthria
• Brain MRI findings of progressive atrophy
• Dystonia leading to gait and speech/swallowing difficulty
• Cognitive/intellectual impairment, behavioral/psychiatric disorders, short stature, and below-normal weight [
• Auditory startle (rare clinical finding; may or may not be present) [
• Corneal clouding (rare)
• Cardiac valvular disease
• Severe skeletal abnormalities
• Short stature
• Normal developmental milestones, cognitive function, and neurologic function
• Abnormal pulmonary function, including obstructive or restrictive lung disease
• Odontoid hypoplasia with subsequent risk for cervical instability
• Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture)
• Gibbus (structural kyphosis due to wedging of one or more adjacent vertebrae)
• Scoliosis
• Pectus carinatum or excavatum
## Suggestive Findings
Macular cherry-red spots
Developmental delay
Developmental regression generally observed by age six months
Hepatosplenomegaly
Hypertrophic or dilated cardiomyopathy
Coarse facial features
Generalized skeletal dysplasia of varying severity
Congenital dermal melanocytosis (Mongolian spots)
Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
Vacuolated lymphocytes and abnormally granulated eosinophils in peripheral blood smear
Late infantile (onset age 1-3 years)
Developmental arrest followed by regression
Corneal clouding (
Motor abnormalities
Progressive and diffuse atrophy on brain imaging
Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
Juvenile (onset age 3-10 years)
Ataxia and progressive impairment of gross and fine motor skills
Progressive dysarthria
Brain MRI findings of progressive atrophy
Dystonia leading to gait and speech/swallowing difficulty
Cognitive/intellectual impairment, behavioral/psychiatric disorders, short stature, and below-normal weight [
Auditory startle (rare clinical finding; may or may not be present) [
Corneal clouding (rare)
Cardiac valvular disease
Severe skeletal abnormalities
Short stature
Normal developmental milestones, cognitive function, and neurologic function
Abnormal pulmonary function, including obstructive or restrictive lung disease
Odontoid hypoplasia with subsequent risk for cervical instability
Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture)
Gibbus (structural kyphosis due to wedging of one or more adjacent vertebrae)
Scoliosis
Pectus carinatum or excavatum
Note: (1) Based on wide variations and subtleties of the radiographic findings in MPS IV, multiple body regions should be evaluated. (2) While the radiographic findings in MPS IVA (caused by biallelic
Elevated glycan biomarkers may be detectable via MS/MS in dried blood spots of newborns with GM1 gangliosidosis [
Note: A glycosaminoglycan screen can be falsely negative; thus, negative results should not deter the clinician from additional testing in an individual with a suspected diagnosis of a
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
• Macular cherry-red spots
• Developmental delay
• Developmental regression generally observed by age six months
• Hepatosplenomegaly
• Hypertrophic or dilated cardiomyopathy
• Coarse facial features
• Generalized skeletal dysplasia of varying severity
• Congenital dermal melanocytosis (Mongolian spots)
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Vacuolated lymphocytes and abnormally granulated eosinophils in peripheral blood smear
• Late infantile (onset age 1-3 years)
• Developmental arrest followed by regression
• Corneal clouding (
• Motor abnormalities
• Progressive and diffuse atrophy on brain imaging
• Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Developmental arrest followed by regression
• Corneal clouding (
• Motor abnormalities
• Progressive and diffuse atrophy on brain imaging
• Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Juvenile (onset age 3-10 years)
• Ataxia and progressive impairment of gross and fine motor skills
• Progressive dysarthria
• Brain MRI findings of progressive atrophy
• Ataxia and progressive impairment of gross and fine motor skills
• Progressive dysarthria
• Brain MRI findings of progressive atrophy
• Developmental arrest followed by regression
• Corneal clouding (
• Motor abnormalities
• Progressive and diffuse atrophy on brain imaging
• Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Ataxia and progressive impairment of gross and fine motor skills
• Progressive dysarthria
• Brain MRI findings of progressive atrophy
• Dystonia leading to gait and speech/swallowing difficulty
• Cognitive/intellectual impairment, behavioral/psychiatric disorders, short stature, and below-normal weight [
• Auditory startle (rare clinical finding; may or may not be present) [
• Corneal clouding (rare)
• Cardiac valvular disease
• Severe skeletal abnormalities
• Short stature
• Normal developmental milestones, cognitive function, and neurologic function
• Abnormal pulmonary function, including obstructive or restrictive lung disease
• Odontoid hypoplasia with subsequent risk for cervical instability
• Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture)
• Gibbus (structural kyphosis due to wedging of one or more adjacent vertebrae)
• Scoliosis
• Pectus carinatum or excavatum
## Clinical Findings
Macular cherry-red spots
Developmental delay
Developmental regression generally observed by age six months
Hepatosplenomegaly
Hypertrophic or dilated cardiomyopathy
Coarse facial features
Generalized skeletal dysplasia of varying severity
Congenital dermal melanocytosis (Mongolian spots)
Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
Vacuolated lymphocytes and abnormally granulated eosinophils in peripheral blood smear
Late infantile (onset age 1-3 years)
Developmental arrest followed by regression
Corneal clouding (
Motor abnormalities
Progressive and diffuse atrophy on brain imaging
Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
Juvenile (onset age 3-10 years)
Ataxia and progressive impairment of gross and fine motor skills
Progressive dysarthria
Brain MRI findings of progressive atrophy
Dystonia leading to gait and speech/swallowing difficulty
Cognitive/intellectual impairment, behavioral/psychiatric disorders, short stature, and below-normal weight [
Auditory startle (rare clinical finding; may or may not be present) [
Corneal clouding (rare)
Cardiac valvular disease
Severe skeletal abnormalities
Short stature
Normal developmental milestones, cognitive function, and neurologic function
Abnormal pulmonary function, including obstructive or restrictive lung disease
• Macular cherry-red spots
• Developmental delay
• Developmental regression generally observed by age six months
• Hepatosplenomegaly
• Hypertrophic or dilated cardiomyopathy
• Coarse facial features
• Generalized skeletal dysplasia of varying severity
• Congenital dermal melanocytosis (Mongolian spots)
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Vacuolated lymphocytes and abnormally granulated eosinophils in peripheral blood smear
• Late infantile (onset age 1-3 years)
• Developmental arrest followed by regression
• Corneal clouding (
• Motor abnormalities
• Progressive and diffuse atrophy on brain imaging
• Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Developmental arrest followed by regression
• Corneal clouding (
• Motor abnormalities
• Progressive and diffuse atrophy on brain imaging
• Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Juvenile (onset age 3-10 years)
• Ataxia and progressive impairment of gross and fine motor skills
• Progressive dysarthria
• Brain MRI findings of progressive atrophy
• Ataxia and progressive impairment of gross and fine motor skills
• Progressive dysarthria
• Brain MRI findings of progressive atrophy
• Developmental arrest followed by regression
• Corneal clouding (
• Motor abnormalities
• Progressive and diffuse atrophy on brain imaging
• Possible hepatosplenomegaly, cardiomyopathy, and/or skeletal abnormalities
• Elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity
• Ataxia and progressive impairment of gross and fine motor skills
• Progressive dysarthria
• Brain MRI findings of progressive atrophy
• Dystonia leading to gait and speech/swallowing difficulty
• Cognitive/intellectual impairment, behavioral/psychiatric disorders, short stature, and below-normal weight [
• Auditory startle (rare clinical finding; may or may not be present) [
• Corneal clouding (rare)
• Cardiac valvular disease
• Severe skeletal abnormalities
• Short stature
• Normal developmental milestones, cognitive function, and neurologic function
• Abnormal pulmonary function, including obstructive or restrictive lung disease
## Radiographic Findings
Odontoid hypoplasia with subsequent risk for cervical instability
Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture)
Gibbus (structural kyphosis due to wedging of one or more adjacent vertebrae)
Scoliosis
Pectus carinatum or excavatum
Note: (1) Based on wide variations and subtleties of the radiographic findings in MPS IV, multiple body regions should be evaluated. (2) While the radiographic findings in MPS IVA (caused by biallelic
• Odontoid hypoplasia with subsequent risk for cervical instability
• Kyphosis (curving of the spine that causes a bowing or rounding of the back, which leads to a hunchback or slouching posture)
• Gibbus (structural kyphosis due to wedging of one or more adjacent vertebrae)
• Scoliosis
• Pectus carinatum or excavatum
## Neuroimaging Findings
## Laboratory Findings
Elevated glycan biomarkers may be detectable via MS/MS in dried blood spots of newborns with GM1 gangliosidosis [
Note: A glycosaminoglycan screen can be falsely negative; thus, negative results should not deter the clinician from additional testing in an individual with a suspected diagnosis of a
## Family History
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The definitive diagnosis of a
The diagnosis of MPS IVB can be confirmed by the combination of keratan sulfate in the urine and decreased enzyme activity for beta-galactosidase enzyme activity in peripheral blood leukocytes or fibroblasts in the absence of intellectual disability.
Beta-Galactosidase Enzyme Activity in
Relative values (% of normal activity)
Although the percent of residual enzyme activity correlates generally with phenotype, it cannot predict the type of GM1 gangliosidosis. The lack of direct correlation between enzyme activity and disease severity may be due to the use of artificial substrates in the in vitro enzyme assay, which may not exactly replicate in vivo enzyme activity with natural substrates. Modifier genes could theoretically alter enzyme activity and thus, disease severity.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Beta-Galactosidase Enzyme Analysis
The definitive diagnosis of a
The diagnosis of MPS IVB can be confirmed by the combination of keratan sulfate in the urine and decreased enzyme activity for beta-galactosidase enzyme activity in peripheral blood leukocytes or fibroblasts in the absence of intellectual disability.
Beta-Galactosidase Enzyme Activity in
Relative values (% of normal activity)
Although the percent of residual enzyme activity correlates generally with phenotype, it cannot predict the type of GM1 gangliosidosis. The lack of direct correlation between enzyme activity and disease severity may be due to the use of artificial substrates in the in vitro enzyme assay, which may not exactly replicate in vivo enzyme activity with natural substrates. Modifier genes could theoretically alter enzyme activity and thus, disease severity.
## Clinical Characteristics
To date, more than 200 individuals have been identified with GM1 gangliosidosis [
Clinical, Skeletal, Neuroimaging, and Biochemical Findings in
– = negative finding; + = positive finding; ± = variable finding among individuals with the disorder; CC = corneal clouding; CRS = cherry-red spot; PA = progressive atrophy
Secondary to bony changes
Oligosaccharide with terminal galactose sugar
False negative results can be observed.
The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late infantile and juvenile) to mild (chronic/adult). While classification into these types is arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, symptoms, rate of progression, and longevity.
Laboratory findings can include elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity [
Early developmental delay with hypotonia;
Exaggerated startle response, followed by spasticity and rapid regression;
Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
Intellectual impairment is common in late stages of the disease.
Behavioral/psychiatric disorders may occur.
Due to extensive molecular heterogeneity, no clear genotype-phenotype correlations have been identified in GM1 gangliosidosis. Generally, pathogenic variants that affect the surface of the beta-galactosidase enzyme tend to result in a less severe phenotype and are associated with type III (adult/chronic) GM1 gangliosidosis, while pathogenic variants that affect the protein core or enzyme active site are associated with the more severe type I (infantile) form of the disease [
MPS IVB is associated with pathogenic variants of
However, some pathogenic variants are associated with both MPS IVB and GM1 gangliosidosis. In the homozygous state, a pathogenic variant typically associated with MPS IVB, when present in compound heterozygosity with another
In the past GM1 gangliosidosis was referred to as beta-galactosidase-1 deficiency or beta-galactosidosis; mucopolysaccharidosis type IVB was referred to as Morquio syndrome type B. These terms should be used when searching for older literature on GM1 gangliosidosis.
The prevalence of chronic/adult GM1 gangliosidosis is higher in the Japanese population, likely due both to a founder effect and possibly a greater awareness of the disorder among Japanese healthcare providers [
• Laboratory findings can include elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity [
• Early developmental delay with hypotonia;
• Exaggerated startle response, followed by spasticity and rapid regression;
• Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
• Early developmental delay with hypotonia;
• Exaggerated startle response, followed by spasticity and rapid regression;
• Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
• Early developmental delay with hypotonia;
• Exaggerated startle response, followed by spasticity and rapid regression;
• Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
•
• Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
• Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
• Intellectual impairment is common in late stages of the disease.
• Behavioral/psychiatric disorders may occur.
• Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
• Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
• Intellectual impairment is common in late stages of the disease.
• Behavioral/psychiatric disorders may occur.
• Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
• Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
• Intellectual impairment is common in late stages of the disease.
• Behavioral/psychiatric disorders may occur.
## Clinical Description
To date, more than 200 individuals have been identified with GM1 gangliosidosis [
Clinical, Skeletal, Neuroimaging, and Biochemical Findings in
– = negative finding; + = positive finding; ± = variable finding among individuals with the disorder; CC = corneal clouding; CRS = cherry-red spot; PA = progressive atrophy
Secondary to bony changes
Oligosaccharide with terminal galactose sugar
False negative results can be observed.
The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late infantile and juvenile) to mild (chronic/adult). While classification into these types is arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, symptoms, rate of progression, and longevity.
Laboratory findings can include elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity [
Early developmental delay with hypotonia;
Exaggerated startle response, followed by spasticity and rapid regression;
Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
Intellectual impairment is common in late stages of the disease.
Behavioral/psychiatric disorders may occur.
• Laboratory findings can include elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity [
• Early developmental delay with hypotonia;
• Exaggerated startle response, followed by spasticity and rapid regression;
• Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
• Early developmental delay with hypotonia;
• Exaggerated startle response, followed by spasticity and rapid regression;
• Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
• Early developmental delay with hypotonia;
• Exaggerated startle response, followed by spasticity and rapid regression;
• Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
•
• Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
• Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
• Intellectual impairment is common in late stages of the disease.
• Behavioral/psychiatric disorders may occur.
• Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
• Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
• Intellectual impairment is common in late stages of the disease.
• Behavioral/psychiatric disorders may occur.
• Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
• Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
• Intellectual impairment is common in late stages of the disease.
• Behavioral/psychiatric disorders may occur.
## GM1 Gangliosidosis
The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late infantile and juvenile) to mild (chronic/adult). While classification into these types is arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, symptoms, rate of progression, and longevity.
Laboratory findings can include elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity [
Early developmental delay with hypotonia;
Exaggerated startle response, followed by spasticity and rapid regression;
Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
Intellectual impairment is common in late stages of the disease.
Behavioral/psychiatric disorders may occur.
• Laboratory findings can include elevated serum concentrations of AST with normal ALT, and increased serum chitotriosidase activity [
• Early developmental delay with hypotonia;
• Exaggerated startle response, followed by spasticity and rapid regression;
• Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
• Early developmental delay with hypotonia;
• Exaggerated startle response, followed by spasticity and rapid regression;
• Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
• Early developmental delay with hypotonia;
• Exaggerated startle response, followed by spasticity and rapid regression;
• Severe central nervous system dysfunction by the end of the first year leading to blindness and deafness; decerebrate rigidity; seizures; and poor feeding, difficulties in swallowing, excess secretions, and risk of aspiration.
•
• Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
• Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
• Intellectual impairment is common in late stages of the disease.
• Behavioral/psychiatric disorders may occur.
• Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
• Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
• Intellectual impairment is common in late stages of the disease.
• Behavioral/psychiatric disorders may occur.
• Typically presents with generalized dystonia leading to unsteady gait and speech disturbance
• Shortly thereafter, most will develop extrapyramidal signs including akinetic-rigid parkinsonism.
• Intellectual impairment is common in late stages of the disease.
• Behavioral/psychiatric disorders may occur.
## Mucopolysaccharidosis Type IVB
## Genotype-Phenotype Correlations
Due to extensive molecular heterogeneity, no clear genotype-phenotype correlations have been identified in GM1 gangliosidosis. Generally, pathogenic variants that affect the surface of the beta-galactosidase enzyme tend to result in a less severe phenotype and are associated with type III (adult/chronic) GM1 gangliosidosis, while pathogenic variants that affect the protein core or enzyme active site are associated with the more severe type I (infantile) form of the disease [
MPS IVB is associated with pathogenic variants of
However, some pathogenic variants are associated with both MPS IVB and GM1 gangliosidosis. In the homozygous state, a pathogenic variant typically associated with MPS IVB, when present in compound heterozygosity with another
## Nomenclature
In the past GM1 gangliosidosis was referred to as beta-galactosidase-1 deficiency or beta-galactosidosis; mucopolysaccharidosis type IVB was referred to as Morquio syndrome type B. These terms should be used when searching for older literature on GM1 gangliosidosis.
## Prevalence
The prevalence of chronic/adult GM1 gangliosidosis is higher in the Japanese population, likely due both to a founder effect and possibly a greater awareness of the disorder among Japanese healthcare providers [
## Genetically Related (Allelic) Disorders
No phenotypes other than those described in this
## Differential Diagnosis
Genetic Disorders of Interest in the Differential Diagnosis of Type I (Infantile) GM1 Gangliosidosis
CSF = cerebrospinal fluid; DiffDx = differential diagnosis; ERG = electroretinogram; TSD = Tay-Sachs disease
The disorders included in
Galactosialidosis and sialidosis are caused by deficiencies in enzymes that form a complex with beta-galactosidase. This high molecular-weight complex includes beta-galactosidase (GM1 gangliosidosis), cathepsin A encoded by
In activator-deficient TSD, enzymatic activity of both beta-hexosaminidase (HEX A) and hexosaminidase B (HEX B) is normal, but GM2 ganglioside accumulation occurs because of a deficit of the intralysosomal glycoprotein ("GM2 activator") that is required for the degradation of GM2 ganglioside.
Progressive weakness and loss of motor skills between ages six and 12 months, associated with an increased startle response, a cherry-red spot of the macula of the retina, and normal-size liver and spleen
In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.
The features of sialidosis II more closely resemble GM1 gangliosidosis than sialidosis I. Sialidosis type I is also known as cherry-red spot myoclonus syndrome. Onset is in the teens and twenties. Gait disturbances and reduced visual acuity are the most common presenting symptoms. With time, myoclonus, ataxia, and reduced vision worsen, but are not life threatening. Intellect is normal.
Genetic Disorders of Interest in the Differential Diagnosis of Type II (Late-Infantile and Juvenile) GM1 Gangliosidosis
–
≤6 mos
Macrocephaly, head lag, hypotonia, seizures
CLN3 disease (Batten disease) (OMIM
–
9-18 yrs
Seizures
Galactosialidosis
+
>12 mos
Seizures
Hepatosplenomegaly w/coarse features, more severe skeletal disease
≥12 mos
Tay-Sachs disease (See
+
3-5 yrs
CSF = cerebrospinal fluid; DiffDx = differential diagnosis; ERG = electroretinogram
The disorders included in
Galactosialidosis and sialidosis are caused by deficiencies in enzymes that form a complex with beta-galactosidase. This high molecular-weight complex includes beta-galactosidase (GM1 gangliosidosis), cathepsin A encoded by
In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.
Some
Genetic Disorders of Interest in the Differential Diagnosis of Type III (Chronic/Adult) GM1 Gangliosidosis
AD spinocerebellar ataxia (SCA) (See
Late onset SMA (See
Adult-onset neuronal ceroid-lipofuscinosis (OMIM
AD
Early-onset
AR
Tay-Sachs disease (See
Juvenile
Later-onset
AD = autosomal dominant; AR = autosomal recessive; CPK = creatinine phosphokinase; DiffDx = differential diagnosis; EKG = electrocardiogram; MOI = mode of inheritance; XL = X-linked
See
In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.
Note: A positive test for anti-GM1 ganglioside antibodies is not indicative of a diagnosis of GM1 gangliosidosis. These test results are associated with multifocal motor neuropathy or Guillain-Barré syndrome [
## GM1 Gangliosidosis
Genetic Disorders of Interest in the Differential Diagnosis of Type I (Infantile) GM1 Gangliosidosis
CSF = cerebrospinal fluid; DiffDx = differential diagnosis; ERG = electroretinogram; TSD = Tay-Sachs disease
The disorders included in
Galactosialidosis and sialidosis are caused by deficiencies in enzymes that form a complex with beta-galactosidase. This high molecular-weight complex includes beta-galactosidase (GM1 gangliosidosis), cathepsin A encoded by
In activator-deficient TSD, enzymatic activity of both beta-hexosaminidase (HEX A) and hexosaminidase B (HEX B) is normal, but GM2 ganglioside accumulation occurs because of a deficit of the intralysosomal glycoprotein ("GM2 activator") that is required for the degradation of GM2 ganglioside.
Progressive weakness and loss of motor skills between ages six and 12 months, associated with an increased startle response, a cherry-red spot of the macula of the retina, and normal-size liver and spleen
In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.
The features of sialidosis II more closely resemble GM1 gangliosidosis than sialidosis I. Sialidosis type I is also known as cherry-red spot myoclonus syndrome. Onset is in the teens and twenties. Gait disturbances and reduced visual acuity are the most common presenting symptoms. With time, myoclonus, ataxia, and reduced vision worsen, but are not life threatening. Intellect is normal.
Genetic Disorders of Interest in the Differential Diagnosis of Type II (Late-Infantile and Juvenile) GM1 Gangliosidosis
–
≤6 mos
Macrocephaly, head lag, hypotonia, seizures
CLN3 disease (Batten disease) (OMIM
–
9-18 yrs
Seizures
Galactosialidosis
+
>12 mos
Seizures
Hepatosplenomegaly w/coarse features, more severe skeletal disease
≥12 mos
Tay-Sachs disease (See
+
3-5 yrs
CSF = cerebrospinal fluid; DiffDx = differential diagnosis; ERG = electroretinogram
The disorders included in
Galactosialidosis and sialidosis are caused by deficiencies in enzymes that form a complex with beta-galactosidase. This high molecular-weight complex includes beta-galactosidase (GM1 gangliosidosis), cathepsin A encoded by
In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.
Some
Genetic Disorders of Interest in the Differential Diagnosis of Type III (Chronic/Adult) GM1 Gangliosidosis
AD spinocerebellar ataxia (SCA) (See
Late onset SMA (See
Adult-onset neuronal ceroid-lipofuscinosis (OMIM
AD
Early-onset
AR
Tay-Sachs disease (See
Juvenile
Later-onset
AD = autosomal dominant; AR = autosomal recessive; CPK = creatinine phosphokinase; DiffDx = differential diagnosis; EKG = electrocardiogram; MOI = mode of inheritance; XL = X-linked
See
In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.
Note: A positive test for anti-GM1 ganglioside antibodies is not indicative of a diagnosis of GM1 gangliosidosis. These test results are associated with multifocal motor neuropathy or Guillain-Barré syndrome [
## Mucopolysaccharidosis Type IVB (MPS IVB)
## Management
No clinical practice guidelines for
It is important to note that all
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with Type I (Infantile) GM1 Gangliosidosis
Neurology eval
Neuroimaging to incl brain MRI
Consider EEG if seizures a concern.
Physical medicine & rehab / PT & OT eval
Gross motor & fine motor skills
Need for adaptive devices
Need for PT (to prevent deformities)
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with Type II (Late-Infantile and Juvenile) GM1 Gangliosidosis
Evaluate for corneal clouding.
Assess visual acuity.
Neurology eval
Neuroimaging to incl brain MRI
Consider EEG if seizures a concern.
Evaluate for spasticity.
Physical medicine & rehab / PT & OT eval
Gross motor & fine motor skills
Mobility, independence in ADL, & need for adaptive devices
Need for PT (to prevent deformities)
Document past & current motor & cognitive function as a baseline.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for IEP
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support.
ADL = activities of daily living; IEP = individualized education program; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with Type III (Chronic/Adult) GM1 Gangliosidosis
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
Assess for psychiatric &/or behavioral disorders incl ADHD, learning disability, depression, anxiety, aggression, OCD.
Evaluate for baseline cognitive skills.
Community or
Social work involvement for support;
Home nursing referral.
ADL = activities of daily living; IEP = individualized education program; MOI = mode of inheritance; OCD = obsessive/compulsive disorder; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with MPS IVB
Evaluate for corneal clouding.
Assess visual acuity.
Baseline exam
Evaluate for clinical signs of spinal cord compression.
Cervical spine (AP, neutral lateral, flexion-extension views)
Entire spine (AP, lateral)
Pelvis (AP, frog leg lateral)
Lower extremities (AP standing)
Lower extremity alignment from hip to ankle if signs of lower extremity misalignment
Baseline MRI of entire spine w/focus on occipitocervical, cervicothoracic, thoracolumbar regions to assess for spinal cord compression
Flexion-extension MRI of cervical spine
To assess mobility, autonomy, joint range of motion, ADL, upper extremity strength
Baseline endurance w/6-min walk test
Baseline pulmonary function testing, polysomnography
Evaluate for airway obstruction & assess inspiratory/expiratory lung volume changes.
Community or
Social work involvement for support.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment and quality of life can be optimized when care is provided by specialists in biochemical genetics, cardiology, orthopedics, and neurology and therapists knowledgeable about
Surgery is best performed in centers with surgeons and anesthesiologists experienced in the care of individuals with lysosomal storage disorders.
Early and ongoing interventions to optimize comfort, mobility, educational and social outcomes are recommended.
Treatment of Manifestations in Individuals with Type I (Infantile) GM1 Gangliosidosis
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
Education of parents/caregivers
Will ↑ longevity but not preserve developmental function
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may be required.
Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
Cervical spine stabilization & care by experienced pediatric anesthesiologist whenever possible
ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Treatment of Manifestations in Individuals with Type II (Late-Infantile and Juvenile) GM1 Gangliosidosis
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
Education of parents/caregivers
Will ↑ longevity but not preserve developmental function
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may often be required.
Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
Cervical spine stabilization & care by experienced pediatric anesthesiologist whenever possible
ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; IEP = individualized education program; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Treatment of Manifestations in Individuals with Type III (Adult/Chronic) GM1 Gangliosidosis
Individualize treatment.
Avoid tricyclic antidepressants, antipsychotics, & electroconvulsive therapy if possible as they may contribute to neurologic worsening.
Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may be required.
Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
If clinical or radiographic findings pose concern for cervical spine instability, cervical spine stabilization & care by experienced anesthesiologist
DD/ID = developmental delay / intellectual disability; IEP = individualized education program; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with MPS IVB
External wrist splints
Wrist fusion to stabilize wrist range of motion
Realignment osteotomies
Surgical tethering of growth plate if detected before growth plate closure
Distal femoral & proximal tibial osteotomies if misalignment detected after growth plate closure
Distal tibial osteotomy for ankle misalignment
Bracing to delay surgical intervention
Spinal fusion if stenosis occurs
Preoperative eval to incl: history of complications w/previous anesthetics; assessment of upper & lower airway anatomy; cardiac & respiratory function
Use preoperative sedative premedication w/caution & appropriate monitoring, due to risk of upper-airway obstruction.
Anterior tongue placement, intubation w/video laryngoscope or fiber-optic bronchoscopy, & smaller-than-expected endotracheal tubes are often required.
For procedures lasting >45 min, intraoperative spinal cord monitoring may be needed to detect exacerbation of preexisting spinal stenosis.
Post-operative management may be complicated by preexisting sleep apnea &/or pulmonary edema.
Review flexion/extension radiographs of lateral cervical spine prior to anesthesia to evaluate for cervical spine instability.
Maintain cervical spine stabilization & neutral neck position at all times during all surgeries.
Maintain mean arterial pressure to ↓ risk of spinal cord injury.
Care by experienced pediatric anesthesiologist capable of inspecting the airway before extubation & performing reintubation if necessary
Educational supports to optimize learning (See
Psychological support to optimize coping skills & quality of life
Occupational counseling
OSA = obstructive sleep apnea; OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
An estate plan should be carefully drafted with the support of a special needs estate attorney, to ensure that the individual with special needs remains qualified for government and state benefits. The plan must include a special needs trust; non-profit organizations may be helpful by serving as the trustee and/or managing the trust [
Eligibility and plans for guardianship will be established at age 18. Special needs attorneys and social workers may be helpful in navigating guardianship decisions. Depending on the individual's cognitive status and decision-making abilities, the family may elect guardianship, a durable power of attorney for medical purposes, and/or supported decision making. If the affected individual has sibs, a simple will should be drafted at this time to protect the child against disqualification for government benefits [
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Recommended Surveillance for Individuals with GM1 Gangliosidosis
Eval by neurologist
Consider EEG if acute change in mental status, sudden decline in activity/milestones, or abnormal movements.
Physical exam to evaluate for new skeletal abnormalities
Physical exam & assessment for new neurologic findings, followed by imaging to evaluate cervical spine instability if indicated
Monitor hip joint stability re risk of hip dislocation.
Obtain straight & frog-leg imaging if pain w/movement or change in mobility (which in neurologically compromised persons can present as inability to ambulate, unexplained crying, or pain).
Recommended Surveillance for Individuals with MPS IVB
Assess for sleep apnea.
Evaluate pulmonary function.
AP = anteroposterior; PT = physical therapist
The following should be avoided:
Positioning that increases aspiration risk during feedings
Seizure medication dosages that result in excessive sedation
See
There are currently several therapies under investigation that offer some promise in altering the outcome for individuals with GM1 gangliosidosis:
Intracisternal injection of AAVrh.10 carrying
Intra-cisterna magna injection of AAVhu68 carrying
Intravenous administration of AAV9 carrying
"Syner-G" regimen (combination of miglustat and the ketogenic diet) for improved outcomes in individuals with types I and II (infantile and juvenile) GM1 gangliosidosis (NCT02030015)
Search
• Neuroimaging to incl brain MRI
• Consider EEG if seizures a concern.
• Gross motor & fine motor skills
• Need for adaptive devices
• Need for PT (to prevent deformities)
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Evaluate for corneal clouding.
• Assess visual acuity.
• Neuroimaging to incl brain MRI
• Consider EEG if seizures a concern.
• Evaluate for spasticity.
• Gross motor & fine motor skills
• Mobility, independence in ADL, & need for adaptive devices
• Need for PT (to prevent deformities)
• Document past & current motor & cognitive function as a baseline.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for IEP
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support.
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
• Assess for psychiatric &/or behavioral disorders incl ADHD, learning disability, depression, anxiety, aggression, OCD.
• Evaluate for baseline cognitive skills.
• Community or
• Social work involvement for support;
• Home nursing referral.
• Evaluate for corneal clouding.
• Assess visual acuity.
• Baseline exam
• Evaluate for clinical signs of spinal cord compression.
• Cervical spine (AP, neutral lateral, flexion-extension views)
• Entire spine (AP, lateral)
• Pelvis (AP, frog leg lateral)
• Lower extremities (AP standing)
• Lower extremity alignment from hip to ankle if signs of lower extremity misalignment
• Baseline MRI of entire spine w/focus on occipitocervical, cervicothoracic, thoracolumbar regions to assess for spinal cord compression
• Flexion-extension MRI of cervical spine
• To assess mobility, autonomy, joint range of motion, ADL, upper extremity strength
• Baseline endurance w/6-min walk test
• Baseline pulmonary function testing, polysomnography
• Evaluate for airway obstruction & assess inspiratory/expiratory lung volume changes.
• Community or
• Social work involvement for support.
• Surgery is best performed in centers with surgeons and anesthesiologists experienced in the care of individuals with lysosomal storage disorders.
• Early and ongoing interventions to optimize comfort, mobility, educational and social outcomes are recommended.
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
• Education of parents/caregivers
• Will ↑ longevity but not preserve developmental function
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
• Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
• Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may be required.
• Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
• Cervical spine stabilization & care by experienced pediatric anesthesiologist whenever possible
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
• Education of parents/caregivers
• Will ↑ longevity but not preserve developmental function
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
• Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
• Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may often be required.
• Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
• Cervical spine stabilization & care by experienced pediatric anesthesiologist whenever possible
• Individualize treatment.
• Avoid tricyclic antidepressants, antipsychotics, & electroconvulsive therapy if possible as they may contribute to neurologic worsening.
• Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
• Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may be required.
• Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
• If clinical or radiographic findings pose concern for cervical spine instability, cervical spine stabilization & care by experienced anesthesiologist
• External wrist splints
• Wrist fusion to stabilize wrist range of motion
• Realignment osteotomies
• Surgical tethering of growth plate if detected before growth plate closure
• Distal femoral & proximal tibial osteotomies if misalignment detected after growth plate closure
• Distal tibial osteotomy for ankle misalignment
• Bracing to delay surgical intervention
• Spinal fusion if stenosis occurs
• Preoperative eval to incl: history of complications w/previous anesthetics; assessment of upper & lower airway anatomy; cardiac & respiratory function
• Use preoperative sedative premedication w/caution & appropriate monitoring, due to risk of upper-airway obstruction.
• Anterior tongue placement, intubation w/video laryngoscope or fiber-optic bronchoscopy, & smaller-than-expected endotracheal tubes are often required.
• For procedures lasting >45 min, intraoperative spinal cord monitoring may be needed to detect exacerbation of preexisting spinal stenosis.
• Post-operative management may be complicated by preexisting sleep apnea &/or pulmonary edema.
• Review flexion/extension radiographs of lateral cervical spine prior to anesthesia to evaluate for cervical spine instability.
• Maintain cervical spine stabilization & neutral neck position at all times during all surgeries.
• Maintain mean arterial pressure to ↓ risk of spinal cord injury.
• Care by experienced pediatric anesthesiologist capable of inspecting the airway before extubation & performing reintubation if necessary
• Educational supports to optimize learning (See
• Psychological support to optimize coping skills & quality of life
• Occupational counseling
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An estate plan should be carefully drafted with the support of a special needs estate attorney, to ensure that the individual with special needs remains qualified for government and state benefits. The plan must include a special needs trust; non-profit organizations may be helpful by serving as the trustee and/or managing the trust [
• Eligibility and plans for guardianship will be established at age 18. Special needs attorneys and social workers may be helpful in navigating guardianship decisions. Depending on the individual's cognitive status and decision-making abilities, the family may elect guardianship, a durable power of attorney for medical purposes, and/or supported decision making. If the affected individual has sibs, a simple will should be drafted at this time to protect the child against disqualification for government benefits [
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Eval by neurologist
• Consider EEG if acute change in mental status, sudden decline in activity/milestones, or abnormal movements.
• Physical exam to evaluate for new skeletal abnormalities
• Physical exam & assessment for new neurologic findings, followed by imaging to evaluate cervical spine instability if indicated
• Monitor hip joint stability re risk of hip dislocation.
• Obtain straight & frog-leg imaging if pain w/movement or change in mobility (which in neurologically compromised persons can present as inability to ambulate, unexplained crying, or pain).
• Assess for sleep apnea.
• Evaluate pulmonary function.
•
• Positioning that increases aspiration risk during feedings
• Seizure medication dosages that result in excessive sedation
• Positioning that increases aspiration risk during feedings
• Seizure medication dosages that result in excessive sedation
• Positioning that increases aspiration risk during feedings
• Seizure medication dosages that result in excessive sedation
• Intracisternal injection of AAVrh.10 carrying
• Intra-cisterna magna injection of AAVhu68 carrying
• Intravenous administration of AAV9 carrying
• "Syner-G" regimen (combination of miglustat and the ketogenic diet) for improved outcomes in individuals with types I and II (infantile and juvenile) GM1 gangliosidosis (NCT02030015)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with Type I (Infantile) GM1 Gangliosidosis
Neurology eval
Neuroimaging to incl brain MRI
Consider EEG if seizures a concern.
Physical medicine & rehab / PT & OT eval
Gross motor & fine motor skills
Need for adaptive devices
Need for PT (to prevent deformities)
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with Type II (Late-Infantile and Juvenile) GM1 Gangliosidosis
Evaluate for corneal clouding.
Assess visual acuity.
Neurology eval
Neuroimaging to incl brain MRI
Consider EEG if seizures a concern.
Evaluate for spasticity.
Physical medicine & rehab / PT & OT eval
Gross motor & fine motor skills
Mobility, independence in ADL, & need for adaptive devices
Need for PT (to prevent deformities)
Document past & current motor & cognitive function as a baseline.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for IEP
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support.
ADL = activities of daily living; IEP = individualized education program; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with Type III (Chronic/Adult) GM1 Gangliosidosis
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
Assess for psychiatric &/or behavioral disorders incl ADHD, learning disability, depression, anxiety, aggression, OCD.
Evaluate for baseline cognitive skills.
Community or
Social work involvement for support;
Home nursing referral.
ADL = activities of daily living; IEP = individualized education program; MOI = mode of inheritance; OCD = obsessive/compulsive disorder; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with MPS IVB
Evaluate for corneal clouding.
Assess visual acuity.
Baseline exam
Evaluate for clinical signs of spinal cord compression.
Cervical spine (AP, neutral lateral, flexion-extension views)
Entire spine (AP, lateral)
Pelvis (AP, frog leg lateral)
Lower extremities (AP standing)
Lower extremity alignment from hip to ankle if signs of lower extremity misalignment
Baseline MRI of entire spine w/focus on occipitocervical, cervicothoracic, thoracolumbar regions to assess for spinal cord compression
Flexion-extension MRI of cervical spine
To assess mobility, autonomy, joint range of motion, ADL, upper extremity strength
Baseline endurance w/6-min walk test
Baseline pulmonary function testing, polysomnography
Evaluate for airway obstruction & assess inspiratory/expiratory lung volume changes.
Community or
Social work involvement for support.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Neuroimaging to incl brain MRI
• Consider EEG if seizures a concern.
• Gross motor & fine motor skills
• Need for adaptive devices
• Need for PT (to prevent deformities)
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Evaluate for corneal clouding.
• Assess visual acuity.
• Neuroimaging to incl brain MRI
• Consider EEG if seizures a concern.
• Evaluate for spasticity.
• Gross motor & fine motor skills
• Mobility, independence in ADL, & need for adaptive devices
• Need for PT (to prevent deformities)
• Document past & current motor & cognitive function as a baseline.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for IEP
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support.
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
• Assess for psychiatric &/or behavioral disorders incl ADHD, learning disability, depression, anxiety, aggression, OCD.
• Evaluate for baseline cognitive skills.
• Community or
• Social work involvement for support;
• Home nursing referral.
• Evaluate for corneal clouding.
• Assess visual acuity.
• Baseline exam
• Evaluate for clinical signs of spinal cord compression.
• Cervical spine (AP, neutral lateral, flexion-extension views)
• Entire spine (AP, lateral)
• Pelvis (AP, frog leg lateral)
• Lower extremities (AP standing)
• Lower extremity alignment from hip to ankle if signs of lower extremity misalignment
• Baseline MRI of entire spine w/focus on occipitocervical, cervicothoracic, thoracolumbar regions to assess for spinal cord compression
• Flexion-extension MRI of cervical spine
• To assess mobility, autonomy, joint range of motion, ADL, upper extremity strength
• Baseline endurance w/6-min walk test
• Baseline pulmonary function testing, polysomnography
• Evaluate for airway obstruction & assess inspiratory/expiratory lung volume changes.
• Community or
• Social work involvement for support.
## Treatment of Manifestations
Treatment and quality of life can be optimized when care is provided by specialists in biochemical genetics, cardiology, orthopedics, and neurology and therapists knowledgeable about
Surgery is best performed in centers with surgeons and anesthesiologists experienced in the care of individuals with lysosomal storage disorders.
Early and ongoing interventions to optimize comfort, mobility, educational and social outcomes are recommended.
Treatment of Manifestations in Individuals with Type I (Infantile) GM1 Gangliosidosis
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
Education of parents/caregivers
Will ↑ longevity but not preserve developmental function
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may be required.
Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
Cervical spine stabilization & care by experienced pediatric anesthesiologist whenever possible
ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Treatment of Manifestations in Individuals with Type II (Late-Infantile and Juvenile) GM1 Gangliosidosis
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
Education of parents/caregivers
Will ↑ longevity but not preserve developmental function
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may often be required.
Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
Cervical spine stabilization & care by experienced pediatric anesthesiologist whenever possible
ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; IEP = individualized education program; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Treatment of Manifestations in Individuals with Type III (Adult/Chronic) GM1 Gangliosidosis
Individualize treatment.
Avoid tricyclic antidepressants, antipsychotics, & electroconvulsive therapy if possible as they may contribute to neurologic worsening.
Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may be required.
Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
If clinical or radiographic findings pose concern for cervical spine instability, cervical spine stabilization & care by experienced anesthesiologist
DD/ID = developmental delay / intellectual disability; IEP = individualized education program; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with MPS IVB
External wrist splints
Wrist fusion to stabilize wrist range of motion
Realignment osteotomies
Surgical tethering of growth plate if detected before growth plate closure
Distal femoral & proximal tibial osteotomies if misalignment detected after growth plate closure
Distal tibial osteotomy for ankle misalignment
Bracing to delay surgical intervention
Spinal fusion if stenosis occurs
Preoperative eval to incl: history of complications w/previous anesthetics; assessment of upper & lower airway anatomy; cardiac & respiratory function
Use preoperative sedative premedication w/caution & appropriate monitoring, due to risk of upper-airway obstruction.
Anterior tongue placement, intubation w/video laryngoscope or fiber-optic bronchoscopy, & smaller-than-expected endotracheal tubes are often required.
For procedures lasting >45 min, intraoperative spinal cord monitoring may be needed to detect exacerbation of preexisting spinal stenosis.
Post-operative management may be complicated by preexisting sleep apnea &/or pulmonary edema.
Review flexion/extension radiographs of lateral cervical spine prior to anesthesia to evaluate for cervical spine instability.
Maintain cervical spine stabilization & neutral neck position at all times during all surgeries.
Maintain mean arterial pressure to ↓ risk of spinal cord injury.
Care by experienced pediatric anesthesiologist capable of inspecting the airway before extubation & performing reintubation if necessary
Educational supports to optimize learning (See
Psychological support to optimize coping skills & quality of life
Occupational counseling
OSA = obstructive sleep apnea; OT = occupational therapy; PT = physical therapy
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
An estate plan should be carefully drafted with the support of a special needs estate attorney, to ensure that the individual with special needs remains qualified for government and state benefits. The plan must include a special needs trust; non-profit organizations may be helpful by serving as the trustee and/or managing the trust [
Eligibility and plans for guardianship will be established at age 18. Special needs attorneys and social workers may be helpful in navigating guardianship decisions. Depending on the individual's cognitive status and decision-making abilities, the family may elect guardianship, a durable power of attorney for medical purposes, and/or supported decision making. If the affected individual has sibs, a simple will should be drafted at this time to protect the child against disqualification for government benefits [
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Surgery is best performed in centers with surgeons and anesthesiologists experienced in the care of individuals with lysosomal storage disorders.
• Early and ongoing interventions to optimize comfort, mobility, educational and social outcomes are recommended.
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
• Education of parents/caregivers
• Will ↑ longevity but not preserve developmental function
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
• Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
• Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may be required.
• Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
• Cervical spine stabilization & care by experienced pediatric anesthesiologist whenever possible
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
• Education of parents/caregivers
• Will ↑ longevity but not preserve developmental function
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
• Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
• Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may often be required.
• Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
• Cervical spine stabilization & care by experienced pediatric anesthesiologist whenever possible
• Individualize treatment.
• Avoid tricyclic antidepressants, antipsychotics, & electroconvulsive therapy if possible as they may contribute to neurologic worsening.
• Preoperative eval incl history of complications w/previous anesthetics & any ongoing issues w/airway obstruction, heart, & respiratory function
• Fiber-optic bronchoscopy & smaller-than-expected endotracheal tubes may be required.
• Review flexion/extension radiographs of lateral cervical spine prior to anesthesia.
• If clinical or radiographic findings pose concern for cervical spine instability, cervical spine stabilization & care by experienced anesthesiologist
• External wrist splints
• Wrist fusion to stabilize wrist range of motion
• Realignment osteotomies
• Surgical tethering of growth plate if detected before growth plate closure
• Distal femoral & proximal tibial osteotomies if misalignment detected after growth plate closure
• Distal tibial osteotomy for ankle misalignment
• Bracing to delay surgical intervention
• Spinal fusion if stenosis occurs
• Preoperative eval to incl: history of complications w/previous anesthetics; assessment of upper & lower airway anatomy; cardiac & respiratory function
• Use preoperative sedative premedication w/caution & appropriate monitoring, due to risk of upper-airway obstruction.
• Anterior tongue placement, intubation w/video laryngoscope or fiber-optic bronchoscopy, & smaller-than-expected endotracheal tubes are often required.
• For procedures lasting >45 min, intraoperative spinal cord monitoring may be needed to detect exacerbation of preexisting spinal stenosis.
• Post-operative management may be complicated by preexisting sleep apnea &/or pulmonary edema.
• Review flexion/extension radiographs of lateral cervical spine prior to anesthesia to evaluate for cervical spine instability.
• Maintain cervical spine stabilization & neutral neck position at all times during all surgeries.
• Maintain mean arterial pressure to ↓ risk of spinal cord injury.
• Care by experienced pediatric anesthesiologist capable of inspecting the airway before extubation & performing reintubation if necessary
• Educational supports to optimize learning (See
• Psychological support to optimize coping skills & quality of life
• Occupational counseling
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An estate plan should be carefully drafted with the support of a special needs estate attorney, to ensure that the individual with special needs remains qualified for government and state benefits. The plan must include a special needs trust; non-profit organizations may be helpful by serving as the trustee and/or managing the trust [
• Eligibility and plans for guardianship will be established at age 18. Special needs attorneys and social workers may be helpful in navigating guardianship decisions. Depending on the individual's cognitive status and decision-making abilities, the family may elect guardianship, a durable power of attorney for medical purposes, and/or supported decision making. If the affected individual has sibs, a simple will should be drafted at this time to protect the child against disqualification for government benefits [
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
An estate plan should be carefully drafted with the support of a special needs estate attorney, to ensure that the individual with special needs remains qualified for government and state benefits. The plan must include a special needs trust; non-profit organizations may be helpful by serving as the trustee and/or managing the trust [
Eligibility and plans for guardianship will be established at age 18. Special needs attorneys and social workers may be helpful in navigating guardianship decisions. Depending on the individual's cognitive status and decision-making abilities, the family may elect guardianship, a durable power of attorney for medical purposes, and/or supported decision making. If the affected individual has sibs, a simple will should be drafted at this time to protect the child against disqualification for government benefits [
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An estate plan should be carefully drafted with the support of a special needs estate attorney, to ensure that the individual with special needs remains qualified for government and state benefits. The plan must include a special needs trust; non-profit organizations may be helpful by serving as the trustee and/or managing the trust [
• Eligibility and plans for guardianship will be established at age 18. Special needs attorneys and social workers may be helpful in navigating guardianship decisions. Depending on the individual's cognitive status and decision-making abilities, the family may elect guardianship, a durable power of attorney for medical purposes, and/or supported decision making. If the affected individual has sibs, a simple will should be drafted at this time to protect the child against disqualification for government benefits [
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Surveillance
Recommended Surveillance for Individuals with GM1 Gangliosidosis
Eval by neurologist
Consider EEG if acute change in mental status, sudden decline in activity/milestones, or abnormal movements.
Physical exam to evaluate for new skeletal abnormalities
Physical exam & assessment for new neurologic findings, followed by imaging to evaluate cervical spine instability if indicated
Monitor hip joint stability re risk of hip dislocation.
Obtain straight & frog-leg imaging if pain w/movement or change in mobility (which in neurologically compromised persons can present as inability to ambulate, unexplained crying, or pain).
Recommended Surveillance for Individuals with MPS IVB
Assess for sleep apnea.
Evaluate pulmonary function.
AP = anteroposterior; PT = physical therapist
• Eval by neurologist
• Consider EEG if acute change in mental status, sudden decline in activity/milestones, or abnormal movements.
• Physical exam to evaluate for new skeletal abnormalities
• Physical exam & assessment for new neurologic findings, followed by imaging to evaluate cervical spine instability if indicated
• Monitor hip joint stability re risk of hip dislocation.
• Obtain straight & frog-leg imaging if pain w/movement or change in mobility (which in neurologically compromised persons can present as inability to ambulate, unexplained crying, or pain).
• Assess for sleep apnea.
• Evaluate pulmonary function.
## Agents/Circumstances to Avoid
The following should be avoided:
Positioning that increases aspiration risk during feedings
Seizure medication dosages that result in excessive sedation
•
• Positioning that increases aspiration risk during feedings
• Seizure medication dosages that result in excessive sedation
• Positioning that increases aspiration risk during feedings
• Seizure medication dosages that result in excessive sedation
• Positioning that increases aspiration risk during feedings
• Seizure medication dosages that result in excessive sedation
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
There are currently several therapies under investigation that offer some promise in altering the outcome for individuals with GM1 gangliosidosis:
Intracisternal injection of AAVrh.10 carrying
Intra-cisterna magna injection of AAVhu68 carrying
Intravenous administration of AAV9 carrying
"Syner-G" regimen (combination of miglustat and the ketogenic diet) for improved outcomes in individuals with types I and II (infantile and juvenile) GM1 gangliosidosis (NCT02030015)
Search
• Intracisternal injection of AAVrh.10 carrying
• Intra-cisterna magna injection of AAVhu68 carrying
• Intravenous administration of AAV9 carrying
• "Syner-G" regimen (combination of miglustat and the ketogenic diet) for improved outcomes in individuals with types I and II (infantile and juvenile) GM1 gangliosidosis (NCT02030015)
## Genetic Counseling
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with a severe
The offspring of an individual with a mild
Note: No studies addressing fertility in individuals with a mild
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with a severe
• The offspring of an individual with a mild
• Note: No studies addressing fertility in individuals with a mild
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with a severe
The offspring of an individual with a mild
Note: No studies addressing fertility in individuals with a mild
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with a severe
• The offspring of an individual with a mild
• Note: No studies addressing fertility in individuals with a mild
## Carrier Detection
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 6890
Albany 94706
Canada
United Kingdom
United Kingdom
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• PO Box 6890
• Albany 94706
•
•
•
•
• Canada
•
•
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
## Molecular Genetics
GLB1-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GLB1-Related Disorders (
Both disorders are caused by pathogenic variants in
GM1 gangliosidosis is caused by pathogenic variants that lead to accumulation of sphingolipid intermediates in the lysosome and, thus, interfere with appropriate functioning of the organelle. A hallmark of GM1 gangliosidosis is degeneration of the CNS, where ganglioside synthesis is the highest. An inverse ratio of enzyme activity and substrate storage has been observed, with the lowest amounts of enzyme activity and highest amounts of storage material noted in neural tissue from individuals with the most severe form: infantile GM1 gangliosidosis [
MPS IVB is caused by pathogenic variants that impair the catabolism of keratan sulfate and have little effect on GM1 ganglioside accumulation. Keratan sulfate accumulation is thought to be the cause of severe skeletal abnormalities.
The mechanism by which GM1 ganglioside or keratan sulfate primarily accumulates has been explored but not yet established. It is hypothesized that the protein structure coded by
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Duplication results in the addition of another G to a series of six G nucleotides.
## Molecular Pathogenesis
Both disorders are caused by pathogenic variants in
GM1 gangliosidosis is caused by pathogenic variants that lead to accumulation of sphingolipid intermediates in the lysosome and, thus, interfere with appropriate functioning of the organelle. A hallmark of GM1 gangliosidosis is degeneration of the CNS, where ganglioside synthesis is the highest. An inverse ratio of enzyme activity and substrate storage has been observed, with the lowest amounts of enzyme activity and highest amounts of storage material noted in neural tissue from individuals with the most severe form: infantile GM1 gangliosidosis [
MPS IVB is caused by pathogenic variants that impair the catabolism of keratan sulfate and have little effect on GM1 ganglioside accumulation. Keratan sulfate accumulation is thought to be the cause of severe skeletal abnormalities.
The mechanism by which GM1 ganglioside or keratan sulfate primarily accumulates has been explored but not yet established. It is hypothesized that the protein structure coded by
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Duplication results in the addition of another G to a series of six G nucleotides.
## Chapter Notes
The Medical Genetics Branch of the National Human Genome Research Institute continues to study the natural history of patients with GM1. Careful phenotyping and advanced imaging facilitate the characterization of disease progression necessary to evaluate the efficacy of therapeutic interventions. The laboratory is also engaged in studying biomarkers of disease progression in clinical samples, particularly CSF. Careful, repeated observations especially in later-onset patients have identified significantly decreased bone density and an increased incidence of odontoid hypoplasia, particularly in juvenile patients [Author, unpublished observations]. These findings may impact surgical decision making and the activities of daily living. A Phase I/II clinical trial investigating the safety and efficacy of intravenous administration of AAV9-GLB1 vector into individuals with type I and type II GM1 gangliosidosis, sponsored by the National Human Genome Research Institute, is currently underway.
Precilla D'Souza, PNP, DNP and Jean Johnston, BA, MS are gratefully acknowledged for providing excellent care for patients and their families.
22 April 2021 (ha) Comprehensive update posted live
29 August 2019 (aa) Revision: Clinical Characteristics [
17 October 2013 (me) Review posted live
24 January 2013 (ct) Original submission
• 22 April 2021 (ha) Comprehensive update posted live
• 29 August 2019 (aa) Revision: Clinical Characteristics [
• 17 October 2013 (me) Review posted live
• 24 January 2013 (ct) Original submission
## Author Notes
The Medical Genetics Branch of the National Human Genome Research Institute continues to study the natural history of patients with GM1. Careful phenotyping and advanced imaging facilitate the characterization of disease progression necessary to evaluate the efficacy of therapeutic interventions. The laboratory is also engaged in studying biomarkers of disease progression in clinical samples, particularly CSF. Careful, repeated observations especially in later-onset patients have identified significantly decreased bone density and an increased incidence of odontoid hypoplasia, particularly in juvenile patients [Author, unpublished observations]. These findings may impact surgical decision making and the activities of daily living. A Phase I/II clinical trial investigating the safety and efficacy of intravenous administration of AAV9-GLB1 vector into individuals with type I and type II GM1 gangliosidosis, sponsored by the National Human Genome Research Institute, is currently underway.
## Acknowledgments
Precilla D'Souza, PNP, DNP and Jean Johnston, BA, MS are gratefully acknowledged for providing excellent care for patients and their families.
## Revision History
22 April 2021 (ha) Comprehensive update posted live
29 August 2019 (aa) Revision: Clinical Characteristics [
17 October 2013 (me) Review posted live
24 January 2013 (ct) Original submission
• 22 April 2021 (ha) Comprehensive update posted live
• 29 August 2019 (aa) Revision: Clinical Characteristics [
• 17 October 2013 (me) Review posted live
• 24 January 2013 (ct) Original submission
## References
## Literature Cited
Image obtained with a slit lamp demonstrating mild-to-moderate corneal clouding in an adolescent with the juvenile form of GM1 gangliosidosis
Picture courtesy of Dr Wahdi Zein, National Eye Institute, National Institutes of Health, Bethesda, MD
Radiographs of the late-infantile form of GM1 gangliosidosis
A. The odontoid process is under-ossified (white arrow). The vertebral bodies are flattened (black arrow).
B. Hip radiographs showing dysostosis multiplex. The infero-lateral portions of the ilia are not formed, leading to slanting of their lower margins (gray bracket). The capital femoral epiphyses are well-rounded, slightly larger and shorter than normal, and in valgus position (white bracket).
C. The vertebral bodies are more severely flattened dorsally than anteriorly (white arrow) and pear-shaped (black arrow). Defective ossification of the anterior portions of the vertebral bodies in the thoraco-lumbar junction results in a hook shape (black arrow).
Brain MRI findings in a child with the late-infantile form of GM1 gangliosidosis
A. At age 3 years 6 months: T
B and C. At age 6 years 10 months: T
|
[] |
17/10/2013
|
22/4/2021
|
29/8/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
gm2a-def
|
gm2a-def
|
[
"GM2 Gangliosidosis, AB Variant",
"Hexosaminidase Activator Deficiency",
"Tay-Sachs Variant AB",
"GM2 Gangliosidosis, AB Variant",
"Hexosaminidase Activator Deficiency",
"Tay-Sachs Variant AB",
"Ganglioside GM2 activator",
"GM2A",
"GM2 Activator Deficiency"
] |
GM2 Activator Deficiency
|
Changrui Xiao, Camilo Toro, Cyndi Tifft
|
Summary Acute infantile GM2 activator deficiency is a neurodegenerative disorder in which infants, who are generally normal at birth, have progressive weakness and slowing of developmental progress between ages four and 12 months. An ensuing developmental plateau is followed by progressively rapid developmental regression. By the second year of life decerebrate posturing, difficulty in swallowing, and worsening seizures lead to an unresponsive vegetative state. Death usually occurs between ages two and three years. The diagnosis of GM2 activator deficiency is established in a proband with suggestive findings of GM2 gangliosidosis, normal beta-hexosaminidase A (HEX A) enzyme activity levels, and biallelic pathogenic (or likely pathogenic) variants in GM2 activator deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for GM2 activator deficiency have been published.
Progressive weakness or loss of motor skills beginning between ages four to 12 months
Decreased attentiveness
Exaggerated startle response
Hypotonia
Hyperreflexia
Seizures
Delayed myelination and hyperintense T
Normal MRI has also been reported [
The diagnosis of GM2 activator deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GM2 activator deficiency overlaps with several biochemically related disorders (GM2 gangliosidoses), most infants with the findings described in
When the phenotypic and laboratory findings suggest the diagnosis of GM2 activator deficiency, molecular genetic testing approaches can include
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by neurodegeneration, epilepsy, and/or hypotonia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in GM2 Activator Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A homozygous 6-kb deletion of exon 2 (
•
• Progressive weakness or loss of motor skills beginning between ages four to 12 months
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Progressive weakness or loss of motor skills beginning between ages four to 12 months
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Progressive weakness or loss of motor skills beginning between ages four to 12 months
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Delayed myelination and hyperintense T
• Normal MRI has also been reported [
• Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• For an introduction to multigene panels click
## Suggestive Findings
Progressive weakness or loss of motor skills beginning between ages four to 12 months
Decreased attentiveness
Exaggerated startle response
Hypotonia
Hyperreflexia
Seizures
Delayed myelination and hyperintense T
Normal MRI has also been reported [
•
• Progressive weakness or loss of motor skills beginning between ages four to 12 months
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Progressive weakness or loss of motor skills beginning between ages four to 12 months
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Progressive weakness or loss of motor skills beginning between ages four to 12 months
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Delayed myelination and hyperintense T
• Normal MRI has also been reported [
## Establishing the Diagnosis
The diagnosis of GM2 activator deficiency
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GM2 activator deficiency overlaps with several biochemically related disorders (GM2 gangliosidoses), most infants with the findings described in
When the phenotypic and laboratory findings suggest the diagnosis of GM2 activator deficiency, molecular genetic testing approaches can include
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by neurodegeneration, epilepsy, and/or hypotonia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in GM2 Activator Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A homozygous 6-kb deletion of exon 2 (
• Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of GM2 activator deficiency, molecular genetic testing approaches can include
Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
For an introduction to multigene panels click
• Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by neurodegeneration, epilepsy, and/or hypotonia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in GM2 Activator Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A homozygous 6-kb deletion of exon 2 (
## Clinical Characteristics
Acute infantile GM2 activator deficiency is a neurodegenerative disorder in which infants, who are generally normal at birth, have progressive weakness and slowing of developmental progress between ages four and 12 months. An ensuing developmental plateau is followed by progressively rapid developmental regression. By the second year of life decerebrate posturing, difficulty in swallowing, and worsening seizures lead to an unresponsive vegetative state. Death usually occurs between ages two and three years.
To date, 13 individuals have been reported with acute infantile GM2 activator deficiency [
Acute Infantile GM2 Activator Deficiency: Frequency of Select Features
Affected infants are generally normal at birth. Progressive weakness, exaggerated startle, and slowing of developmental progress is typically noted between ages four to 12 months. Decreasing visual attentiveness and unusual eye movements including poor fix-and-follow, typically noted at age three to six months, may be the first signs prompting parents to seek medical attention; subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all affected children.
Affected infants reach a developmental plateau followed by developmental regression typically between ages six to ten months. After age eight to ten months, disease progression is rapid. Voluntary movements diminish and the infant becomes progressively less responsive. Vision deteriorates rapidly.
Seizures and myoclonic jerks are common by age 12 months. Partial complex seizures or absence seizures that are initially subtle typically become more severe and more frequent.
Progressive enlargement of the head resulting from reactive cerebral gliosis beginning by age 18 months followed by ventriculomegaly commonly seen in GM2 gangliosidosis has been inconsistently reported in GM2 activator deficiency [
Further deterioration in the second year of life results in decerebrate posturing, difficulty in swallowing, worsening seizures, and finally an unresponsive, vegetative state.
Three members of one family with childhood-onset progressive cognitive decline, hyperkinetic movement disorder, and global cerebral atrophy were homozygous for the
Another unrelated individual with a childhood-onset progressive movement disorder, cognitive decline, and epilepsy was compound heterozygous for a
The phenotype in these two families likely represents a subacute juvenile form of GM2 activator deficiency similar to that seen in other GM2 gangliosidoses.
No genotype-phenotype correlations have been identified.
GM2 activator deficiency was one of several disorders, including Tay-Sachs disease (see
To distinguish GM2 activator deficiency from Tay-Sachs disease and Sandhoff disease – both of which also involve GM2 ganglioside accumulation because of a shared biochemical pathway for the enzymes involved – GM2 activator deficiency is also referred to as "GM2 gangliosidosis, AB variant" or "Tay-Sachs disease variant AB."
To date, 13 individuals have been reported with infantile-onset GM2 activator deficiency [
## Clinical Description
Acute infantile GM2 activator deficiency is a neurodegenerative disorder in which infants, who are generally normal at birth, have progressive weakness and slowing of developmental progress between ages four and 12 months. An ensuing developmental plateau is followed by progressively rapid developmental regression. By the second year of life decerebrate posturing, difficulty in swallowing, and worsening seizures lead to an unresponsive vegetative state. Death usually occurs between ages two and three years.
To date, 13 individuals have been reported with acute infantile GM2 activator deficiency [
Acute Infantile GM2 Activator Deficiency: Frequency of Select Features
Affected infants are generally normal at birth. Progressive weakness, exaggerated startle, and slowing of developmental progress is typically noted between ages four to 12 months. Decreasing visual attentiveness and unusual eye movements including poor fix-and-follow, typically noted at age three to six months, may be the first signs prompting parents to seek medical attention; subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all affected children.
Affected infants reach a developmental plateau followed by developmental regression typically between ages six to ten months. After age eight to ten months, disease progression is rapid. Voluntary movements diminish and the infant becomes progressively less responsive. Vision deteriorates rapidly.
Seizures and myoclonic jerks are common by age 12 months. Partial complex seizures or absence seizures that are initially subtle typically become more severe and more frequent.
Progressive enlargement of the head resulting from reactive cerebral gliosis beginning by age 18 months followed by ventriculomegaly commonly seen in GM2 gangliosidosis has been inconsistently reported in GM2 activator deficiency [
Further deterioration in the second year of life results in decerebrate posturing, difficulty in swallowing, worsening seizures, and finally an unresponsive, vegetative state.
Three members of one family with childhood-onset progressive cognitive decline, hyperkinetic movement disorder, and global cerebral atrophy were homozygous for the
Another unrelated individual with a childhood-onset progressive movement disorder, cognitive decline, and epilepsy was compound heterozygous for a
The phenotype in these two families likely represents a subacute juvenile form of GM2 activator deficiency similar to that seen in other GM2 gangliosidoses.
## Acute Infantile GM2 Activator Deficiency
Affected infants are generally normal at birth. Progressive weakness, exaggerated startle, and slowing of developmental progress is typically noted between ages four to 12 months. Decreasing visual attentiveness and unusual eye movements including poor fix-and-follow, typically noted at age three to six months, may be the first signs prompting parents to seek medical attention; subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all affected children.
Affected infants reach a developmental plateau followed by developmental regression typically between ages six to ten months. After age eight to ten months, disease progression is rapid. Voluntary movements diminish and the infant becomes progressively less responsive. Vision deteriorates rapidly.
Seizures and myoclonic jerks are common by age 12 months. Partial complex seizures or absence seizures that are initially subtle typically become more severe and more frequent.
Progressive enlargement of the head resulting from reactive cerebral gliosis beginning by age 18 months followed by ventriculomegaly commonly seen in GM2 gangliosidosis has been inconsistently reported in GM2 activator deficiency [
Further deterioration in the second year of life results in decerebrate posturing, difficulty in swallowing, worsening seizures, and finally an unresponsive, vegetative state.
## Possible Subacute Juvenile GM2 Activator Deficiency
Three members of one family with childhood-onset progressive cognitive decline, hyperkinetic movement disorder, and global cerebral atrophy were homozygous for the
Another unrelated individual with a childhood-onset progressive movement disorder, cognitive decline, and epilepsy was compound heterozygous for a
The phenotype in these two families likely represents a subacute juvenile form of GM2 activator deficiency similar to that seen in other GM2 gangliosidoses.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
GM2 activator deficiency was one of several disorders, including Tay-Sachs disease (see
To distinguish GM2 activator deficiency from Tay-Sachs disease and Sandhoff disease – both of which also involve GM2 ganglioside accumulation because of a shared biochemical pathway for the enzymes involved – GM2 activator deficiency is also referred to as "GM2 gangliosidosis, AB variant" or "Tay-Sachs disease variant AB."
## Prevalence
To date, 13 individuals have been reported with infantile-onset GM2 activator deficiency [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic Disorders of Interest in the Differential Diagnosis of Acute Infantile GM2 Activator Deficiency
ERG = electroretinogram
The disorders included in
## Management
No clinical practice guidelines for acute infantile GM2 activator deficiency have been published.
To establish the extent of disease and needs in an individual diagnosed with acute infantile GM2 activator deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Acute Infantile GM2 Activator Deficiency
To incl brain MRI
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Need for adaptive devices
Need for PT (to prevent deformities)
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support;
Home nursing referral.
Assess health care decisions in context of best interest of child & values & preferences of family.
For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams.
EEG = electroencephalogram; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
There is no cure for GM2 activator deficiency.
Supportive treatment to provide adequate nutrition and hydration, manage infectious disease, protect the airway, and control seizures involves multidisciplinary care by specialists in relevant fields (see
Supportive Treatment of Individuals with Acute Infantile GM2 Activator Deficiency
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
Education of parents/caregivers
Assess health care decisions in context of best interest of child & values & preferences of family.
For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
There are no formal guidelines for surveillance for individuals with acute infantile GM2 activator deficiency.
Recommended Surveillance for Individuals with Acute Infantile GM2 Activator Deficiency
OT/PT assessment of ADL & need for splinting for contractures/scoliosis
Durable medical equipment for mobility
ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Avoid the following:
Positioning that increases aspiration risk during feedings
Seizure medication dosages that result in excessive sedation
See
Search
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Need for adaptive devices
• Need for PT (to prevent deformities)
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Assess health care decisions in context of best interest of child & values & preferences of family.
• For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams.
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
• Education of parents/caregivers
• Assess health care decisions in context of best interest of child & values & preferences of family.
• For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams.
• OT/PT assessment of ADL & need for splinting for contractures/scoliosis
• Durable medical equipment for mobility
• Positioning that increases aspiration risk during feedings
• Seizure medication dosages that result in excessive sedation
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with acute infantile GM2 activator deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Acute Infantile GM2 Activator Deficiency
To incl brain MRI
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Need for adaptive devices
Need for PT (to prevent deformities)
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support;
Home nursing referral.
Assess health care decisions in context of best interest of child & values & preferences of family.
For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams.
EEG = electroencephalogram; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Need for adaptive devices
• Need for PT (to prevent deformities)
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Assess health care decisions in context of best interest of child & values & preferences of family.
• For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams.
## Treatment of Manifestations
There is no cure for GM2 activator deficiency.
Supportive treatment to provide adequate nutrition and hydration, manage infectious disease, protect the airway, and control seizures involves multidisciplinary care by specialists in relevant fields (see
Supportive Treatment of Individuals with Acute Infantile GM2 Activator Deficiency
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
Education of parents/caregivers
Assess health care decisions in context of best interest of child & values & preferences of family.
For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASMs.
• Education of parents/caregivers
• Assess health care decisions in context of best interest of child & values & preferences of family.
• For difficult life-prolonging decisions or clarification of treatment options, consider further consultation w/independent clinical teams.
## Surveillance
There are no formal guidelines for surveillance for individuals with acute infantile GM2 activator deficiency.
Recommended Surveillance for Individuals with Acute Infantile GM2 Activator Deficiency
OT/PT assessment of ADL & need for splinting for contractures/scoliosis
Durable medical equipment for mobility
ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
• OT/PT assessment of ADL & need for splinting for contractures/scoliosis
• Durable medical equipment for mobility
## Agents/Circumstances to Avoid
Avoid the following:
Positioning that increases aspiration risk during feedings
Seizure medication dosages that result in excessive sedation
• Positioning that increases aspiration risk during feedings
• Seizure medication dosages that result in excessive sedation
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
GM2 activator deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
GM2 activator deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
GM2 Activator Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GM2 Activator Deficiency (
GM2 activator protein is a substrate-specific cofactor that, together with the enzyme beta-hexosaminidase A (HEX A), catalyzes the degradation of GM2 gangliosides. Gangliosides (normally present in neurons in very small quantities) are progressively stored in neurons, leading to neuronal impairment and loss and causing the characteristic central nervous system and peripheral nervous system neurodegeneration.
HEX A comprises an alpha subunit and a beta subunit encoded by the genes
The forms of GM2 gangliosidosis are
A representative diagram of the interaction between these proteins can be found in
Hexosaminidase Enzyme Findings in GM2 Gangliosidoses
In Tay-Sachs disease total hexosaminidase activity (i.e., HEX A plus HEX B) is decreased, whereas HEX B activity is normal.
In Sandhoff disease both HEX A activity and HEX B activity, as well as total hexosaminidase activity, are decreased; however, the percent contribution from HEX A is increased, because the percent contribution from HEX B is disproportionately decreased by loss of the function of the beta subunit.
In GM2 activator deficiency HEX A and HEX B activity are both normal.
Disease severity in Tay-Sachs and Sandhoff disease is inversely correlated to the residual rate of GM2 ganglioside catabolism. Residual conversion rate of less than 0.5% is thought to correlate with infantile disease, while rates of 2%-4% correlate with juvenile or late-onset forms of Tay-Sachs and Sandhoff disease. Although the pathophysiology of subacute juvenile GM2 activator deficiency is likely also related to residual ganglioside catabolism rates, to date experiments to quantify GM2 conversion rate have not been reported.
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
GM2 activator protein is a substrate-specific cofactor that, together with the enzyme beta-hexosaminidase A (HEX A), catalyzes the degradation of GM2 gangliosides. Gangliosides (normally present in neurons in very small quantities) are progressively stored in neurons, leading to neuronal impairment and loss and causing the characteristic central nervous system and peripheral nervous system neurodegeneration.
HEX A comprises an alpha subunit and a beta subunit encoded by the genes
The forms of GM2 gangliosidosis are
A representative diagram of the interaction between these proteins can be found in
Hexosaminidase Enzyme Findings in GM2 Gangliosidoses
In Tay-Sachs disease total hexosaminidase activity (i.e., HEX A plus HEX B) is decreased, whereas HEX B activity is normal.
In Sandhoff disease both HEX A activity and HEX B activity, as well as total hexosaminidase activity, are decreased; however, the percent contribution from HEX A is increased, because the percent contribution from HEX B is disproportionately decreased by loss of the function of the beta subunit.
In GM2 activator deficiency HEX A and HEX B activity are both normal.
Disease severity in Tay-Sachs and Sandhoff disease is inversely correlated to the residual rate of GM2 ganglioside catabolism. Residual conversion rate of less than 0.5% is thought to correlate with infantile disease, while rates of 2%-4% correlate with juvenile or late-onset forms of Tay-Sachs and Sandhoff disease. Although the pathophysiology of subacute juvenile GM2 activator deficiency is likely also related to residual ganglioside catabolism rates, to date experiments to quantify GM2 conversion rate have not been reported.
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Dr Tifft and Dr Toro are actively involved in clinical research regarding individuals with GM2 activator deficiency. They would be happy to communicate with persons who have any questions regarding diagnosis of GM2 activator deficiency or other considerations.
Dr Tifft, Dr Toro, and Dr Xiao are also interested in hearing from clinicians treating families affected by a GM2 gangliosidosis in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
This work was supported by funds from the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
The authors wish to acknowledge all participants in the "Natural History of Glycosphingolipid and Glycoprotein Storage Disorders" study at the NIH (
25 August 2022 (bp) Review posted live
10 June 2022 (cx) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 25 August 2022 (bp) Review posted live
• 10 June 2022 (cx) Original submission
## Author Notes
Dr Tifft and Dr Toro are actively involved in clinical research regarding individuals with GM2 activator deficiency. They would be happy to communicate with persons who have any questions regarding diagnosis of GM2 activator deficiency or other considerations.
Dr Tifft, Dr Toro, and Dr Xiao are also interested in hearing from clinicians treating families affected by a GM2 gangliosidosis in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
## Acknowledgments
This work was supported by funds from the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
The authors wish to acknowledge all participants in the "Natural History of Glycosphingolipid and Glycoprotein Storage Disorders" study at the NIH (
## Revision History
25 August 2022 (bp) Review posted live
10 June 2022 (cx) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 25 August 2022 (bp) Review posted live
• 10 June 2022 (cx) Original submission
## References
## Literature Cited
|
[] |
25/8/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
gm3-def
|
gm3-def
|
[
"Amish Infantile Epilepsy Syndrome",
"Salt and Pepper Developmental Regression Syndrome",
"ST3GAL5-CDG",
"ST3GAL5 Deficiency",
"Amish Infantile Epilepsy Syndrome",
"Salt and Pepper Developmental Regression Syndrome",
"ST3GAL5-CDG",
"ST3GAL5 Deficiency",
"Lactosylceramide alpha-2,3-sialyltransferase",
"ST3GAL5",
"GM3 Synthase Deficiency"
] |
GM3 Synthase Deficiency
|
Vincent Cruz, Baozhong Xin, Heng Wang
|
Summary Early clinical features of GM3 synthase deficiency include infantile onset of severe irritability with feeding difficulties, early and intractable seizures, growth failure with acquired microcephaly, sensorineural hearing impairment, hypotonia, and poor visual function. Over time, affected individuals experience severe-to-profound developmental delay and intellectual disability, can develop dystonia with hyperkinetic movements, and may develop pigmentary skin changes of the hands and feet. Affected individuals often have frequent ear infections and pneumonia without evidence of immune dysfunction. The diagnosis of GM3 synthase deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in GM3 synthase deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
No consensus clinical diagnostic criteria for GM3 synthase deficiency have been published.
GM3 synthase deficiency
Severe infantile irritability with feeding difficulties
Epilepsy, including infantile spasms, tonic-clonic, myoclonic, and/or generalized seizures
Growth failure
Sensorineural hearing impairment
Acquired (e.g., postnatal) progressive microcephaly
Hypotonia
Cortical visual impairment or optic atrophy
Frequent otitis media and pneumonia
Severe-to-profound developmental delay and intellectual disability
Dystonia and hyperkinetic movement disorders, including choreoathetosis and dyskinesia
Acquired skin hyper- and hypopigmentation anomalies that may change dynamically over time
Scoliosis
The following studies typically are normal or nondiagnostic:
Plasma very long-chain fatty acids
Plasma amino acids
Urine organic acids
Plasma total and free carnitine
Plasma acylcarnitine profile
Serum ammonia
Non-specific abnormalities in serum O-glycan and N-glycan profiles that are not diagnostic of a congenital disorder of glycosylation
Note: Plasma GM3 ganglioside concentration is extremely low or undetectable. However, this test is not widely clinically available, although it may be available in some specialized academic centers.
The diagnosis of GM3 synthase deficiency
Note: (1) Affected individuals also have significantly reduced quantification of GM3 ganglioside levels in blood plasma or in cultured skin fibroblasts [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of GM3 synthase deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for the c.862C>T (p.Arg288Ter) founder pathogenic variant in individuals of Old Order Amish ancestry or the c.740G>A (p.Gly247Asp) founder pathogenic variant in individuals of La Réunion Island ancestry can be performed first [
For an introduction to multigene panels click
When the diagnosis of GM3 synthase deficiency has not been considered, comprehensive genomic testing may be performed.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in GM3 Synthase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no reported cases of GM3 synthase deficiency were due to either whole- or partial-gene deletions or duplications [
• Severe infantile irritability with feeding difficulties
• Epilepsy, including infantile spasms, tonic-clonic, myoclonic, and/or generalized seizures
• Growth failure
• Sensorineural hearing impairment
• Acquired (e.g., postnatal) progressive microcephaly
• Hypotonia
• Cortical visual impairment or optic atrophy
• Frequent otitis media and pneumonia
• Severe-to-profound developmental delay and intellectual disability
• Dystonia and hyperkinetic movement disorders, including choreoathetosis and dyskinesia
• Acquired skin hyper- and hypopigmentation anomalies that may change dynamically over time
• Scoliosis
• The following studies typically are normal or nondiagnostic:
• Plasma very long-chain fatty acids
• Plasma amino acids
• Urine organic acids
• Plasma total and free carnitine
• Plasma acylcarnitine profile
• Serum ammonia
• Plasma very long-chain fatty acids
• Plasma amino acids
• Urine organic acids
• Plasma total and free carnitine
• Plasma acylcarnitine profile
• Serum ammonia
• Non-specific abnormalities in serum O-glycan and N-glycan profiles that are not diagnostic of a congenital disorder of glycosylation
• Note: Plasma GM3 ganglioside concentration is extremely low or undetectable. However, this test is not widely clinically available, although it may be available in some specialized academic centers.
• Plasma very long-chain fatty acids
• Plasma amino acids
• Urine organic acids
• Plasma total and free carnitine
• Plasma acylcarnitine profile
• Serum ammonia
• Note: Targeted analysis for the c.862C>T (p.Arg288Ter) founder pathogenic variant in individuals of Old Order Amish ancestry or the c.740G>A (p.Gly247Asp) founder pathogenic variant in individuals of La Réunion Island ancestry can be performed first [
• For an introduction to multigene panels click
## Suggestive Findings
GM3 synthase deficiency
Severe infantile irritability with feeding difficulties
Epilepsy, including infantile spasms, tonic-clonic, myoclonic, and/or generalized seizures
Growth failure
Sensorineural hearing impairment
Acquired (e.g., postnatal) progressive microcephaly
Hypotonia
Cortical visual impairment or optic atrophy
Frequent otitis media and pneumonia
Severe-to-profound developmental delay and intellectual disability
Dystonia and hyperkinetic movement disorders, including choreoathetosis and dyskinesia
Acquired skin hyper- and hypopigmentation anomalies that may change dynamically over time
Scoliosis
The following studies typically are normal or nondiagnostic:
Plasma very long-chain fatty acids
Plasma amino acids
Urine organic acids
Plasma total and free carnitine
Plasma acylcarnitine profile
Serum ammonia
Non-specific abnormalities in serum O-glycan and N-glycan profiles that are not diagnostic of a congenital disorder of glycosylation
Note: Plasma GM3 ganglioside concentration is extremely low or undetectable. However, this test is not widely clinically available, although it may be available in some specialized academic centers.
• Severe infantile irritability with feeding difficulties
• Epilepsy, including infantile spasms, tonic-clonic, myoclonic, and/or generalized seizures
• Growth failure
• Sensorineural hearing impairment
• Acquired (e.g., postnatal) progressive microcephaly
• Hypotonia
• Cortical visual impairment or optic atrophy
• Frequent otitis media and pneumonia
• Severe-to-profound developmental delay and intellectual disability
• Dystonia and hyperkinetic movement disorders, including choreoathetosis and dyskinesia
• Acquired skin hyper- and hypopigmentation anomalies that may change dynamically over time
• Scoliosis
• The following studies typically are normal or nondiagnostic:
• Plasma very long-chain fatty acids
• Plasma amino acids
• Urine organic acids
• Plasma total and free carnitine
• Plasma acylcarnitine profile
• Serum ammonia
• Plasma very long-chain fatty acids
• Plasma amino acids
• Urine organic acids
• Plasma total and free carnitine
• Plasma acylcarnitine profile
• Serum ammonia
• Non-specific abnormalities in serum O-glycan and N-glycan profiles that are not diagnostic of a congenital disorder of glycosylation
• Note: Plasma GM3 ganglioside concentration is extremely low or undetectable. However, this test is not widely clinically available, although it may be available in some specialized academic centers.
• Plasma very long-chain fatty acids
• Plasma amino acids
• Urine organic acids
• Plasma total and free carnitine
• Plasma acylcarnitine profile
• Serum ammonia
## Establishing the Diagnosis
The diagnosis of GM3 synthase deficiency
Note: (1) Affected individuals also have significantly reduced quantification of GM3 ganglioside levels in blood plasma or in cultured skin fibroblasts [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of GM3 synthase deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for the c.862C>T (p.Arg288Ter) founder pathogenic variant in individuals of Old Order Amish ancestry or the c.740G>A (p.Gly247Asp) founder pathogenic variant in individuals of La Réunion Island ancestry can be performed first [
For an introduction to multigene panels click
When the diagnosis of GM3 synthase deficiency has not been considered, comprehensive genomic testing may be performed.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in GM3 Synthase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no reported cases of GM3 synthase deficiency were due to either whole- or partial-gene deletions or duplications [
• Note: Targeted analysis for the c.862C>T (p.Arg288Ter) founder pathogenic variant in individuals of Old Order Amish ancestry or the c.740G>A (p.Gly247Asp) founder pathogenic variant in individuals of La Réunion Island ancestry can be performed first [
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of GM3 synthase deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for the c.862C>T (p.Arg288Ter) founder pathogenic variant in individuals of Old Order Amish ancestry or the c.740G>A (p.Gly247Asp) founder pathogenic variant in individuals of La Réunion Island ancestry can be performed first [
For an introduction to multigene panels click
• Note: Targeted analysis for the c.862C>T (p.Arg288Ter) founder pathogenic variant in individuals of Old Order Amish ancestry or the c.740G>A (p.Gly247Asp) founder pathogenic variant in individuals of La Réunion Island ancestry can be performed first [
• For an introduction to multigene panels click
## Option 2
When the diagnosis of GM3 synthase deficiency has not been considered, comprehensive genomic testing may be performed.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in GM3 Synthase Deficiency
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date, no reported cases of GM3 synthase deficiency were due to either whole- or partial-gene deletions or duplications [
## Clinical Characteristics
GM3 synthase deficiency likely represents a spectrum of disease severity [
Select Features of GM3 Synthase Deficiency
Typically severe, beginning in infancy
Caregivers may report sleepless nights.
Typically beginning in infancy
Frequently characterized as epileptic encephalopathy
Seizures are often refractory to medical therapy (see
Optic atrophy
Cortical blindness
May be underreported without rigorous testing
Not present at birth
Reportedly dynamic,
May be mistaken for freckling
GERD = gastroesophageal reflux disease
Some features may develop and/or progress over time, making the estimate of the number of affected individuals who have each feature dependent on age at the time of evaluation.
Children may briefly meet early developmental milestones, despite hypotonia, until onset of seizure activity. However, few affected individuals achieve early developmental milestones, consistent with infantile-onset developmental arrest.
Ultimately, most affected individuals are nonverbal, lack purposeful movements, and are wheelchair bound with little or no expressive or receptive language skills. However, there are a few cases of ambulatory individuals who may represent a milder form of the disorder.
Seizures typically begin in infancy around the time of developmental stagnation and with EEG studies consistent with epileptic encephalopathy.
There is no single seizure type that is typical or pathognomonic for GM3 synthase deficiency. Seizures can range from focal to generalized, with or without motor onset.
Affected individuals may display multiple types of seizures, including generalized tonic-clonic, myoclonic, tonic, atonic, and behavior arrest [
Generalized tonic-clonic seizures were the most commonly reported by
Approximately 17% of children will meet criteria for infantile spasms (i.e., West Syndrome) [
Disorganized backgrounds, multifocal discharges, and absent sleep/wake cycles
Background slow spike-and-wave patterns (found in 75%) and hypsarrhythmia
These EEG findings may fulfill clinical criteria for epilepsy syndromes, including Lennox-Gestaut syndrome or West syndrome.
Bruxism, torticollis, torsion, and various other dystonic findings have been variably reported in individual cases.
Chorea, ballismus/hemiballsimus, stereotypy, limb/facial dyskinesia, and myoclonus have been described in children and young adults [
Diffuse cerebral atrophy is the most consistent late disease finding. With disease progression, neurodegeneration may be observed.
In contrast, serial MRIs were reported as normal until at least age 13 years in one symptomatic affected individual [
Poor feeding in infancy is reported in nearly all affected children. It may be the presenting symptom, as it often precedes the onset of seizures, growth failure, or developmental delay.
Feeding difficulties are often accompanied by irritability.
No particular formula or diet has been shown to improve feeding, and assisted feeding may be necessary.
Improved weight gain and growth improvements with oral ganglioside supplementation and nutritional support with gastrostomy tube (G-tube) placement have both been reported (see
Visual evoked potentials and ERGs may be normal, indicating retained retinal function as late as the teenage years, and are likely not beneficial in the diagnosis of GM synthase deficiency.
There are variable reports of optic nerve pallor on standard funduscopic examination.
Optic atrophy in combination with visual cortical blindness is likely to cause permanent and irreversible vision loss without known treatments [
The skin findings are flat macules, typically lentigo-sized, that can be either hypo- or hyperpigmented, found on the dorsal aspect of hands and feet. These lesions are often mistaken for freckles.
Lesions may be "dynamic" and spontaneously resolve or worsen over time without clear cause.
Skin findings may be less obvious on individuals with lighter skin tones.
The presence of typical skin findings may be helpful in the diagnosis of older individuals; however, they are not seen in infancy or early childhood, nor are they constant. Therefore, a lack of skin changes does not preclude the diagnosis.
Frequent otitis media and pneumonia have been reported as common long-term comorbidities of GM3 synthase deficiency, although there has been no evidence of immune dysfunction in affected individuals [
Progressive scoliosis has also been reported [
No genotype-phenotype correlations for
GM3 synthase deficiency has been referred to as "Amish infantile epilepsy syndrome" and as "salt and pepper developmental regression syndrome" in the published literature, although these designations are considered misleading and somewhat archaic.
Careful review of the original literature reveals that some publications reference "regression" without specific or concrete definitions or descriptions of the purported developmental skills lost or the timing of the purported regression.
In GM3 synthase deficiency, significant, objective developmental milestones are rarely (if ever) met, so they cannot be subsequently lost. Instead, the developmental trajectory is more accurately described as developmental arrest without attainment.
With disease progression, neurodegeneration may be observed, but the term "regression" should be reserved for conditions in which there are clearly defined and profound loss of skills.
GM3 synthase deficiency is rare. More than 100 cases have been reported in the literature in several different populations.
The overall prevalence is higher in the Old Order Amish of North America due to the pathogenic founder variant c.862C>T (p.Arg288Ter). The estimated carrier frequency for this population is 1.7% (Anabaptist Variant Server, retrived 8-1-22). Note that this pathogenic variant has also been reported in affected individuals from other populations (French and Pakistani) unrelated to the Old Order Amish, and therefore may represent a recurrent pathogenic variant [
The overall prevalence and carrier frequency is unknown in individuals of La Réunion Island ancestry. All affected individuals with known La Réunion Island ancestry are either homozygous or compound heterozygous for the pathogenic founder variant c.740G>A (p.Gly247Asp) [
• Typically severe, beginning in infancy
• Caregivers may report sleepless nights.
• Typically beginning in infancy
• Frequently characterized as epileptic encephalopathy
• Seizures are often refractory to medical therapy (see
• Optic atrophy
• Cortical blindness
• May be underreported without rigorous testing
• Not present at birth
• Reportedly dynamic,
• May be mistaken for freckling
• Children may briefly meet early developmental milestones, despite hypotonia, until onset of seizure activity. However, few affected individuals achieve early developmental milestones, consistent with infantile-onset developmental arrest.
• Ultimately, most affected individuals are nonverbal, lack purposeful movements, and are wheelchair bound with little or no expressive or receptive language skills. However, there are a few cases of ambulatory individuals who may represent a milder form of the disorder.
• Seizures typically begin in infancy around the time of developmental stagnation and with EEG studies consistent with epileptic encephalopathy.
• There is no single seizure type that is typical or pathognomonic for GM3 synthase deficiency. Seizures can range from focal to generalized, with or without motor onset.
• Affected individuals may display multiple types of seizures, including generalized tonic-clonic, myoclonic, tonic, atonic, and behavior arrest [
• Generalized tonic-clonic seizures were the most commonly reported by
• Approximately 17% of children will meet criteria for infantile spasms (i.e., West Syndrome) [
• Generalized tonic-clonic seizures were the most commonly reported by
• Approximately 17% of children will meet criteria for infantile spasms (i.e., West Syndrome) [
• Generalized tonic-clonic seizures were the most commonly reported by
• Approximately 17% of children will meet criteria for infantile spasms (i.e., West Syndrome) [
• Disorganized backgrounds, multifocal discharges, and absent sleep/wake cycles
• Background slow spike-and-wave patterns (found in 75%) and hypsarrhythmia
• Bruxism, torticollis, torsion, and various other dystonic findings have been variably reported in individual cases.
• Chorea, ballismus/hemiballsimus, stereotypy, limb/facial dyskinesia, and myoclonus have been described in children and young adults [
• Diffuse cerebral atrophy is the most consistent late disease finding. With disease progression, neurodegeneration may be observed.
• In contrast, serial MRIs were reported as normal until at least age 13 years in one symptomatic affected individual [
• Poor feeding in infancy is reported in nearly all affected children. It may be the presenting symptom, as it often precedes the onset of seizures, growth failure, or developmental delay.
• Feeding difficulties are often accompanied by irritability.
• No particular formula or diet has been shown to improve feeding, and assisted feeding may be necessary.
• Improved weight gain and growth improvements with oral ganglioside supplementation and nutritional support with gastrostomy tube (G-tube) placement have both been reported (see
• Visual evoked potentials and ERGs may be normal, indicating retained retinal function as late as the teenage years, and are likely not beneficial in the diagnosis of GM synthase deficiency.
• There are variable reports of optic nerve pallor on standard funduscopic examination.
• Optic atrophy in combination with visual cortical blindness is likely to cause permanent and irreversible vision loss without known treatments [
• The skin findings are flat macules, typically lentigo-sized, that can be either hypo- or hyperpigmented, found on the dorsal aspect of hands and feet. These lesions are often mistaken for freckles.
• Lesions may be "dynamic" and spontaneously resolve or worsen over time without clear cause.
• Skin findings may be less obvious on individuals with lighter skin tones.
• The presence of typical skin findings may be helpful in the diagnosis of older individuals; however, they are not seen in infancy or early childhood, nor are they constant. Therefore, a lack of skin changes does not preclude the diagnosis.
• Frequent otitis media and pneumonia have been reported as common long-term comorbidities of GM3 synthase deficiency, although there has been no evidence of immune dysfunction in affected individuals [
• Progressive scoliosis has also been reported [
• Careful review of the original literature reveals that some publications reference "regression" without specific or concrete definitions or descriptions of the purported developmental skills lost or the timing of the purported regression.
• In GM3 synthase deficiency, significant, objective developmental milestones are rarely (if ever) met, so they cannot be subsequently lost. Instead, the developmental trajectory is more accurately described as developmental arrest without attainment.
• With disease progression, neurodegeneration may be observed, but the term "regression" should be reserved for conditions in which there are clearly defined and profound loss of skills.
• Careful review of the original literature reveals that some publications reference "regression" without specific or concrete definitions or descriptions of the purported developmental skills lost or the timing of the purported regression.
• In GM3 synthase deficiency, significant, objective developmental milestones are rarely (if ever) met, so they cannot be subsequently lost. Instead, the developmental trajectory is more accurately described as developmental arrest without attainment.
• With disease progression, neurodegeneration may be observed, but the term "regression" should be reserved for conditions in which there are clearly defined and profound loss of skills.
• Careful review of the original literature reveals that some publications reference "regression" without specific or concrete definitions or descriptions of the purported developmental skills lost or the timing of the purported regression.
• In GM3 synthase deficiency, significant, objective developmental milestones are rarely (if ever) met, so they cannot be subsequently lost. Instead, the developmental trajectory is more accurately described as developmental arrest without attainment.
• With disease progression, neurodegeneration may be observed, but the term "regression" should be reserved for conditions in which there are clearly defined and profound loss of skills.
## Clinical Description
GM3 synthase deficiency likely represents a spectrum of disease severity [
Select Features of GM3 Synthase Deficiency
Typically severe, beginning in infancy
Caregivers may report sleepless nights.
Typically beginning in infancy
Frequently characterized as epileptic encephalopathy
Seizures are often refractory to medical therapy (see
Optic atrophy
Cortical blindness
May be underreported without rigorous testing
Not present at birth
Reportedly dynamic,
May be mistaken for freckling
GERD = gastroesophageal reflux disease
Some features may develop and/or progress over time, making the estimate of the number of affected individuals who have each feature dependent on age at the time of evaluation.
Children may briefly meet early developmental milestones, despite hypotonia, until onset of seizure activity. However, few affected individuals achieve early developmental milestones, consistent with infantile-onset developmental arrest.
Ultimately, most affected individuals are nonverbal, lack purposeful movements, and are wheelchair bound with little or no expressive or receptive language skills. However, there are a few cases of ambulatory individuals who may represent a milder form of the disorder.
Seizures typically begin in infancy around the time of developmental stagnation and with EEG studies consistent with epileptic encephalopathy.
There is no single seizure type that is typical or pathognomonic for GM3 synthase deficiency. Seizures can range from focal to generalized, with or without motor onset.
Affected individuals may display multiple types of seizures, including generalized tonic-clonic, myoclonic, tonic, atonic, and behavior arrest [
Generalized tonic-clonic seizures were the most commonly reported by
Approximately 17% of children will meet criteria for infantile spasms (i.e., West Syndrome) [
Disorganized backgrounds, multifocal discharges, and absent sleep/wake cycles
Background slow spike-and-wave patterns (found in 75%) and hypsarrhythmia
These EEG findings may fulfill clinical criteria for epilepsy syndromes, including Lennox-Gestaut syndrome or West syndrome.
Bruxism, torticollis, torsion, and various other dystonic findings have been variably reported in individual cases.
Chorea, ballismus/hemiballsimus, stereotypy, limb/facial dyskinesia, and myoclonus have been described in children and young adults [
Diffuse cerebral atrophy is the most consistent late disease finding. With disease progression, neurodegeneration may be observed.
In contrast, serial MRIs were reported as normal until at least age 13 years in one symptomatic affected individual [
Poor feeding in infancy is reported in nearly all affected children. It may be the presenting symptom, as it often precedes the onset of seizures, growth failure, or developmental delay.
Feeding difficulties are often accompanied by irritability.
No particular formula or diet has been shown to improve feeding, and assisted feeding may be necessary.
Improved weight gain and growth improvements with oral ganglioside supplementation and nutritional support with gastrostomy tube (G-tube) placement have both been reported (see
Visual evoked potentials and ERGs may be normal, indicating retained retinal function as late as the teenage years, and are likely not beneficial in the diagnosis of GM synthase deficiency.
There are variable reports of optic nerve pallor on standard funduscopic examination.
Optic atrophy in combination with visual cortical blindness is likely to cause permanent and irreversible vision loss without known treatments [
The skin findings are flat macules, typically lentigo-sized, that can be either hypo- or hyperpigmented, found on the dorsal aspect of hands and feet. These lesions are often mistaken for freckles.
Lesions may be "dynamic" and spontaneously resolve or worsen over time without clear cause.
Skin findings may be less obvious on individuals with lighter skin tones.
The presence of typical skin findings may be helpful in the diagnosis of older individuals; however, they are not seen in infancy or early childhood, nor are they constant. Therefore, a lack of skin changes does not preclude the diagnosis.
Frequent otitis media and pneumonia have been reported as common long-term comorbidities of GM3 synthase deficiency, although there has been no evidence of immune dysfunction in affected individuals [
Progressive scoliosis has also been reported [
• Typically severe, beginning in infancy
• Caregivers may report sleepless nights.
• Typically beginning in infancy
• Frequently characterized as epileptic encephalopathy
• Seizures are often refractory to medical therapy (see
• Optic atrophy
• Cortical blindness
• May be underreported without rigorous testing
• Not present at birth
• Reportedly dynamic,
• May be mistaken for freckling
• Children may briefly meet early developmental milestones, despite hypotonia, until onset of seizure activity. However, few affected individuals achieve early developmental milestones, consistent with infantile-onset developmental arrest.
• Ultimately, most affected individuals are nonverbal, lack purposeful movements, and are wheelchair bound with little or no expressive or receptive language skills. However, there are a few cases of ambulatory individuals who may represent a milder form of the disorder.
• Seizures typically begin in infancy around the time of developmental stagnation and with EEG studies consistent with epileptic encephalopathy.
• There is no single seizure type that is typical or pathognomonic for GM3 synthase deficiency. Seizures can range from focal to generalized, with or without motor onset.
• Affected individuals may display multiple types of seizures, including generalized tonic-clonic, myoclonic, tonic, atonic, and behavior arrest [
• Generalized tonic-clonic seizures were the most commonly reported by
• Approximately 17% of children will meet criteria for infantile spasms (i.e., West Syndrome) [
• Generalized tonic-clonic seizures were the most commonly reported by
• Approximately 17% of children will meet criteria for infantile spasms (i.e., West Syndrome) [
• Generalized tonic-clonic seizures were the most commonly reported by
• Approximately 17% of children will meet criteria for infantile spasms (i.e., West Syndrome) [
• Disorganized backgrounds, multifocal discharges, and absent sleep/wake cycles
• Background slow spike-and-wave patterns (found in 75%) and hypsarrhythmia
• Bruxism, torticollis, torsion, and various other dystonic findings have been variably reported in individual cases.
• Chorea, ballismus/hemiballsimus, stereotypy, limb/facial dyskinesia, and myoclonus have been described in children and young adults [
• Diffuse cerebral atrophy is the most consistent late disease finding. With disease progression, neurodegeneration may be observed.
• In contrast, serial MRIs were reported as normal until at least age 13 years in one symptomatic affected individual [
• Poor feeding in infancy is reported in nearly all affected children. It may be the presenting symptom, as it often precedes the onset of seizures, growth failure, or developmental delay.
• Feeding difficulties are often accompanied by irritability.
• No particular formula or diet has been shown to improve feeding, and assisted feeding may be necessary.
• Improved weight gain and growth improvements with oral ganglioside supplementation and nutritional support with gastrostomy tube (G-tube) placement have both been reported (see
• Visual evoked potentials and ERGs may be normal, indicating retained retinal function as late as the teenage years, and are likely not beneficial in the diagnosis of GM synthase deficiency.
• There are variable reports of optic nerve pallor on standard funduscopic examination.
• Optic atrophy in combination with visual cortical blindness is likely to cause permanent and irreversible vision loss without known treatments [
• The skin findings are flat macules, typically lentigo-sized, that can be either hypo- or hyperpigmented, found on the dorsal aspect of hands and feet. These lesions are often mistaken for freckles.
• Lesions may be "dynamic" and spontaneously resolve or worsen over time without clear cause.
• Skin findings may be less obvious on individuals with lighter skin tones.
• The presence of typical skin findings may be helpful in the diagnosis of older individuals; however, they are not seen in infancy or early childhood, nor are they constant. Therefore, a lack of skin changes does not preclude the diagnosis.
• Frequent otitis media and pneumonia have been reported as common long-term comorbidities of GM3 synthase deficiency, although there has been no evidence of immune dysfunction in affected individuals [
• Progressive scoliosis has also been reported [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
## Nomenclature
GM3 synthase deficiency has been referred to as "Amish infantile epilepsy syndrome" and as "salt and pepper developmental regression syndrome" in the published literature, although these designations are considered misleading and somewhat archaic.
Careful review of the original literature reveals that some publications reference "regression" without specific or concrete definitions or descriptions of the purported developmental skills lost or the timing of the purported regression.
In GM3 synthase deficiency, significant, objective developmental milestones are rarely (if ever) met, so they cannot be subsequently lost. Instead, the developmental trajectory is more accurately described as developmental arrest without attainment.
With disease progression, neurodegeneration may be observed, but the term "regression" should be reserved for conditions in which there are clearly defined and profound loss of skills.
• Careful review of the original literature reveals that some publications reference "regression" without specific or concrete definitions or descriptions of the purported developmental skills lost or the timing of the purported regression.
• In GM3 synthase deficiency, significant, objective developmental milestones are rarely (if ever) met, so they cannot be subsequently lost. Instead, the developmental trajectory is more accurately described as developmental arrest without attainment.
• With disease progression, neurodegeneration may be observed, but the term "regression" should be reserved for conditions in which there are clearly defined and profound loss of skills.
• Careful review of the original literature reveals that some publications reference "regression" without specific or concrete definitions or descriptions of the purported developmental skills lost or the timing of the purported regression.
• In GM3 synthase deficiency, significant, objective developmental milestones are rarely (if ever) met, so they cannot be subsequently lost. Instead, the developmental trajectory is more accurately described as developmental arrest without attainment.
• With disease progression, neurodegeneration may be observed, but the term "regression" should be reserved for conditions in which there are clearly defined and profound loss of skills.
• Careful review of the original literature reveals that some publications reference "regression" without specific or concrete definitions or descriptions of the purported developmental skills lost or the timing of the purported regression.
• In GM3 synthase deficiency, significant, objective developmental milestones are rarely (if ever) met, so they cannot be subsequently lost. Instead, the developmental trajectory is more accurately described as developmental arrest without attainment.
• With disease progression, neurodegeneration may be observed, but the term "regression" should be reserved for conditions in which there are clearly defined and profound loss of skills.
## Prevalence
GM3 synthase deficiency is rare. More than 100 cases have been reported in the literature in several different populations.
The overall prevalence is higher in the Old Order Amish of North America due to the pathogenic founder variant c.862C>T (p.Arg288Ter). The estimated carrier frequency for this population is 1.7% (Anabaptist Variant Server, retrived 8-1-22). Note that this pathogenic variant has also been reported in affected individuals from other populations (French and Pakistani) unrelated to the Old Order Amish, and therefore may represent a recurrent pathogenic variant [
The overall prevalence and carrier frequency is unknown in individuals of La Réunion Island ancestry. All affected individuals with known La Réunion Island ancestry are either homozygous or compound heterozygous for the pathogenic founder variant c.740G>A (p.Gly247Asp) [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Selected Genes of Interest in the Differential Diagnosis of GM3 Synthase Deficiency
Most other CDGs are assoc w/congenital, not acquired, microcephaly.
Skeletal findings (incl enlarged fontanel), liver dysfunction, enteropathy, & hypoglycemia are not seen in GM3 synthase deficiency.
Old Order Amish founder variant
Seizures, DD
Relative macrocephaly is seen in FXS, whereas GM3 synthase is assoc w/relative normal head size at birth followed by acquired microcephaly.
Seizures & irritability are not defining features of FXS.
Note: The physical & behavioral features seen in males w/FXS have been reported in females heterozygous for the
Skin dyspigmentation, visual deficits, & hearing impairment are not defining features of Rett syndrome.
Profound regression w/significant loss of acquired developmental skills is not often seen in GM3 synthase deficiency.
Old Order Amish founder variant
Microcephaly, seizures, feeding intolerances, neonatal hypotonia, irritability
Congenital hearing impairment & acquired microcephaly are not reported in DEE15.
Structural brain malformations noted on imaging in DEE15 may not be present in GM3 synthase deficiency.
AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; DD = developmental delay; MOI = mode of inheritance; XL = X-linked
Most congenital disorders of N-linked glycosylation and multiple pathways are inherited in an autosomal recessive manner.
A recurrent splice acceptor site pathogenic variant (c.1411-2A>G) in intron 12 is seen in persons of Amish ancestry and represents an ancient founder variant (see
• Most other CDGs are assoc w/congenital, not acquired, microcephaly.
• Skeletal findings (incl enlarged fontanel), liver dysfunction, enteropathy, & hypoglycemia are not seen in GM3 synthase deficiency.
• Old Order Amish founder variant
• Seizures, DD
• Relative macrocephaly is seen in FXS, whereas GM3 synthase is assoc w/relative normal head size at birth followed by acquired microcephaly.
• Seizures & irritability are not defining features of FXS.
• Note: The physical & behavioral features seen in males w/FXS have been reported in females heterozygous for the
• Skin dyspigmentation, visual deficits, & hearing impairment are not defining features of Rett syndrome.
• Profound regression w/significant loss of acquired developmental skills is not often seen in GM3 synthase deficiency.
• Old Order Amish founder variant
• Microcephaly, seizures, feeding intolerances, neonatal hypotonia, irritability
• Congenital hearing impairment & acquired microcephaly are not reported in DEE15.
• Structural brain malformations noted on imaging in DEE15 may not be present in GM3 synthase deficiency.
## Management
No clinical practice guidelines for GM3 synthase deficiency have been published.
To establish the extent of disease and needs in an individual diagnosed with GM3 synthase deficiency, the evaluations summarized
GM3 Synthase Deficiency: Recommended Evaluations Following Initial Diagnosis
GERD
Constipation
Seizures
Otitis media
Other infections
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Irritability
Sleep disturbances
Self-injurious behaviors
Consider eval for GERD.
Consider swallow eval of aspiration risk & nutritional status.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; AEP = auditory evoked potential; DPOAE = distortion-product otoacoustic emission; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for GM3 synthase deficiency.
GM3 Synthase Deficiency: Treatment of Manifestations
Consider standard therapies such as proton pump inhibitors for GERD, motility agents for constipation, ASM for seizures, & typical antibiotics for infections, as needed.
Off-label use of SSRIs may be considered when precipitating factors are not identified [Authors, personal observations].
No ASM has been demonstrated effective specifically for this disorder.
ASM treatment may be only partially effective & multiple ASMs may be required.
Education of parents/caregivers
Anticipatory guidance on proper use of rescue medications for seizure activity & possibility of drug-resistant epilepsy
There is no particular medication that has been proven to be superior for treatment of insomnia.
Antihistamines, melatonin, benzodiazepines, & alpha-adrenergic agonists may be appropriate on case-by-case basis.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Gastrostomy tube placement does not appear to significantly alter growth trajectory.
Oral ganglioside supplementation & nutritional support w/gastrostomy tube has not produced lasting changes in growth parameters
Children: through early intervention programs &/or school district
Adults: referral to low vision clinic &/or community vision services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
GM3 Synthase Deficiency: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Monitor for signs/symptoms of pneumonia.
Non-invasive SpO
See
Recent attempts to ameliorate the effects of the loss of function in GM3 synthase deficiency by oral supplementation with a diet high in the products of the missing enzyme (GM3 gangliosides) showed only modest short-term benefit for affected individuals in a single-arm open label study (
Search
• GERD
• Constipation
• Seizures
• Otitis media
• Other infections
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Irritability
• Sleep disturbances
• Self-injurious behaviors
• Consider eval for GERD.
• Consider swallow eval of aspiration risk & nutritional status.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Consider standard therapies such as proton pump inhibitors for GERD, motility agents for constipation, ASM for seizures, & typical antibiotics for infections, as needed.
• Off-label use of SSRIs may be considered when precipitating factors are not identified [Authors, personal observations].
• No ASM has been demonstrated effective specifically for this disorder.
• ASM treatment may be only partially effective & multiple ASMs may be required.
• Education of parents/caregivers
• Anticipatory guidance on proper use of rescue medications for seizure activity & possibility of drug-resistant epilepsy
• There is no particular medication that has been proven to be superior for treatment of insomnia.
• Antihistamines, melatonin, benzodiazepines, & alpha-adrenergic agonists may be appropriate on case-by-case basis.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
• Gastrostomy tube placement does not appear to significantly alter growth trajectory.
• Oral ganglioside supplementation & nutritional support w/gastrostomy tube has not produced lasting changes in growth parameters
• Children: through early intervention programs &/or school district
• Adults: referral to low vision clinic &/or community vision services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Monitor for signs/symptoms of pneumonia.
• Non-invasive SpO
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with GM3 synthase deficiency, the evaluations summarized
GM3 Synthase Deficiency: Recommended Evaluations Following Initial Diagnosis
GERD
Constipation
Seizures
Otitis media
Other infections
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Irritability
Sleep disturbances
Self-injurious behaviors
Consider eval for GERD.
Consider swallow eval of aspiration risk & nutritional status.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; AEP = auditory evoked potential; DPOAE = distortion-product otoacoustic emission; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• GERD
• Constipation
• Seizures
• Otitis media
• Other infections
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Irritability
• Sleep disturbances
• Self-injurious behaviors
• Consider eval for GERD.
• Consider swallow eval of aspiration risk & nutritional status.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for GM3 synthase deficiency.
GM3 Synthase Deficiency: Treatment of Manifestations
Consider standard therapies such as proton pump inhibitors for GERD, motility agents for constipation, ASM for seizures, & typical antibiotics for infections, as needed.
Off-label use of SSRIs may be considered when precipitating factors are not identified [Authors, personal observations].
No ASM has been demonstrated effective specifically for this disorder.
ASM treatment may be only partially effective & multiple ASMs may be required.
Education of parents/caregivers
Anticipatory guidance on proper use of rescue medications for seizure activity & possibility of drug-resistant epilepsy
There is no particular medication that has been proven to be superior for treatment of insomnia.
Antihistamines, melatonin, benzodiazepines, & alpha-adrenergic agonists may be appropriate on case-by-case basis.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Gastrostomy tube placement does not appear to significantly alter growth trajectory.
Oral ganglioside supplementation & nutritional support w/gastrostomy tube has not produced lasting changes in growth parameters
Children: through early intervention programs &/or school district
Adults: referral to low vision clinic &/or community vision services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Consider standard therapies such as proton pump inhibitors for GERD, motility agents for constipation, ASM for seizures, & typical antibiotics for infections, as needed.
• Off-label use of SSRIs may be considered when precipitating factors are not identified [Authors, personal observations].
• No ASM has been demonstrated effective specifically for this disorder.
• ASM treatment may be only partially effective & multiple ASMs may be required.
• Education of parents/caregivers
• Anticipatory guidance on proper use of rescue medications for seizure activity & possibility of drug-resistant epilepsy
• There is no particular medication that has been proven to be superior for treatment of insomnia.
• Antihistamines, melatonin, benzodiazepines, & alpha-adrenergic agonists may be appropriate on case-by-case basis.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
• Gastrostomy tube placement does not appear to significantly alter growth trajectory.
• Oral ganglioside supplementation & nutritional support w/gastrostomy tube has not produced lasting changes in growth parameters
• Children: through early intervention programs &/or school district
• Adults: referral to low vision clinic &/or community vision services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
GM3 Synthase Deficiency: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Monitor for signs/symptoms of pneumonia.
Non-invasive SpO
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Monitor for signs/symptoms of pneumonia.
• Non-invasive SpO
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Recent attempts to ameliorate the effects of the loss of function in GM3 synthase deficiency by oral supplementation with a diet high in the products of the missing enzyme (GM3 gangliosides) showed only modest short-term benefit for affected individuals in a single-arm open label study (
Search
## Genetic Counseling
GM3 synthase deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
The carrier frequencies of
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• The carrier frequencies of
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
GM3 synthase deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are presumed to be heterozygous for an
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
The carrier frequencies of
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• The carrier frequencies of
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
•
•
•
•
•
• Canada
•
## Molecular Genetics
GM3 Synthase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GM3 Synthase Deficiency (
Broadly speaking,
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Broadly speaking,
Variants listed in the table have been provided by the authors.
## Chapter Notes
DDC Clinic – Center for Special Needs Children is located in Middlefield, Ohio, USA. In the heart of the world's fourth-largest Amish settlement, DDC Clinic was founded in 1998 by a group of Amish families who were committed to helping special needs children get the care they needed.
Since its humble beginnings, DDC Clinic has grown into a world-class medical facility with cutting-edge research capabilities and an onsite certified molecular diagnostics laboratory serving patients, families, and health professionals worldwide.
Our work encompasses three critical areas of medical services – patient care, research, and education. We provide personalized medical care for special needs children with nearly 200 different rare conditions, and we have served more than 1,500 patient families in 35 US states, Canada, Australia, Europe, and Asia.
For more information, or to contact the authors, go to
The authors wholeheartedly thank the hundreds of families from the Plain Community affected by GM3 synthase deficiency under the care of DDC Clinic – Center for Special Needs Children. They are the true experts and have graciously allowed us to share their experiences and insights of the disorder with the world. Without their continued support, this chapter would not be possible.
20 July 2023 (ma) Review posted live
30 September 2022 (vc) Original submission
• 20 July 2023 (ma) Review posted live
• 30 September 2022 (vc) Original submission
## Author Notes
DDC Clinic – Center for Special Needs Children is located in Middlefield, Ohio, USA. In the heart of the world's fourth-largest Amish settlement, DDC Clinic was founded in 1998 by a group of Amish families who were committed to helping special needs children get the care they needed.
Since its humble beginnings, DDC Clinic has grown into a world-class medical facility with cutting-edge research capabilities and an onsite certified molecular diagnostics laboratory serving patients, families, and health professionals worldwide.
Our work encompasses three critical areas of medical services – patient care, research, and education. We provide personalized medical care for special needs children with nearly 200 different rare conditions, and we have served more than 1,500 patient families in 35 US states, Canada, Australia, Europe, and Asia.
For more information, or to contact the authors, go to
## Acknowledgments
The authors wholeheartedly thank the hundreds of families from the Plain Community affected by GM3 synthase deficiency under the care of DDC Clinic – Center for Special Needs Children. They are the true experts and have graciously allowed us to share their experiences and insights of the disorder with the world. Without their continued support, this chapter would not be possible.
## Revision History
20 July 2023 (ma) Review posted live
30 September 2022 (vc) Original submission
• 20 July 2023 (ma) Review posted live
• 30 September 2022 (vc) Original submission
## References
## Literature Cited
|
[] |
20/7/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
gnai1-ndd
|
gnai1-ndd
|
[
"Guanine nucleotide-binding protein G(i) subunit alpha-1",
"GNAI1",
"GNAI1-Related Neurodevelopmental Disorder"
] |
Emily Bonkowski, Esmat Fathi, Heather C Mefford
|
Summary The diagnosis of
|
## Diagnosis
Mild-to-profound developmental delay
Hypotonia
Mild-to-profound intellectual disability
Neurobehavioral/psychiatric manifestations (autism spectrum disorder, temper tantrums, anxiety, agitation, aggression, and attention-deficit/hyperactivity disorder)
Epilepsy (absence, generalized tonic-clonic, focal-onset impaired awareness)
Atrophy (global)
Delayed myelination
Choroid plexus cysts
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
To date, no large intragenic deletions/duplications have been reported in individuals with
• Mild-to-profound developmental delay
• Hypotonia
• Mild-to-profound intellectual disability
• Neurobehavioral/psychiatric manifestations (autism spectrum disorder, temper tantrums, anxiety, agitation, aggression, and attention-deficit/hyperactivity disorder)
• Epilepsy (absence, generalized tonic-clonic, focal-onset impaired awareness)
• Atrophy (global)
• Delayed myelination
• Choroid plexus cysts
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Suggestive Findings
Mild-to-profound developmental delay
Hypotonia
Mild-to-profound intellectual disability
Neurobehavioral/psychiatric manifestations (autism spectrum disorder, temper tantrums, anxiety, agitation, aggression, and attention-deficit/hyperactivity disorder)
Epilepsy (absence, generalized tonic-clonic, focal-onset impaired awareness)
Atrophy (global)
Delayed myelination
Choroid plexus cysts
• Mild-to-profound developmental delay
• Hypotonia
• Mild-to-profound intellectual disability
• Neurobehavioral/psychiatric manifestations (autism spectrum disorder, temper tantrums, anxiety, agitation, aggression, and attention-deficit/hyperactivity disorder)
• Epilepsy (absence, generalized tonic-clonic, focal-onset impaired awareness)
• Atrophy (global)
• Delayed myelination
• Choroid plexus cysts
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
To date, no large intragenic deletions/duplications have been reported in individuals with
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Clinical Characteristics
Select Features of
Based on
One individual with
No genotype-phenotype correlations have been identified.
Fewer than 30 individuals have been reported to have
## Clinical Description
Select Features of
Based on
One individual with
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
Fewer than 30 individuals have been reported to have
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The phenotypic features associated with
•
•
•
•
•
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Scoliosis
Hip dysplasia
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Evaluate height & weight.
Gastroenterology / nutrition / feeding team eval
Assess for constipation.
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Assess for new seizures.
Monitor those w/known seizures as clinically indicated.
Physical medicine, OT/PT assessment of mobility, self-help skills
Assess for scoliosis.
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Scoliosis
• Hip dysplasia
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Evaluate height & weight.
• Gastroenterology / nutrition / feeding team eval
• Assess for constipation.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Assess for new seizures.
• Monitor those w/known seizures as clinically indicated.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Assess for scoliosis.
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Scoliosis
Hip dysplasia
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Evaluate height & weight.
Gastroenterology / nutrition / feeding team eval
Assess for constipation.
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Scoliosis
• Hip dysplasia
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Evaluate height & weight.
• Gastroenterology / nutrition / feeding team eval
• Assess for constipation.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Assess for new seizures.
Monitor those w/known seizures as clinically indicated.
Physical medicine, OT/PT assessment of mobility, self-help skills
Assess for scoliosis.
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
• Assess for new seizures.
• Monitor those w/known seizures as clinically indicated.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Assess for scoliosis.
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most probands reported to date with
A proband with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and to inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
* A parent with somatic and germline mosaicism for a
If a parent of the proband is known to have the
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Most probands reported to date with
• A proband with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and to inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is known to have the
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Most probands reported to date with
A proband with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and to inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
* A parent with somatic and germline mosaicism for a
If a parent of the proband is known to have the
If the
• Most probands reported to date with
• A proband with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and to inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is known to have the
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
Canada
•
•
•
•
•
• Canada
•
•
•
•
• Canada
•
•
•
•
•
•
## Molecular Genetics
GNAI1-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GNAI1-Related Neurodevelopmental Disorder (
Gαi1 couples negatively to adenylyl cyclase (AC) to inhibit the production of cyclic adenosine monophosphate (cAMP) with downstream impact on the MAPK/ERK pathway, while their G protein βγ partners mediate the Akt-mTOR and other pathways, which are important in regulation of cell proliferation and growth [
To date, at least 17 pathogenic variants in
## Molecular Pathogenesis
Gαi1 couples negatively to adenylyl cyclase (AC) to inhibit the production of cyclic adenosine monophosphate (cAMP) with downstream impact on the MAPK/ERK pathway, while their G protein βγ partners mediate the Akt-mTOR and other pathways, which are important in regulation of cell proliferation and growth [
To date, at least 17 pathogenic variants in
## Chapter Notes
Dr Mefford (
1 August 2024 (sw) Review posted live
8 September 2023 (hm) Original submission
• 1 August 2024 (sw) Review posted live
• 8 September 2023 (hm) Original submission
## Author Notes
Dr Mefford (
## Revision History
1 August 2024 (sw) Review posted live
8 September 2023 (hm) Original submission
• 1 August 2024 (sw) Review posted live
• 8 September 2023 (hm) Original submission
## References
## Literature Cited
|
[] |
1/8/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
gnal-dystonia
|
gnal-dystonia
|
[
"DYT25",
"GNAL-Related Dystonia",
"GNAL-Related Dystonia",
"DYT25",
"Guanine nucleotide-binding protein G(olf) subunit alpha",
"GNAL",
"DYT-GNAL"
] |
DYT-
|
Angela B Deutschländer, Zbigniew K Wszolek
|
Summary DYT- DYT- The diagnosis of DYT- DYT- Most individuals with autosomal dominant DYT-
|
## Diagnosis
No formal diagnostic criteria have been established for DYT-
DYT-
DYT-
Isolated; no neurologic abnormalities other than tremor evident on neurologic examination
Age at onset typically in adulthood; rarely in childhood [
Most commonly focal and segmental; rarely generalized [
Onset typically in the cervical region and commonly progressing to the cranial region (oromandibular/jaw, larynx, blepharospasm) and/or to one arm
Brain magnetic resonance imaging and computed tomography results are normal, showing no structural intracranial lesions that could be considered a cause of acquired dystonia.
Consistent with autosomal dominant inheritance (i.e., includes both familial cases and simplex cases [a single occurrence in a family]). The one exception is autosomal recessive inheritance reported in two Turkish sibs [
The diagnosis of DYT-
A single report found a homozygous
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the phenotype of DYT-
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in DYT-
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Isolated; no neurologic abnormalities other than tremor evident on neurologic examination
• Age at onset typically in adulthood; rarely in childhood [
• Most commonly focal and segmental; rarely generalized [
• Onset typically in the cervical region and commonly progressing to the cranial region (oromandibular/jaw, larynx, blepharospasm) and/or to one arm
• For an introduction to multigene panels click
• If exome sequencing is not diagnostic,
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
DYT-
DYT-
Isolated; no neurologic abnormalities other than tremor evident on neurologic examination
Age at onset typically in adulthood; rarely in childhood [
Most commonly focal and segmental; rarely generalized [
Onset typically in the cervical region and commonly progressing to the cranial region (oromandibular/jaw, larynx, blepharospasm) and/or to one arm
Brain magnetic resonance imaging and computed tomography results are normal, showing no structural intracranial lesions that could be considered a cause of acquired dystonia.
Consistent with autosomal dominant inheritance (i.e., includes both familial cases and simplex cases [a single occurrence in a family]). The one exception is autosomal recessive inheritance reported in two Turkish sibs [
• Isolated; no neurologic abnormalities other than tremor evident on neurologic examination
• Age at onset typically in adulthood; rarely in childhood [
• Most commonly focal and segmental; rarely generalized [
• Onset typically in the cervical region and commonly progressing to the cranial region (oromandibular/jaw, larynx, blepharospasm) and/or to one arm
## Clinical Findings
DYT-
Isolated; no neurologic abnormalities other than tremor evident on neurologic examination
Age at onset typically in adulthood; rarely in childhood [
Most commonly focal and segmental; rarely generalized [
Onset typically in the cervical region and commonly progressing to the cranial region (oromandibular/jaw, larynx, blepharospasm) and/or to one arm
• Isolated; no neurologic abnormalities other than tremor evident on neurologic examination
• Age at onset typically in adulthood; rarely in childhood [
• Most commonly focal and segmental; rarely generalized [
• Onset typically in the cervical region and commonly progressing to the cranial region (oromandibular/jaw, larynx, blepharospasm) and/or to one arm
## Neuroimaging Studies
Brain magnetic resonance imaging and computed tomography results are normal, showing no structural intracranial lesions that could be considered a cause of acquired dystonia.
## Family History
Consistent with autosomal dominant inheritance (i.e., includes both familial cases and simplex cases [a single occurrence in a family]). The one exception is autosomal recessive inheritance reported in two Turkish sibs [
## Establishing the Diagnosis
The diagnosis of DYT-
A single report found a homozygous
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the phenotype of DYT-
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in DYT-
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• If exome sequencing is not diagnostic,
• For an introduction to comprehensive genomic testing click
## Molecular Genetic Testing
Because the phenotype of DYT-
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in DYT-
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
• If exome sequencing is not diagnostic,
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
DYT-
Since its original description [
62 individuals with a heterozygous
Two sibs (from a consanguineous union) homozygous for a
Data available on 56 individuals revealed the following regarding the first body region affected by dystonia:
Cervical region: 78%
Larynx: 9%
Oromandibular region/jaw/tongue: 7%
Leg: two individuals
Face: one individual
Other initial manifestations were dystonic arm tremor (2 individuals) and isolated head tremor (1 individual).
In a study of 28 individuals, dystonia remained focal in 12 and became segmental in 13 or generalized in three [
In 62 individuals the sites involved during the disease course included the following:
Cervical dystonia: 84%
Oromandibular dystonia including dystonia of the jaw and tongue: 29%
Upper facial dystonia including blepharospasm: 22.6%
Dystonia of the arm or isolated dystonic tremor of the arm: 29%
Laryngeal dystonia: 21%
Truncal dystonia: 16%
Dystonia in a leg: 8%
Tremor was also frequently reported, most commonly as dystonic head and/or arm tremor.
Speech involvement was reported in 44% of 28 affected individuals [
To date the only individuals known to have biallelic DYT-
No clinically relevant genotype-phenotype correlations are known for either heterozygous or biallelic
The penetrance for heterozygous DYT-
14 unaffected heterozygotes (mean age: 29 years, age range: 9-51 years) identified in three of four families [
One unaffected heterozygote who was a parent of two offspring with DYT-
One unaffected heterozygote who was the mother of a 40-year-old with laryngeal dystonia [
Following the new naming system for the genetic dystonias in which the causative gene has been confirmed, the prefix "DYT" is followed by the gene symbol [
DYT-
Studies in families of northern European descent with primary torsion dystonia of mixed European origin [
In contrast, in studies including mostly simplex cases (i.e., a single occurrence in a family) with mostly isolated dystonia, the prevalence was about 0.5% (0-1.1%) [
A study on 57 individuals with isolated laryngeal dystonia found a slightly higher prevalence of 1.8% [
• 62 individuals with a heterozygous
• Two sibs (from a consanguineous union) homozygous for a
• Cervical region: 78%
• Larynx: 9%
• Oromandibular region/jaw/tongue: 7%
• Leg: two individuals
• Face: one individual
• Cervical dystonia: 84%
• Oromandibular dystonia including dystonia of the jaw and tongue: 29%
• Upper facial dystonia including blepharospasm: 22.6%
• Dystonia of the arm or isolated dystonic tremor of the arm: 29%
• Laryngeal dystonia: 21%
• Truncal dystonia: 16%
• Dystonia in a leg: 8%
• 14 unaffected heterozygotes (mean age: 29 years, age range: 9-51 years) identified in three of four families [
• One unaffected heterozygote who was a parent of two offspring with DYT-
• One unaffected heterozygote who was the mother of a 40-year-old with laryngeal dystonia [
## Clinical Description
DYT-
Since its original description [
62 individuals with a heterozygous
Two sibs (from a consanguineous union) homozygous for a
Data available on 56 individuals revealed the following regarding the first body region affected by dystonia:
Cervical region: 78%
Larynx: 9%
Oromandibular region/jaw/tongue: 7%
Leg: two individuals
Face: one individual
Other initial manifestations were dystonic arm tremor (2 individuals) and isolated head tremor (1 individual).
In a study of 28 individuals, dystonia remained focal in 12 and became segmental in 13 or generalized in three [
In 62 individuals the sites involved during the disease course included the following:
Cervical dystonia: 84%
Oromandibular dystonia including dystonia of the jaw and tongue: 29%
Upper facial dystonia including blepharospasm: 22.6%
Dystonia of the arm or isolated dystonic tremor of the arm: 29%
Laryngeal dystonia: 21%
Truncal dystonia: 16%
Dystonia in a leg: 8%
Tremor was also frequently reported, most commonly as dystonic head and/or arm tremor.
Speech involvement was reported in 44% of 28 affected individuals [
To date the only individuals known to have biallelic DYT-
• 62 individuals with a heterozygous
• Two sibs (from a consanguineous union) homozygous for a
• Cervical region: 78%
• Larynx: 9%
• Oromandibular region/jaw/tongue: 7%
• Leg: two individuals
• Face: one individual
• Cervical dystonia: 84%
• Oromandibular dystonia including dystonia of the jaw and tongue: 29%
• Upper facial dystonia including blepharospasm: 22.6%
• Dystonia of the arm or isolated dystonic tremor of the arm: 29%
• Laryngeal dystonia: 21%
• Truncal dystonia: 16%
• Dystonia in a leg: 8%
## Heterozygous DYT-
Data available on 56 individuals revealed the following regarding the first body region affected by dystonia:
Cervical region: 78%
Larynx: 9%
Oromandibular region/jaw/tongue: 7%
Leg: two individuals
Face: one individual
Other initial manifestations were dystonic arm tremor (2 individuals) and isolated head tremor (1 individual).
In a study of 28 individuals, dystonia remained focal in 12 and became segmental in 13 or generalized in three [
In 62 individuals the sites involved during the disease course included the following:
Cervical dystonia: 84%
Oromandibular dystonia including dystonia of the jaw and tongue: 29%
Upper facial dystonia including blepharospasm: 22.6%
Dystonia of the arm or isolated dystonic tremor of the arm: 29%
Laryngeal dystonia: 21%
Truncal dystonia: 16%
Dystonia in a leg: 8%
Tremor was also frequently reported, most commonly as dystonic head and/or arm tremor.
Speech involvement was reported in 44% of 28 affected individuals [
• Cervical region: 78%
• Larynx: 9%
• Oromandibular region/jaw/tongue: 7%
• Leg: two individuals
• Face: one individual
• Cervical dystonia: 84%
• Oromandibular dystonia including dystonia of the jaw and tongue: 29%
• Upper facial dystonia including blepharospasm: 22.6%
• Dystonia of the arm or isolated dystonic tremor of the arm: 29%
• Laryngeal dystonia: 21%
• Truncal dystonia: 16%
• Dystonia in a leg: 8%
## Biallelic DYT-
To date the only individuals known to have biallelic DYT-
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations are known for either heterozygous or biallelic
## Penetrance
The penetrance for heterozygous DYT-
14 unaffected heterozygotes (mean age: 29 years, age range: 9-51 years) identified in three of four families [
One unaffected heterozygote who was a parent of two offspring with DYT-
One unaffected heterozygote who was the mother of a 40-year-old with laryngeal dystonia [
• 14 unaffected heterozygotes (mean age: 29 years, age range: 9-51 years) identified in three of four families [
• One unaffected heterozygote who was a parent of two offspring with DYT-
• One unaffected heterozygote who was the mother of a 40-year-old with laryngeal dystonia [
## Nomenclature
Following the new naming system for the genetic dystonias in which the causative gene has been confirmed, the prefix "DYT" is followed by the gene symbol [
## Prevalence
DYT-
Studies in families of northern European descent with primary torsion dystonia of mixed European origin [
In contrast, in studies including mostly simplex cases (i.e., a single occurrence in a family) with mostly isolated dystonia, the prevalence was about 0.5% (0-1.1%) [
A study on 57 individuals with isolated laryngeal dystonia found a slightly higher prevalence of 1.8% [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
See
Autosomal Dominant Disorders to Consider in the Differential Diagnosis of DYT-
Median: 13 yrs (range: 2-49 yrs)
Median: 13 yrs (range 2-62 yrs)
Mean: 48 yrs (range: 8-69 yrs)
Mean:14 yrs (range 4-44 yrs)
Early onset, typically childhood; late onset in some
60% to 70% progress to generalized (or multifocal) dystonia.
~20% have focal dystonia, most frequently writer's cramp.
Ashkenazi Jewish ancestry common
Reduced penetrance of ~30%
More rapid progression
Face & neck typically spared
Cervical dystonia
Myoclonic jerks typical of DYT-SGCE have been described in DYT-
Action-induced, alcohol-responsive myoclonic jerks
Psychiatric features common (incl alcohol dependence)
Adult-onset craniocervical dystonia
Laryngeal dystonia
Upper-limb dystonia (incl arm tremor)
See
Cervical dystonia may be the only presentation in DYT-
• Median: 13 yrs (range: 2-49 yrs)
• Median: 13 yrs (range 2-62 yrs)
• Mean: 48 yrs (range: 8-69 yrs)
• Mean:14 yrs (range 4-44 yrs)
• Early onset, typically childhood; late onset in some
• 60% to 70% progress to generalized (or multifocal) dystonia.
• ~20% have focal dystonia, most frequently writer's cramp.
• Ashkenazi Jewish ancestry common
• Reduced penetrance of ~30%
• More rapid progression
• Face & neck typically spared
• Cervical dystonia
• Myoclonic jerks typical of DYT-SGCE have been described in DYT-
• Action-induced, alcohol-responsive myoclonic jerks
• Psychiatric features common (incl alcohol dependence)
• Adult-onset craniocervical dystonia
• Laryngeal dystonia
• Upper-limb dystonia (incl arm tremor)
## Management
To establish the extent of disease and needs in an individual diagnosed with DYT-
Recommended Evaluations Following Initial Diagnosis in Individuals with DYT-
Burke-Fahn-Marsden dystonia rating scale (BFMDRS)
Unified Dystonia Rating Scale (UDRS)
Global Dystonia Rating Scale (GDS)
Eval for botulinum toxin injections into laryngeal muscles by otorhinolaryngologist
Eval by speech therapist
Voluntary maneuver that temporarily reduces the severity of dystonic postures or movements
All treatment options are symptomatic.
Oral drugs currently used to treat dystonia:
Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
Baclofen
Benzodiazepines (diazepam, clonazepam, lorazepam)
Additional drugs that may be considered:
Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
Antiepileptics; e.g., gabapentin [
Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
Two individuals with DYT-
One individual with DYT-
In three individuals, cervical dystonia improved significantly, while cranial dystonia (including dysarthria) and limb dystonia did not improve or worsened [
Follow up includes more frequent visits in the first weeks and months after surgery in order to determine the best stimulation parameters.
Depression and anxiety are treated as per standard practice. Of note, dopamine-depleting agents, anticholinergics, and other drugs may cause or worsen psychiatric and cognitive features.
Follow up with a neurologist specializing in movement disorders several times a year is recommended to monitor for the following:
Worsening of dystonia
Development of new manifestations
Medication side effects
Issues related to DBS treatment including side effects such as hypokinesia and battery life
Regular monitoring for psychiatric and cognitive features is indicated; medication adjustments and consultation with a psychiatrist may be necessary.
Dystonia of limbs can worsen if affected limbs are casted or braced. Similarly, neck collars should be avoided in persons with cervical dystonia.
See
Controlled human studies on the safety of baclofen use during pregnancy have not been completed. Several case reports of baclofen use in the first trimester of pregnancy with normal fetal outcome have been published. Third-trimester exposure may lead to abnormalities in neonatal adaptation.
The use of diazepam during the first trimester of pregnancy may be associated with an increased risk of cleft palate; thus, in situations where use of a benzodiazepine during pregnancy is required, other medications (e.g., lorazepam or clonazepam) may be preferable. Third-trimester use of a benzodiazepine may lead to neonatal complications, such as decreased tone and/or sedation.
Botulinum toxin injections are typically avoided during pregnancy and breastfeeding. However, in several case reports of women who received botulinum toxin A injections in the first trimester of pregnancy, infants were born at full term with no complications.
Data are insufficient to determine if the use of trihexyphenidyl during pregnancy has an effect on the developing fetus.
See
The following clinical trials (identified by NCT number) on DBS in "primary dystonia" are listed in ClinicalTrials.gov. (The term "primary dystonia" currently is mainly used for genetic or idiopathic forms of isolated dystonia without a consistent pathologic/structural change.) Note that none is specifically recruiting individuals with DYT-
Other rTMS studies conducted or recruiting:
Search
• Burke-Fahn-Marsden dystonia rating scale (BFMDRS)
• Unified Dystonia Rating Scale (UDRS)
• Global Dystonia Rating Scale (GDS)
• Eval for botulinum toxin injections into laryngeal muscles by otorhinolaryngologist
• Eval by speech therapist
• Oral drugs currently used to treat dystonia:
• Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
• Baclofen
• Benzodiazepines (diazepam, clonazepam, lorazepam)
• Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
• Baclofen
• Benzodiazepines (diazepam, clonazepam, lorazepam)
• Additional drugs that may be considered:
• Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
• Antiepileptics; e.g., gabapentin [
• Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
• Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
• Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
• Antiepileptics; e.g., gabapentin [
• Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
• Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
• Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
• Baclofen
• Benzodiazepines (diazepam, clonazepam, lorazepam)
• Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
• Antiepileptics; e.g., gabapentin [
• Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
• Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
• Two individuals with DYT-
• One individual with DYT-
• In three individuals, cervical dystonia improved significantly, while cranial dystonia (including dysarthria) and limb dystonia did not improve or worsened [
• Worsening of dystonia
• Development of new manifestations
• Medication side effects
• Issues related to DBS treatment including side effects such as hypokinesia and battery life
• Other rTMS studies conducted or recruiting:
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with DYT-
Recommended Evaluations Following Initial Diagnosis in Individuals with DYT-
Burke-Fahn-Marsden dystonia rating scale (BFMDRS)
Unified Dystonia Rating Scale (UDRS)
Global Dystonia Rating Scale (GDS)
Eval for botulinum toxin injections into laryngeal muscles by otorhinolaryngologist
Eval by speech therapist
Voluntary maneuver that temporarily reduces the severity of dystonic postures or movements
• Burke-Fahn-Marsden dystonia rating scale (BFMDRS)
• Unified Dystonia Rating Scale (UDRS)
• Global Dystonia Rating Scale (GDS)
• Eval for botulinum toxin injections into laryngeal muscles by otorhinolaryngologist
• Eval by speech therapist
## Treatment of Manifestations
All treatment options are symptomatic.
Oral drugs currently used to treat dystonia:
Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
Baclofen
Benzodiazepines (diazepam, clonazepam, lorazepam)
Additional drugs that may be considered:
Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
Antiepileptics; e.g., gabapentin [
Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
Two individuals with DYT-
One individual with DYT-
In three individuals, cervical dystonia improved significantly, while cranial dystonia (including dysarthria) and limb dystonia did not improve or worsened [
Follow up includes more frequent visits in the first weeks and months after surgery in order to determine the best stimulation parameters.
Depression and anxiety are treated as per standard practice. Of note, dopamine-depleting agents, anticholinergics, and other drugs may cause or worsen psychiatric and cognitive features.
• Oral drugs currently used to treat dystonia:
• Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
• Baclofen
• Benzodiazepines (diazepam, clonazepam, lorazepam)
• Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
• Baclofen
• Benzodiazepines (diazepam, clonazepam, lorazepam)
• Additional drugs that may be considered:
• Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
• Antiepileptics; e.g., gabapentin [
• Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
• Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
• Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
• Antiepileptics; e.g., gabapentin [
• Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
• Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
• Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
• Baclofen
• Benzodiazepines (diazepam, clonazepam, lorazepam)
• Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
• Antiepileptics; e.g., gabapentin [
• Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
• Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
• Two individuals with DYT-
• One individual with DYT-
• In three individuals, cervical dystonia improved significantly, while cranial dystonia (including dysarthria) and limb dystonia did not improve or worsened [
## Dystonia
All treatment options are symptomatic.
Oral drugs currently used to treat dystonia:
Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
Baclofen
Benzodiazepines (diazepam, clonazepam, lorazepam)
Additional drugs that may be considered:
Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
Antiepileptics; e.g., gabapentin [
Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
Two individuals with DYT-
One individual with DYT-
In three individuals, cervical dystonia improved significantly, while cranial dystonia (including dysarthria) and limb dystonia did not improve or worsened [
Follow up includes more frequent visits in the first weeks and months after surgery in order to determine the best stimulation parameters.
• Oral drugs currently used to treat dystonia:
• Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
• Baclofen
• Benzodiazepines (diazepam, clonazepam, lorazepam)
• Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
• Baclofen
• Benzodiazepines (diazepam, clonazepam, lorazepam)
• Additional drugs that may be considered:
• Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
• Antiepileptics; e.g., gabapentin [
• Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
• Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
• Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
• Antiepileptics; e.g., gabapentin [
• Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
• Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
• Anticholinergics (trihexyphenidyl is most widely used; benztropine). These need to be monitored especially for cognitive side effects.
• Baclofen
• Benzodiazepines (diazepam, clonazepam, lorazepam)
• Levodopa. Note: levodopa/carbidopa was not beneficial in individuals with DYT-
• Antiepileptics; e.g., gabapentin [
• Dopamine-depleting agents, most importantly tetrabenazine, which requires monitoring for psychiatric side effects (depressive episodes). Note: Tetrabenazine provided no benefit in one individual with DYT-
• Propanolol, cyclobenzaprine, trabenazine, and ethopropazine reported in a recent study [
• Two individuals with DYT-
• One individual with DYT-
• In three individuals, cervical dystonia improved significantly, while cranial dystonia (including dysarthria) and limb dystonia did not improve or worsened [
## Psychiatric Comorbidities
Depression and anxiety are treated as per standard practice. Of note, dopamine-depleting agents, anticholinergics, and other drugs may cause or worsen psychiatric and cognitive features.
## Surveillance
Follow up with a neurologist specializing in movement disorders several times a year is recommended to monitor for the following:
Worsening of dystonia
Development of new manifestations
Medication side effects
Issues related to DBS treatment including side effects such as hypokinesia and battery life
Regular monitoring for psychiatric and cognitive features is indicated; medication adjustments and consultation with a psychiatrist may be necessary.
• Worsening of dystonia
• Development of new manifestations
• Medication side effects
• Issues related to DBS treatment including side effects such as hypokinesia and battery life
## Agents/Circumstances to Avoid
Dystonia of limbs can worsen if affected limbs are casted or braced. Similarly, neck collars should be avoided in persons with cervical dystonia.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Controlled human studies on the safety of baclofen use during pregnancy have not been completed. Several case reports of baclofen use in the first trimester of pregnancy with normal fetal outcome have been published. Third-trimester exposure may lead to abnormalities in neonatal adaptation.
The use of diazepam during the first trimester of pregnancy may be associated with an increased risk of cleft palate; thus, in situations where use of a benzodiazepine during pregnancy is required, other medications (e.g., lorazepam or clonazepam) may be preferable. Third-trimester use of a benzodiazepine may lead to neonatal complications, such as decreased tone and/or sedation.
Botulinum toxin injections are typically avoided during pregnancy and breastfeeding. However, in several case reports of women who received botulinum toxin A injections in the first trimester of pregnancy, infants were born at full term with no complications.
Data are insufficient to determine if the use of trihexyphenidyl during pregnancy has an effect on the developing fetus.
See
## Therapies Under Investigation
The following clinical trials (identified by NCT number) on DBS in "primary dystonia" are listed in ClinicalTrials.gov. (The term "primary dystonia" currently is mainly used for genetic or idiopathic forms of isolated dystonia without a consistent pathologic/structural change.) Note that none is specifically recruiting individuals with DYT-
Other rTMS studies conducted or recruiting:
Search
• Other rTMS studies conducted or recruiting:
## Genetic Counseling
DYT-
Autosomal recessive inheritance of DYT-
About 65% of individuals diagnosed with DYT-
Some individuals diagnosed with DYT-
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
The family history of some affected individuals may appear to be negative for DYT-
If the parents have been tested for the
A parent of the proband has the
The
If the parents have not been tested for the
Of note, several families with unaffected parents and multiple affected sibs of a proband have been reported [
Each child of an individual with DYT-
Because of significant intrafamilial phenotypic variability, an affected child may be more severely or less severely affected than the parent who transmitted the pathogenic variant.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• About 65% of individuals diagnosed with DYT-
• Some individuals diagnosed with DYT-
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• The family history of some affected individuals may appear to be negative for DYT-
• If the parents have been tested for the
• A parent of the proband has the
• The
• A parent of the proband has the
• The
• If the parents have not been tested for the
• Of note, several families with unaffected parents and multiple affected sibs of a proband have been reported [
• A parent of the proband has the
• The
• Each child of an individual with DYT-
• Because of significant intrafamilial phenotypic variability, an affected child may be more severely or less severely affected than the parent who transmitted the pathogenic variant.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
DYT-
Autosomal recessive inheritance of DYT-
## Risk to Family Members – Autosomal Dominant Inheritance
About 65% of individuals diagnosed with DYT-
Some individuals diagnosed with DYT-
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
The family history of some affected individuals may appear to be negative for DYT-
If the parents have been tested for the
A parent of the proband has the
The
If the parents have not been tested for the
Of note, several families with unaffected parents and multiple affected sibs of a proband have been reported [
Each child of an individual with DYT-
Because of significant intrafamilial phenotypic variability, an affected child may be more severely or less severely affected than the parent who transmitted the pathogenic variant.
• About 65% of individuals diagnosed with DYT-
• Some individuals diagnosed with DYT-
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• The family history of some affected individuals may appear to be negative for DYT-
• If the parents have been tested for the
• A parent of the proband has the
• The
• A parent of the proband has the
• The
• If the parents have not been tested for the
• Of note, several families with unaffected parents and multiple affected sibs of a proband have been reported [
• A parent of the proband has the
• The
• Each child of an individual with DYT-
• Because of significant intrafamilial phenotypic variability, an affected child may be more severely or less severely affected than the parent who transmitted the pathogenic variant.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Connecting People for Dystonia
Belgium
United Kingdom
Germany
Dystonia Medical Research Foundation
•
•
•
• Connecting People for Dystonia
• Belgium
•
•
•
•
• United Kingdom
•
•
•
•
• Germany
•
•
• Dystonia Medical Research Foundation
•
## Molecular Genetics
DYT-GNAL: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for DYT-GNAL (
In addition, one splice site variant [
Twenty-eight pathogenic variants were found only in a single family. Two pathogenic variants were reported in two independent studies: c.274-5T>C [
Variants listed in the table have been provided by the authors.
Gα(olf) was first identified in the olfactory epithelium as a G protein subunit that mediates odorant signaling. It was later found to be widely expressed in the brain, especially in motor regions that have been linked to dystonia pathogenesis. Gα(olf) is expressed at high levels in the striatum (striatal medium spiny neurons, MSNs), postsynaptically in dopaminoceptive neurons and/or cholinergic interneurons (reviewed by
## Chapter Notes
AD is supported by the Max Kade Foundation and a gift from Carl Edward Bolch Jr and Susan Bass Bolch. ZKW is partially supported by the NIH/NINDS P50 NS072187, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation and the James C and Sarah K Kennedy Fund for Neurodegenerative Disease Research at the Mayo Clinic in Florida), the Sol Goldman Charitable Trust, and a gift from Donald G and Jodi P Heeringa.
3 January 2019 (bp) Review posted live
19 December 2017 (ad) Original submission
• 3 January 2019 (bp) Review posted live
• 19 December 2017 (ad) Original submission
## Acknowledgments
AD is supported by the Max Kade Foundation and a gift from Carl Edward Bolch Jr and Susan Bass Bolch. ZKW is partially supported by the NIH/NINDS P50 NS072187, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation and the James C and Sarah K Kennedy Fund for Neurodegenerative Disease Research at the Mayo Clinic in Florida), the Sol Goldman Charitable Trust, and a gift from Donald G and Jodi P Heeringa.
## Revision History
3 January 2019 (bp) Review posted live
19 December 2017 (ad) Original submission
• 3 January 2019 (bp) Review posted live
• 19 December 2017 (ad) Original submission
## References
## Literature Cited
|
[] |
3/1/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
gnao1-dis
|
gnao1-dis
|
[
"GNAO1-Associated Disorder",
"GNAO1-Associated Epileptic Encephalopathy and Movement Disorder",
"GNAO1-Associated Epileptic Encephalopathy and Movement Disorder",
"GNAO1-Associated Disorder",
"Guanine nucleotide-binding protein G(o) subunit alpha",
"GNAO1",
"GNAO1-Related Disorder"
] |
Lauren Briere, Moritz Thiel, David A Sweetser, Anne Koy, Erika Axeen
|
Summary Epilepsy can be either DEE (onset typically within the first year of life of drug-resistant epilepsy in which developmental delays are attributed to the underlying diagnosis as well as the impact of uncontrolled seizures) or varying seizure types (onset typically between ages three and ten years of focal or generalized tonic-clonic seizures that may be infrequent or well controlled with anti-seizure medications). Movement disorders are characterized by dystonia and choreoathetosis, most commonly a mixed pattern of persistent or paroxysmal dyskinesia that affects the whole body. Exacerbations of the hyperkinetic movement disorder, which can be spontaneous or triggered (e.g., by intercurrent illness, emotional stress, voluntary movements), can last minutes to weeks. Hyperkinetic crises (including status dystonicus) are characterized by temporarily increased and nearly continuous involuntary movements or dystonic posturing that can be life-threatening. Deaths in early childhood have been reported due to medically refractory epilepsy or hyperkinetic crises, but the phenotypic spectrum includes milder presentations, including in adults. As many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with The diagnosis of
|
AD = autosomal dominant; MOI = mode of inheritance
The international League Against Epilepsy defines DEE as an epileptic encephalopathy where the developmental impairment relates to the underlying etiology as well as uncontrolled epileptic activity.
## Diagnosis
No consensus clinical diagnostic criteria for
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Combined data from all published cases to date (See collected citations in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
One whole-gene deletion [
While not included in the percentages above, at least four contiguous gene deletions including
•
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
•
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Combined data from all published cases to date (See collected citations in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
One whole-gene deletion [
While not included in the percentages above, at least four contiguous gene deletions including
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date, information on more than 200 individuals with
Approximately half (50%-65%) of affected individuals have seizures and/or are diagnosed with epilepsy. While seizures may be refractory to anti-seizure medications (ASMs), some individuals have only a single seizure [
Developmental and epileptic encephalopathy (DEE) is the most common epilepsy phenotype, occurring in 69% of individuals with epilepsy [
Seizures in those with DEE are typically drug resistant. Individuals have global developmental delay, axial hypotonia, and feeding difficulties in infancy. Development of abnormal movements (chorea, choreoathetosis, dystonia, ataxia, hyperkinetic crises) is variable and can occur months to years after an established diagnosis of epilepsy.
There is no specific EEG abnormality associated with
During the first year of life, delay in motor development is significantly influenced by the severity of hypotonia. The more profound the hypotonia, the later the individuals achieve their motor milestones [
Balance can be impaired due to axial muscular hypotonia, dystonic posturing of the neck, trunk, and extremities, and dyskinesia of the extremities. Although about 20% of individuals achieve independent ambulation, about 80% never do and depend on help for mobility [
Assessment of cognition is limited by the young age of many individuals and/or testing that typically depends on verbal communication and motor tasks [
Despite the lack of expressive language, receptive language is often a relative strength [
The broad range of cognitive abilities in
The vast majority of affected individuals have a hyperkinetic movement disorder [
Most individuals show a mixed pattern of persistent or paroxysmal dyskinesia that affect the whole body. Exacerbations of the hyperkinetic movement disorder, a characteristic feature, can occur spontaneously or can be triggered by intercurrent illnesses (e.g., febrile infections) as well as by emotional stress, excitement, voluntary movements, or change in position [
Almost half of individuals experience prolonged exacerbations leading to life-threatening hyperkinetic crises (including status dystonicus), which are characterized by temporarily increased and nearly continuous involuntary movements or dystonic posturing. Accompanying problems can include impaired respiration, lack of sleep, dehydration, electrolyte imbalance, autonomic dysregulation, and rhabdomyolysis [
Cervical and oropharyngeal dystonia, with involvement of the laryngeal muscles, can lead to dysarthria (60%-80%) or even anarthria (20%-30%) [
Chewing and swallowing are often impaired due to involuntary or dysfunctional tongue movements and weakness of the jaw muscles. A subset of individuals (20%-40%) need help with feeding as they can eat only very small portions or food with a soft consistency. Percutaneous endoscopic gastrostomy (PEG) or nasogastric feeding tube are often required (30%-50%) [
While the onset of movement disorders typically ranges from ages one to four years, some infants manifest movement disorders during the first weeks of life [
Individuals with symptom onset during early infancy and severe impairment of motor development are more likely to have hyperkinetic crises; in contrast, individuals with late onset and less severe motor impairment (i.e., are able to walk) and normal intellect or only mild intellectual disability appear to be at lower risk [
Significant axial hypotonia is often the first manifestation of
While most individuals (particularly children younger than age five years) have a normal brain MRI [
It is unknown whether life span in
Although a number of deaths in children have been reported [
Deaths reported due to neurologic disease include the following:
While immune dysfunction has not been described in individuals with
More than 200 individuals with pathogenic variants in
To date, genotype-phenotype correlations have been described for several recurrent
In addition, accumulating data may point to haploinsufficiency variants being associated with milder phenotypes, without epileptic encephalopathy or severe global developmental delay or intellectual disability [
DD = developmental delay; DEE = developmental and epileptic encephalopathy; ID = intellectual disability; NR = not reported
Movement disorders are typically not the presenting manifestation. More often, initial presenting manifestations are seizures and/or hypotonia and developmental delay.
Not all reports provide this information. Of those that do, many do not distinguish between DD and ID.
One of three affected family members reported by
Approximately 200 individuals have been reported with
## Clinical Description
To date, information on more than 200 individuals with
Approximately half (50%-65%) of affected individuals have seizures and/or are diagnosed with epilepsy. While seizures may be refractory to anti-seizure medications (ASMs), some individuals have only a single seizure [
Developmental and epileptic encephalopathy (DEE) is the most common epilepsy phenotype, occurring in 69% of individuals with epilepsy [
Seizures in those with DEE are typically drug resistant. Individuals have global developmental delay, axial hypotonia, and feeding difficulties in infancy. Development of abnormal movements (chorea, choreoathetosis, dystonia, ataxia, hyperkinetic crises) is variable and can occur months to years after an established diagnosis of epilepsy.
There is no specific EEG abnormality associated with
During the first year of life, delay in motor development is significantly influenced by the severity of hypotonia. The more profound the hypotonia, the later the individuals achieve their motor milestones [
Balance can be impaired due to axial muscular hypotonia, dystonic posturing of the neck, trunk, and extremities, and dyskinesia of the extremities. Although about 20% of individuals achieve independent ambulation, about 80% never do and depend on help for mobility [
Assessment of cognition is limited by the young age of many individuals and/or testing that typically depends on verbal communication and motor tasks [
Despite the lack of expressive language, receptive language is often a relative strength [
The broad range of cognitive abilities in
The vast majority of affected individuals have a hyperkinetic movement disorder [
Most individuals show a mixed pattern of persistent or paroxysmal dyskinesia that affect the whole body. Exacerbations of the hyperkinetic movement disorder, a characteristic feature, can occur spontaneously or can be triggered by intercurrent illnesses (e.g., febrile infections) as well as by emotional stress, excitement, voluntary movements, or change in position [
Almost half of individuals experience prolonged exacerbations leading to life-threatening hyperkinetic crises (including status dystonicus), which are characterized by temporarily increased and nearly continuous involuntary movements or dystonic posturing. Accompanying problems can include impaired respiration, lack of sleep, dehydration, electrolyte imbalance, autonomic dysregulation, and rhabdomyolysis [
Cervical and oropharyngeal dystonia, with involvement of the laryngeal muscles, can lead to dysarthria (60%-80%) or even anarthria (20%-30%) [
Chewing and swallowing are often impaired due to involuntary or dysfunctional tongue movements and weakness of the jaw muscles. A subset of individuals (20%-40%) need help with feeding as they can eat only very small portions or food with a soft consistency. Percutaneous endoscopic gastrostomy (PEG) or nasogastric feeding tube are often required (30%-50%) [
While the onset of movement disorders typically ranges from ages one to four years, some infants manifest movement disorders during the first weeks of life [
Individuals with symptom onset during early infancy and severe impairment of motor development are more likely to have hyperkinetic crises; in contrast, individuals with late onset and less severe motor impairment (i.e., are able to walk) and normal intellect or only mild intellectual disability appear to be at lower risk [
Significant axial hypotonia is often the first manifestation of
While most individuals (particularly children younger than age five years) have a normal brain MRI [
It is unknown whether life span in
Although a number of deaths in children have been reported [
Deaths reported due to neurologic disease include the following:
While immune dysfunction has not been described in individuals with
## Epilepsy
Approximately half (50%-65%) of affected individuals have seizures and/or are diagnosed with epilepsy. While seizures may be refractory to anti-seizure medications (ASMs), some individuals have only a single seizure [
Developmental and epileptic encephalopathy (DEE) is the most common epilepsy phenotype, occurring in 69% of individuals with epilepsy [
Seizures in those with DEE are typically drug resistant. Individuals have global developmental delay, axial hypotonia, and feeding difficulties in infancy. Development of abnormal movements (chorea, choreoathetosis, dystonia, ataxia, hyperkinetic crises) is variable and can occur months to years after an established diagnosis of epilepsy.
There is no specific EEG abnormality associated with
## Developmental Delay and Intellectual Disability
During the first year of life, delay in motor development is significantly influenced by the severity of hypotonia. The more profound the hypotonia, the later the individuals achieve their motor milestones [
Balance can be impaired due to axial muscular hypotonia, dystonic posturing of the neck, trunk, and extremities, and dyskinesia of the extremities. Although about 20% of individuals achieve independent ambulation, about 80% never do and depend on help for mobility [
Assessment of cognition is limited by the young age of many individuals and/or testing that typically depends on verbal communication and motor tasks [
Despite the lack of expressive language, receptive language is often a relative strength [
The broad range of cognitive abilities in
## Movement Disorder
The vast majority of affected individuals have a hyperkinetic movement disorder [
Most individuals show a mixed pattern of persistent or paroxysmal dyskinesia that affect the whole body. Exacerbations of the hyperkinetic movement disorder, a characteristic feature, can occur spontaneously or can be triggered by intercurrent illnesses (e.g., febrile infections) as well as by emotional stress, excitement, voluntary movements, or change in position [
Almost half of individuals experience prolonged exacerbations leading to life-threatening hyperkinetic crises (including status dystonicus), which are characterized by temporarily increased and nearly continuous involuntary movements or dystonic posturing. Accompanying problems can include impaired respiration, lack of sleep, dehydration, electrolyte imbalance, autonomic dysregulation, and rhabdomyolysis [
Cervical and oropharyngeal dystonia, with involvement of the laryngeal muscles, can lead to dysarthria (60%-80%) or even anarthria (20%-30%) [
Chewing and swallowing are often impaired due to involuntary or dysfunctional tongue movements and weakness of the jaw muscles. A subset of individuals (20%-40%) need help with feeding as they can eat only very small portions or food with a soft consistency. Percutaneous endoscopic gastrostomy (PEG) or nasogastric feeding tube are often required (30%-50%) [
While the onset of movement disorders typically ranges from ages one to four years, some infants manifest movement disorders during the first weeks of life [
Individuals with symptom onset during early infancy and severe impairment of motor development are more likely to have hyperkinetic crises; in contrast, individuals with late onset and less severe motor impairment (i.e., are able to walk) and normal intellect or only mild intellectual disability appear to be at lower risk [
## Muscular Hypotonia
Significant axial hypotonia is often the first manifestation of
## Other Common Features
## Neuroimaging
While most individuals (particularly children younger than age five years) have a normal brain MRI [
## Prognosis
It is unknown whether life span in
Although a number of deaths in children have been reported [
Deaths reported due to neurologic disease include the following:
While immune dysfunction has not been described in individuals with
## Genotype-Phenotype Correlations
More than 200 individuals with pathogenic variants in
To date, genotype-phenotype correlations have been described for several recurrent
In addition, accumulating data may point to haploinsufficiency variants being associated with milder phenotypes, without epileptic encephalopathy or severe global developmental delay or intellectual disability [
DD = developmental delay; DEE = developmental and epileptic encephalopathy; ID = intellectual disability; NR = not reported
Movement disorders are typically not the presenting manifestation. More often, initial presenting manifestations are seizures and/or hypotonia and developmental delay.
Not all reports provide this information. Of those that do, many do not distinguish between DD and ID.
One of three affected family members reported by
## Prevalence
Approximately 200 individuals have been reported with
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The phenotypic features associated with
•
•
•
•
•
•
•
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
For evidence of DD/ID, epilepsy, & movement disorder
For those w/abnormal movements, eval by movement specialist is recommended.
Perform EEG if seizures are a concern. Distinguishing between dystonia & seizure can be a challenge.
Consider brain MRI if not previously performed.
For all persons w/speech delay, ensure hearing is normal.
Evaluate need for communication aids.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / individual education program
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Orthopedics eval for scoliosis &/or joint deformity
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Standardized treatment w/ASM by experienced child neurologist. Seizures can be drug resistant, w/those w/ongoing seizures reporting a mean of 3.1 medications trialed.
Persons w/refractory seizures may benefit from referral to epileptologist.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Use of benzodiazepines is often limited by tolerance & side effects.
Education of parents/caregivers
Obtain home videos of concerning events for clinician review.
Consider video EEG to distinguish abnormal movements from seizures if there is a diagnostic concern.
Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
Consider orthopedic aids (e.g., ankle-foot orthoses, walkers) to support & maintain ambulation.
Because dystonia can lead to irreversible joint contractures, scoliosis, &/or hip dislocation, early initiation of regular PT is essential to maintain function & mobility & prevent secondary orthopedic complications.
Consider need for positioning & mobility devices, disability parking placard.
Combination therapy is often necessary.
Consider treatment w/tetrabenazine, gabapentin, clonidine, trihexyphenidyl, oral baclofen.
Benzodiazepines are often necessary as additional first-line therapeutics. Levodopa & ASMs (such as topiramate, valproate, levetiracetam) may have some additional efficacy in controlling hyperkinetic movements in some persons.
Botulinum toxin injections should be considered for focal dystonia.
When movement disorders are drug resistant, incl during hyperkinetic crises, consider DBS of globus pallidus internus (target of choice in most persons), or subthalamic nucleus as well as pallidotomy, which can lead to substantial reduction of hyperkinetic movements.
Persons may benefit from referral to movement disorder specialist.
Parents / other care providers might consider maintaining movement disorder logs (time w/movement disorder symptoms / waking time) to estimate severity & treatment response.
Add or intensify pharmacotherapy, e.g., high doses of benzodiazepines, clonidine, chloral hydrate (if available) to induce sleep. Escalate to intravenous infusions of sedatives if needed.
If pharmacotherapy fails, consider emergency placement of DBS.
Educate parents re risk of hyperkinetic crises & communicate emergency plan.
Avoid or treat triggers & risk factors (infection, electrolyte imbalances, or lack of sleep).
Early intervention is essential.
Feeding therapy
Nutritionists are important to assess calorie needs & ↓ risk of malnutrition.
Gastrostomy tube placement may be required for persistent feeding issues.
↑ calorie intake if movement disorder is present.
Monitor for constipation.
Stool softeners, prokinetics, osmotic agents, or laxatives as needed
Caused by neurologic dysfunction & poor intestinal motility, often accentuated by medication
Can trigger movement disorder
Behavioral regulation
Pharmacotherapy
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ACTH = adrenocorticotropic hormone; ASM = anti-seizure medication; DBS = deep brain stimulation; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Prolonged exacerbation of the hyperkinetic movement disorder requires hospitalization and, when severe, intensive care management. Infections or catabolic states are often triggers, while in some individuals, potential causes are unknown. The often poor nutritional status due to feeding problems can prolong hospital stays.
Although sudden unexpected death in epilepsy (SUDEP) has not specifically been reported in
While immune dysfunction has not been described in
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For increased muscle tone like in dystonia, consider involving appropriate specialists to aid in management of tone reduction by pharmacotherapy, or orthopedic procedures.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
OT = occupational therapy; PT = physical therapy
See
Using
Search
• For evidence of DD/ID, epilepsy, & movement disorder
• For those w/abnormal movements, eval by movement specialist is recommended.
• Perform EEG if seizures are a concern. Distinguishing between dystonia & seizure can be a challenge.
• Consider brain MRI if not previously performed.
• For all persons w/speech delay, ensure hearing is normal.
• Evaluate need for communication aids.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / individual education program
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Orthopedics eval for scoliosis &/or joint deformity
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Standardized treatment w/ASM by experienced child neurologist. Seizures can be drug resistant, w/those w/ongoing seizures reporting a mean of 3.1 medications trialed.
• Persons w/refractory seizures may benefit from referral to epileptologist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Use of benzodiazepines is often limited by tolerance & side effects.
• Education of parents/caregivers
• Obtain home videos of concerning events for clinician review.
• Consider video EEG to distinguish abnormal movements from seizures if there is a diagnostic concern.
• Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
• Consider orthopedic aids (e.g., ankle-foot orthoses, walkers) to support & maintain ambulation.
• Because dystonia can lead to irreversible joint contractures, scoliosis, &/or hip dislocation, early initiation of regular PT is essential to maintain function & mobility & prevent secondary orthopedic complications.
• Consider need for positioning & mobility devices, disability parking placard.
• Combination therapy is often necessary.
• Consider treatment w/tetrabenazine, gabapentin, clonidine, trihexyphenidyl, oral baclofen.
• Benzodiazepines are often necessary as additional first-line therapeutics. Levodopa & ASMs (such as topiramate, valproate, levetiracetam) may have some additional efficacy in controlling hyperkinetic movements in some persons.
• Botulinum toxin injections should be considered for focal dystonia.
• When movement disorders are drug resistant, incl during hyperkinetic crises, consider DBS of globus pallidus internus (target of choice in most persons), or subthalamic nucleus as well as pallidotomy, which can lead to substantial reduction of hyperkinetic movements.
• Persons may benefit from referral to movement disorder specialist.
• Parents / other care providers might consider maintaining movement disorder logs (time w/movement disorder symptoms / waking time) to estimate severity & treatment response.
• Add or intensify pharmacotherapy, e.g., high doses of benzodiazepines, clonidine, chloral hydrate (if available) to induce sleep. Escalate to intravenous infusions of sedatives if needed.
• If pharmacotherapy fails, consider emergency placement of DBS.
• Educate parents re risk of hyperkinetic crises & communicate emergency plan.
• Avoid or treat triggers & risk factors (infection, electrolyte imbalances, or lack of sleep).
• Early intervention is essential.
• Feeding therapy
• Nutritionists are important to assess calorie needs & ↓ risk of malnutrition.
• Gastrostomy tube placement may be required for persistent feeding issues.
• ↑ calorie intake if movement disorder is present.
• Monitor for constipation.
• Stool softeners, prokinetics, osmotic agents, or laxatives as needed
• Caused by neurologic dysfunction & poor intestinal motility, often accentuated by medication
• Can trigger movement disorder
• Behavioral regulation
• Pharmacotherapy
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For increased muscle tone like in dystonia, consider involving appropriate specialists to aid in management of tone reduction by pharmacotherapy, or orthopedic procedures.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
For evidence of DD/ID, epilepsy, & movement disorder
For those w/abnormal movements, eval by movement specialist is recommended.
Perform EEG if seizures are a concern. Distinguishing between dystonia & seizure can be a challenge.
Consider brain MRI if not previously performed.
For all persons w/speech delay, ensure hearing is normal.
Evaluate need for communication aids.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / individual education program
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Orthopedics eval for scoliosis &/or joint deformity
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• For evidence of DD/ID, epilepsy, & movement disorder
• For those w/abnormal movements, eval by movement specialist is recommended.
• Perform EEG if seizures are a concern. Distinguishing between dystonia & seizure can be a challenge.
• Consider brain MRI if not previously performed.
• For all persons w/speech delay, ensure hearing is normal.
• Evaluate need for communication aids.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / individual education program
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Orthopedics eval for scoliosis &/or joint deformity
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for
Standardized treatment w/ASM by experienced child neurologist. Seizures can be drug resistant, w/those w/ongoing seizures reporting a mean of 3.1 medications trialed.
Persons w/refractory seizures may benefit from referral to epileptologist.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Use of benzodiazepines is often limited by tolerance & side effects.
Education of parents/caregivers
Obtain home videos of concerning events for clinician review.
Consider video EEG to distinguish abnormal movements from seizures if there is a diagnostic concern.
Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
Consider orthopedic aids (e.g., ankle-foot orthoses, walkers) to support & maintain ambulation.
Because dystonia can lead to irreversible joint contractures, scoliosis, &/or hip dislocation, early initiation of regular PT is essential to maintain function & mobility & prevent secondary orthopedic complications.
Consider need for positioning & mobility devices, disability parking placard.
Combination therapy is often necessary.
Consider treatment w/tetrabenazine, gabapentin, clonidine, trihexyphenidyl, oral baclofen.
Benzodiazepines are often necessary as additional first-line therapeutics. Levodopa & ASMs (such as topiramate, valproate, levetiracetam) may have some additional efficacy in controlling hyperkinetic movements in some persons.
Botulinum toxin injections should be considered for focal dystonia.
When movement disorders are drug resistant, incl during hyperkinetic crises, consider DBS of globus pallidus internus (target of choice in most persons), or subthalamic nucleus as well as pallidotomy, which can lead to substantial reduction of hyperkinetic movements.
Persons may benefit from referral to movement disorder specialist.
Parents / other care providers might consider maintaining movement disorder logs (time w/movement disorder symptoms / waking time) to estimate severity & treatment response.
Add or intensify pharmacotherapy, e.g., high doses of benzodiazepines, clonidine, chloral hydrate (if available) to induce sleep. Escalate to intravenous infusions of sedatives if needed.
If pharmacotherapy fails, consider emergency placement of DBS.
Educate parents re risk of hyperkinetic crises & communicate emergency plan.
Avoid or treat triggers & risk factors (infection, electrolyte imbalances, or lack of sleep).
Early intervention is essential.
Feeding therapy
Nutritionists are important to assess calorie needs & ↓ risk of malnutrition.
Gastrostomy tube placement may be required for persistent feeding issues.
↑ calorie intake if movement disorder is present.
Monitor for constipation.
Stool softeners, prokinetics, osmotic agents, or laxatives as needed
Caused by neurologic dysfunction & poor intestinal motility, often accentuated by medication
Can trigger movement disorder
Behavioral regulation
Pharmacotherapy
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ACTH = adrenocorticotropic hormone; ASM = anti-seizure medication; DBS = deep brain stimulation; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
Prolonged exacerbation of the hyperkinetic movement disorder requires hospitalization and, when severe, intensive care management. Infections or catabolic states are often triggers, while in some individuals, potential causes are unknown. The often poor nutritional status due to feeding problems can prolong hospital stays.
Although sudden unexpected death in epilepsy (SUDEP) has not specifically been reported in
While immune dysfunction has not been described in
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For increased muscle tone like in dystonia, consider involving appropriate specialists to aid in management of tone reduction by pharmacotherapy, or orthopedic procedures.
• Standardized treatment w/ASM by experienced child neurologist. Seizures can be drug resistant, w/those w/ongoing seizures reporting a mean of 3.1 medications trialed.
• Persons w/refractory seizures may benefit from referral to epileptologist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Use of benzodiazepines is often limited by tolerance & side effects.
• Education of parents/caregivers
• Obtain home videos of concerning events for clinician review.
• Consider video EEG to distinguish abnormal movements from seizures if there is a diagnostic concern.
• Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
• Consider orthopedic aids (e.g., ankle-foot orthoses, walkers) to support & maintain ambulation.
• Because dystonia can lead to irreversible joint contractures, scoliosis, &/or hip dislocation, early initiation of regular PT is essential to maintain function & mobility & prevent secondary orthopedic complications.
• Consider need for positioning & mobility devices, disability parking placard.
• Combination therapy is often necessary.
• Consider treatment w/tetrabenazine, gabapentin, clonidine, trihexyphenidyl, oral baclofen.
• Benzodiazepines are often necessary as additional first-line therapeutics. Levodopa & ASMs (such as topiramate, valproate, levetiracetam) may have some additional efficacy in controlling hyperkinetic movements in some persons.
• Botulinum toxin injections should be considered for focal dystonia.
• When movement disorders are drug resistant, incl during hyperkinetic crises, consider DBS of globus pallidus internus (target of choice in most persons), or subthalamic nucleus as well as pallidotomy, which can lead to substantial reduction of hyperkinetic movements.
• Persons may benefit from referral to movement disorder specialist.
• Parents / other care providers might consider maintaining movement disorder logs (time w/movement disorder symptoms / waking time) to estimate severity & treatment response.
• Add or intensify pharmacotherapy, e.g., high doses of benzodiazepines, clonidine, chloral hydrate (if available) to induce sleep. Escalate to intravenous infusions of sedatives if needed.
• If pharmacotherapy fails, consider emergency placement of DBS.
• Educate parents re risk of hyperkinetic crises & communicate emergency plan.
• Avoid or treat triggers & risk factors (infection, electrolyte imbalances, or lack of sleep).
• Early intervention is essential.
• Feeding therapy
• Nutritionists are important to assess calorie needs & ↓ risk of malnutrition.
• Gastrostomy tube placement may be required for persistent feeding issues.
• ↑ calorie intake if movement disorder is present.
• Monitor for constipation.
• Stool softeners, prokinetics, osmotic agents, or laxatives as needed
• Caused by neurologic dysfunction & poor intestinal motility, often accentuated by medication
• Can trigger movement disorder
• Behavioral regulation
• Pharmacotherapy
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For increased muscle tone like in dystonia, consider involving appropriate specialists to aid in management of tone reduction by pharmacotherapy, or orthopedic procedures.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For increased muscle tone like in dystonia, consider involving appropriate specialists to aid in management of tone reduction by pharmacotherapy, or orthopedic procedures.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For increased muscle tone like in dystonia, consider involving appropriate specialists to aid in management of tone reduction by pharmacotherapy, or orthopedic procedures.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Using
Search
## Genetic Counseling
Vertical transmission from an affected parent to an affected child has been reported in several families with milder phenotypes [
Risk to Family Members
Almost all probands reported to date with severe
Some probands with milder
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with apparent germline (or somatic and germline) mosaicism * [
* A parent with somatic and germline mosaicism for a
If the
If a parent of the proband is known to have the
Each child of an individual with
Individuals with severe
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Almost all probands reported to date with severe
• Some probands with milder
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with apparent germline (or somatic and germline) mosaicism * [
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with apparent germline (or somatic and germline) mosaicism * [
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with apparent germline (or somatic and germline) mosaicism * [
• * A parent with somatic and germline mosaicism for a
• If the
• If a parent of the proband is known to have the
• Each child of an individual with
• Individuals with severe
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
Vertical transmission from an affected parent to an affected child has been reported in several families with milder phenotypes [
Risk to Family Members
Almost all probands reported to date with severe
Some probands with milder
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with apparent germline (or somatic and germline) mosaicism * [
* A parent with somatic and germline mosaicism for a
If the
If a parent of the proband is known to have the
Each child of an individual with
Individuals with severe
• Almost all probands reported to date with severe
• Some probands with milder
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with apparent germline (or somatic and germline) mosaicism * [
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with apparent germline (or somatic and germline) mosaicism * [
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with apparent germline (or somatic and germline) mosaicism * [
• * A parent with somatic and germline mosaicism for a
• If the
• If a parent of the proband is known to have the
• Each child of an individual with
• Individuals with severe
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Spain
Italy
Finland
Netherlands
Canada
•
• Spain
•
•
• Italy
•
•
• Finland
•
•
•
•
• Netherlands
•
•
•
•
•
•
• Canada
•
•
•
•
•
•
•
## Molecular Genetics
GNAO1-Related Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GNAO1-Related Disorder (
Gαo, the major G protein α subunit in the nervous system, is essential for nervous system development and functionality [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Gαo, the major G protein α subunit in the nervous system, is essential for nervous system development and functionality [
Variants listed in the table have been provided by the authors.
## Chapter Notes
Department of Pediatrics and Center for Genomic Medicine
Massachusetts General Hospital, Boston, Massachusetts
Email:
Lauren is a Genetic Counselor and Study Coordinator for the Undiagnosed Diseases Network, Harvard Clinical Site, Massachusetts General Hospital. She has extensive experience in prenatal and general genetics counseling and a focus on rare and undiagnosed diseases and variant interpretation.
University Hospital of Cologne, Cologne Germany
Email:
Dr Thiel is a resident in pediatric neurology and a clinician-scientist with a research focus on
Web page:
Chief of Medical Genetics and Metabolism
MGH Site Director Undiagnosed Diseases Network
Co-Director Harvard Affiliated Hospitals NORD Rare Disease Center of Excellence
Department of Pediatrics and Center for Genomic Medicine
Massachusetts General Hospital, Boston, Massachusetts
Dr Sweetser is a biochemical and medical genetics clinician-researcher with a focus on understanding and diagnosing rare and undiagnosed diseases. He has a clinical and research focus on rare neurodevelopmental disorders.
Web pages:
Consultant Pediatric Neurology
University hospital of cologne, cologne, germany
email:
Dr Koy is a pediatric neurologist and clinician-scientist with a clinical and research interest in movement disorders and deep brain stimulation in children. She is involved in the German
Web page:
Assistant Professor of Neurology and Pediatrics, University of Virginia
Email:
Dr Axeen is a pediatric neurologist and epileptologist with an interest in genetic epilepsies. She serves on the scientific advisory board for the Bow Foundation and is the epileptologist for the Natural History of
Web pages:
We want to thank all the patients and their families for taking part in different studies, trials, and registries all around the world. We would also like to thank the parents for supporting scientists focusing on
Dr Axeen has received a grant from the Bow Foundation in support of her ongoing work with
9 November 2023 (bp) Review posted live
21 February 2023 (ds) Original submission
•
•
•
•
• 9 November 2023 (bp) Review posted live
• 21 February 2023 (ds) Original submission
## Author Notes
Department of Pediatrics and Center for Genomic Medicine
Massachusetts General Hospital, Boston, Massachusetts
Email:
Lauren is a Genetic Counselor and Study Coordinator for the Undiagnosed Diseases Network, Harvard Clinical Site, Massachusetts General Hospital. She has extensive experience in prenatal and general genetics counseling and a focus on rare and undiagnosed diseases and variant interpretation.
University Hospital of Cologne, Cologne Germany
Email:
Dr Thiel is a resident in pediatric neurology and a clinician-scientist with a research focus on
Web page:
Chief of Medical Genetics and Metabolism
MGH Site Director Undiagnosed Diseases Network
Co-Director Harvard Affiliated Hospitals NORD Rare Disease Center of Excellence
Department of Pediatrics and Center for Genomic Medicine
Massachusetts General Hospital, Boston, Massachusetts
Dr Sweetser is a biochemical and medical genetics clinician-researcher with a focus on understanding and diagnosing rare and undiagnosed diseases. He has a clinical and research focus on rare neurodevelopmental disorders.
Web pages:
Consultant Pediatric Neurology
University hospital of cologne, cologne, germany
email:
Dr Koy is a pediatric neurologist and clinician-scientist with a clinical and research interest in movement disorders and deep brain stimulation in children. She is involved in the German
Web page:
Assistant Professor of Neurology and Pediatrics, University of Virginia
Email:
Dr Axeen is a pediatric neurologist and epileptologist with an interest in genetic epilepsies. She serves on the scientific advisory board for the Bow Foundation and is the epileptologist for the Natural History of
Web pages:
•
•
•
•
## Acknowledgments
We want to thank all the patients and their families for taking part in different studies, trials, and registries all around the world. We would also like to thank the parents for supporting scientists focusing on
Dr Axeen has received a grant from the Bow Foundation in support of her ongoing work with
## Revision History
9 November 2023 (bp) Review posted live
21 February 2023 (ds) Original submission
• 9 November 2023 (bp) Review posted live
• 21 February 2023 (ds) Original submission
## References
## Literature Cited
|
[] |
9/11/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
gnas-dis
|
gnas-dis
|
[
"Gsα Deficiency",
"Gsa Deficiency",
"Pseudohypoparathyroidism Ia (PHP-Ia)",
"Progressive Osseus Heteroplasia (POH)",
"Pseudohypoparathyroidism Ib (PHP-Ib)",
"Guanine nucleotide-binding protein G(s) subunit alpha isoforms short",
"Syntaxin-16",
"GNAS",
"STX16",
"Disorders of GNAS Inactivation"
] |
Disorders of
|
Chad R Haldeman-Englert, Anna CE Hurst, Michael A Levine
|
Summary Disorders of PHP-Ia and PHP-Ic are characterized by: End-organ resistance to endocrine hormones including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH), growth hormone-releasing hormone (GHRH), and CNS neurotransmitters (leading to obesity and variable degrees of intellectual disability and developmental delay); and The Albright hereditary osteodystrophy (AHO) phenotype (short stature, round facies, and subcutaneous ossifications) and brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb). Although PHP-Ib is characterized principally by PTH resistance, some individuals also have partial TSH resistance and mild features of AHO (e.g., brachydactyly). PPHP, a more limited form of PHP-Ia, is characterized by various manifestations of the AHO phenotype without the hormone resistance or obesity. POH and OC are even more restricted variants of PPHP: POH consists of dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia. OC consists of extra-skeletal ossification that is limited to the dermis and subcutaneous tissues. The diagnosis of a disorder of PHP-Ia,.-Ib, and -Ic are associated with reduced or absent expression/function of the protein Gsα (encoded by the maternal An inactivating A genetic alteration in the imprinting regulatory elements in the Isolated epimutations Paternal 20q disomy PPHP and POH/OC phenotypes are associated with lack of expression/function of Gsα encoded by the paternal Endocrine function: measurement of serum concentration of PTH, calcium and phosphate, TSH and free T4, and urinary calcium excretion; Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing); New and/or enlarging ectopic ossifications; Development of and/or progression of cataracts; and Psychoeducational needs regarding school assistance / educational support and developmental therapies (e.g., physical, occupational, and speech therapy). Disorders of Each child of an individual with a disorder of
|
Pseudohypoparathyroidism Ia (PHP-Ia)
Pseudohypoparathyroidism Ib (PHP-Ib)
Pseudohypoparathyroidism Ic (PHP-Ic)
Pseudopseudohypoparathyroidism (PPHP)
Progressive osseous heteroplasia (POH)
Osteoma cutis (OC)
For other genetic causes of these phenotypes see
• Pseudohypoparathyroidism Ia (PHP-Ia)
• Pseudohypoparathyroidism Ib (PHP-Ib)
• Pseudohypoparathyroidism Ic (PHP-Ic)
• Pseudopseudohypoparathyroidism (PPHP)
• Progressive osseous heteroplasia (POH)
• Osteoma cutis (OC)
## Diagnosis
No specific clinical criteria establish the diagnosis of a disorder of
A disorder of
End-organ resistance to several endocrine hormones:
Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency
Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease
Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.
In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.
Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.
Calcitonin, with asymptomatic hypercalcitonemia
CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay
Note: Many affected individuals have normal neurocognitive function.
Albright hereditary osteodystrophy (AHO) phenotype:
Short stature
Round facies
Subcutaneous ossifications
Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)
Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.
Intrauterine growth restriction
PTH resistance, the principal endocrine abnormality
In some affected individuals:
Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [
Mild brachydactyly (despite absence of the classic AHO phenotype)
Enhanced intrauterine growth [
Madelung deformity [
The diagnosis of a disorder of
The
An inactivating
A genetic alteration in the imprinting regulatory elements in the
Isolated epimutations [
Uniparental paternal 20q disomy [
The
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because of the varied manifestations of the disorders of
When the clinical and endocrine findings suggest one of the distinctive phenotypes, molecular genetic testing approaches can include
Note: In persons with the PHP-Ib phenotype,
Note: in some cases, deletions encompassing the whole
A multigene panel that includes
For an introduction to multigene panels click
When the phenotype is indistinguishable from other inherited disorders with similar endocrine abnormalities,
For an introduction to comprehensive genomic testing click
Note: Genomic testing does not allow characterization of imprinting defects.
Molecular Genetic Testing Used in Disorders of
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Includes: two girls with a very small interstitial deletion of the long arm of chromosome 20 presenting with severe pre- and postnatal growth restriction and clinical manifestations suggestive of PPHP [
Methylation analysis examines differentially methylated regions (DMRs) of the
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the
Includes UPD(20q)pat [
Relevant for testing those with the PHP-Ib phenotype who: do not have an identified maternal
• End-organ resistance to several endocrine hormones:
• Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency
• Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease
• Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.
• In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.
• Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.
• Calcitonin, with asymptomatic hypercalcitonemia
• CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay
• Note: Many affected individuals have normal neurocognitive function.
• Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency
• Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease
• Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.
• In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.
• Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.
• Calcitonin, with asymptomatic hypercalcitonemia
• CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay
• Note: Many affected individuals have normal neurocognitive function.
• Albright hereditary osteodystrophy (AHO) phenotype:
• Short stature
• Round facies
• Subcutaneous ossifications
• Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)
• Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.
• Intrauterine growth restriction
• Short stature
• Round facies
• Subcutaneous ossifications
• Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)
• Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.
• Intrauterine growth restriction
• Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency
• Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease
• Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.
• In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.
• Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.
• Calcitonin, with asymptomatic hypercalcitonemia
• CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay
• Note: Many affected individuals have normal neurocognitive function.
• Short stature
• Round facies
• Subcutaneous ossifications
• Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)
• Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.
• Intrauterine growth restriction
• PTH resistance, the principal endocrine abnormality
• In some affected individuals:
• Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [
• Mild brachydactyly (despite absence of the classic AHO phenotype)
• Enhanced intrauterine growth [
• Madelung deformity [
• Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [
• Mild brachydactyly (despite absence of the classic AHO phenotype)
• Enhanced intrauterine growth [
• Madelung deformity [
• Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [
• Mild brachydactyly (despite absence of the classic AHO phenotype)
• Enhanced intrauterine growth [
• Madelung deformity [
• An inactivating
• A genetic alteration in the imprinting regulatory elements in the
• Isolated epimutations [
• Uniparental paternal 20q disomy [
• Note: In persons with the PHP-Ib phenotype,
• Note: in some cases, deletions encompassing the whole
• Note: in some cases, deletions encompassing the whole
• Note: in some cases, deletions encompassing the whole
• A multigene panel that includes
• For an introduction to multigene panels click
## Suggestive Findings
A disorder of
End-organ resistance to several endocrine hormones:
Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency
Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease
Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.
In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.
Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.
Calcitonin, with asymptomatic hypercalcitonemia
CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay
Note: Many affected individuals have normal neurocognitive function.
Albright hereditary osteodystrophy (AHO) phenotype:
Short stature
Round facies
Subcutaneous ossifications
Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)
Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.
Intrauterine growth restriction
PTH resistance, the principal endocrine abnormality
In some affected individuals:
Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [
Mild brachydactyly (despite absence of the classic AHO phenotype)
Enhanced intrauterine growth [
Madelung deformity [
• End-organ resistance to several endocrine hormones:
• Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency
• Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease
• Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.
• In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.
• Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.
• Calcitonin, with asymptomatic hypercalcitonemia
• CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay
• Note: Many affected individuals have normal neurocognitive function.
• Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency
• Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease
• Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.
• In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.
• Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.
• Calcitonin, with asymptomatic hypercalcitonemia
• CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay
• Note: Many affected individuals have normal neurocognitive function.
• Albright hereditary osteodystrophy (AHO) phenotype:
• Short stature
• Round facies
• Subcutaneous ossifications
• Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)
• Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.
• Intrauterine growth restriction
• Short stature
• Round facies
• Subcutaneous ossifications
• Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)
• Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.
• Intrauterine growth restriction
• Parathyroid hormone (PTH), usually manifest as elevated PTH levels, hyperphosphatemia, and hypocalcemia, in the absence of vitamin D deficiency or magnesium deficiency
• Thyroid-stimulating hormone (TSH), manifest as hypothyroidism and elevated TSH levels in the absence of goiter or evidence of autoimmune thyroid disease
• Gonadotropins (LH and FSH), which may manifest in some females as reduced fertility and menstrual disorders/irregularities and in some males as cryptorchidism (often bilateral) and elevated LH and FSH levels.
• In some females, metabolic or endocrine disturbances may alter LH and FSH secretion to produce the biochemical appearance of hypothalamic amenorrhea.
• Growth hormone-releasing hormone (GHRH), manifest as growth hormone (hGH) deficiency with consequent poor growth and/or short stature, in 50% to 80% of the individuals tested. Note that IGF1 levels are often normal at diagnosis.
• Calcitonin, with asymptomatic hypercalcitonemia
• CNS neurotransmitters, leading to obesity and variable degrees of intellectual disability and developmental delay
• Note: Many affected individuals have normal neurocognitive function.
• Short stature
• Round facies
• Subcutaneous ossifications
• Brachydactyly type E (shortening mainly of the 4th and/or 5th metacarpals and metatarsals and distal phalanx of the thumb)
• Note: Shortened metacarpals may be recognized by the replacement of knuckles by dimples when making a fist.
• Intrauterine growth restriction
• PTH resistance, the principal endocrine abnormality
• In some affected individuals:
• Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [
• Mild brachydactyly (despite absence of the classic AHO phenotype)
• Enhanced intrauterine growth [
• Madelung deformity [
• Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [
• Mild brachydactyly (despite absence of the classic AHO phenotype)
• Enhanced intrauterine growth [
• Madelung deformity [
• Partial TSH resistance with slightly elevated TSH levels and generally normal (or low) serum concentrations of thyroid hormones [
• Mild brachydactyly (despite absence of the classic AHO phenotype)
• Enhanced intrauterine growth [
• Madelung deformity [
## Establishing the Diagnosis
The diagnosis of a disorder of
The
An inactivating
A genetic alteration in the imprinting regulatory elements in the
Isolated epimutations [
Uniparental paternal 20q disomy [
The
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because of the varied manifestations of the disorders of
When the clinical and endocrine findings suggest one of the distinctive phenotypes, molecular genetic testing approaches can include
Note: In persons with the PHP-Ib phenotype,
Note: in some cases, deletions encompassing the whole
A multigene panel that includes
For an introduction to multigene panels click
When the phenotype is indistinguishable from other inherited disorders with similar endocrine abnormalities,
For an introduction to comprehensive genomic testing click
Note: Genomic testing does not allow characterization of imprinting defects.
Molecular Genetic Testing Used in Disorders of
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Includes: two girls with a very small interstitial deletion of the long arm of chromosome 20 presenting with severe pre- and postnatal growth restriction and clinical manifestations suggestive of PPHP [
Methylation analysis examines differentially methylated regions (DMRs) of the
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the
Includes UPD(20q)pat [
Relevant for testing those with the PHP-Ib phenotype who: do not have an identified maternal
• An inactivating
• A genetic alteration in the imprinting regulatory elements in the
• Isolated epimutations [
• Uniparental paternal 20q disomy [
• Note: In persons with the PHP-Ib phenotype,
• Note: in some cases, deletions encompassing the whole
• Note: in some cases, deletions encompassing the whole
• Note: in some cases, deletions encompassing the whole
• A multigene panel that includes
• For an introduction to multigene panels click
## Option 1
When the clinical and endocrine findings suggest one of the distinctive phenotypes, molecular genetic testing approaches can include
Note: In persons with the PHP-Ib phenotype,
Note: in some cases, deletions encompassing the whole
A multigene panel that includes
For an introduction to multigene panels click
• Note: In persons with the PHP-Ib phenotype,
• Note: in some cases, deletions encompassing the whole
• Note: in some cases, deletions encompassing the whole
• Note: in some cases, deletions encompassing the whole
• A multigene panel that includes
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from other inherited disorders with similar endocrine abnormalities,
For an introduction to comprehensive genomic testing click
Note: Genomic testing does not allow characterization of imprinting defects.
Molecular Genetic Testing Used in Disorders of
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Includes: two girls with a very small interstitial deletion of the long arm of chromosome 20 presenting with severe pre- and postnatal growth restriction and clinical manifestations suggestive of PPHP [
Methylation analysis examines differentially methylated regions (DMRs) of the
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the
Includes UPD(20q)pat [
Relevant for testing those with the PHP-Ib phenotype who: do not have an identified maternal
## Clinical Characteristics
Disorders of
The term pseudohypoparathyroidism (PHP) refers to disorders with hypocalcemia and hyperphosphatemia (which are typical of hypoparathyroidism) that result from end-organ resistance to ‒ rather than deficiency of ‒ parathyroid hormone (PTH).
PHP-Ia and PHP-Ic have a similar phenotype and are distinguished only by
The development of the endocrine features occurs over time. The earliest manifestation of hormone resistance is usually mild hypothyroidism, which is often discovered during newborn screening as an elevated TSH with normal serum levels of thyroid hormones. The average age at diagnosis of PHP-Ia is around age seven years, when PTH resistance and hypocalcemia are recognized; however, individuals with milder manifestations may not be diagnosed until the third decade of life [
Occasionally, early PTH resistance is associated with hypercalcemia rather than hypocalcemia. Presumably, in these individuals the kidney retains the ability to increase production of 1,25(OH)
As in PTH-deficient hypoparathyroidism, protracted hypocalcemia and hyperphosphatemia lead to ectopic calcification, particularly in the brain at the grey-white cerebral intersection and the basal ganglia and ocular lenses, manifesting as posterior subcapsular cataracts.
Bone density is often increased [
Unrecognized hypocalcemia may present with tetany, seizures, or laryngeal spasm; seizures appear to be more common, independent of hypocalcemia [
Sleep apnea is also common (45% of individuals), but is only partly explained by obesity, as individuals with PHP-Ia have a fourfold increased risk for sleep apnea compared to similarly obese individuals. This increase may be due to hypotonia as well as the effects of Gsα inactivation on the normal sleep cycle [
Linear growth may initially be normal or advanced due to obesity; bone age is frequently advanced beyond chronologic age [
Affected individuals display clinical features of Albright hereditary osteodystrophy (AHO) comprising a round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification of the dermis and subcutaneous tissues. Macrocephaly relative to height is typical: 40% have a head circumference above the 90th percentile [
The most common musculoskeletal feature is brachydactyly; brachydactyly type E is manifest as shortened metacarpals (particularly 4th and 5th) and metatarsals (particularly 3rd and 4th) plus brachydactyly type D, manifest as shortening of the distal phalanx of the thumb.
Even in the absence of brachymetacarpia, individuals with AHO usually have brachydactyly type D, a shortened distal thumb phalanx and short, broad thumbnails, associated radiographically with cone-shaped epiphyses [
Brachydactyly may lead to carpal tunnel syndrome with symptomatic paresthesia, which may be confused with the symptoms of hypocalcemia [
Other reported musculoskeletal features include craniosynostosis, hyperostosis of the cranial vault, absence of normal caudal widening of the lumbar interpedicular distances (associated with spinal stenosis), ossification of paravertebral ligaments, shortened distal ulnas, bowing of the tibia and radius, small capital femoral epiphyses, coxa vara, coxa valga, increased prevalence of bony exostoses, and carpal tunnel syndrome [
Ectopic ossifications are most commonly cutaneous, either within subdermal fat or in the dermis. They are located most commonly in the scalp and extremities (particularly the periarticular areas of the hands and feet). These lesions may be very small and asymptomatic, or painful; occasionally lesions can extrude a chalky material. Removal of ectopic ossifications does not result in progression or exacerbation although they may recur if removal is incomplete [
Other areas of ectopic ossification include the sclera and choroid of the eye and cardiac ventricular septum. Visceral involvement is rare [
Dental changes such as enamel hypoplasia, widened root canals, shortened roots with open apices, thickened laminar dura, and delayed dental eruption have been noted in more than 30% of affected individuals, often with impacted second molars [
PHP-Ib consists of PTH resistance with partial resistance to TSH in some affected individuals. Partial TSH resistance manifests as slightly elevated serum TSH levels with generally normal (or low) serum concentrations of thyroid hormones [
Poorly treated PTH resistance can lead to hyperparathyroid bone disease or tertiary hyperparathyroidism. Very rarely bone density can be elevated [
Patterns of excessive growth or weight gain have been described in newborns or during early infancy and childhood.
Individuals with PHP-Ib may have growth-plate defects such as mild brachydactyly or a Madelung deformity-like defect [
The average age of diagnosis for symptomatic individuals is age ten to 12 years [
The phenotype is heterogeneous with a wide differential diagnosis (see
Intrauterine growth restriction is common.
Ectopic ossifications are frequent and almost pathognomonic of Gsα deficiency.
Individuals with PPHP have normocalcemia and no endocrine defects, but have the physical phenotype of Albright hereditary osteodystrophy.
Obesity and intellectual disabilities (10%) are less prevalent than in PHP-Ia [
Individuals with POH have no endocrine defects or features of AHO, but have progressive ectopic ossification that extends to deep connective tissues, often with debilitating effects [
Of note, POH-like ossifications have been observed rarely in individuals with AHO or PHP-1a.
Individuals with OC develop ossification limited to the dermis and subcutaneous tissues.
Phenotypes and Genetic Mechanisms of Disorders of
From
AHO = Albright hereditary osteodystrophy; DMR = differentially methylated region; IUGR = intrauterine growth restriction; PHP = pseudohypoparathyroidism; PTH = parathyroid hormone; TSH = thyroid-stimulating hormone
See
Multiple hormone resistance, resistance to PTH, TSH, and GHRH; often gonadotropins (LH and FSH) as well
AHO comprising round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification
Chromosome abnormalities of
Impairs coupling of Gsα to heptahelical receptors. See
Associated mainly with pathogenic variants in
No clear correlation appears to exist between the type and location of
However, two unique variants affecting both the stability and the activity of Gsα have been described in three unrelated individuals with PHP1a who presented with additional clinical features reflecting enhanced Gsα activity:
A missense variant associated with typical PHP1a features as well as testotoxicosis [
A four amino-acid insertion within the Gsα GDP/GTP-binding site identified in a brother and sister with PHP1a with transient neonatal diarrhea and pancreatic insufficiency who inherited the insertion from their unaffected mother, who had germline mosaicism [
Disorders of
The estimated prevalence for pseudohypoparathyroidism (PHP) and Albright hereditary osteodystrophy (AHO) is approximately 0.79 per 100,000 (according to the Orphanet Report Series, November 2008).
A Japanese study estimated the prevalence of PHP at 3.4 per 1 million individuals [
The prevalence of POH has never been estimated. It is likely extremely rare: fewer than 60 clinically confirmed individuals worldwide have been reported [
• Occasionally, early PTH resistance is associated with hypercalcemia rather than hypocalcemia. Presumably, in these individuals the kidney retains the ability to increase production of 1,25(OH)
• As in PTH-deficient hypoparathyroidism, protracted hypocalcemia and hyperphosphatemia lead to ectopic calcification, particularly in the brain at the grey-white cerebral intersection and the basal ganglia and ocular lenses, manifesting as posterior subcapsular cataracts.
• Bone density is often increased [
• Unrecognized hypocalcemia may present with tetany, seizures, or laryngeal spasm; seizures appear to be more common, independent of hypocalcemia [
• A missense variant associated with typical PHP1a features as well as testotoxicosis [
• A four amino-acid insertion within the Gsα GDP/GTP-binding site identified in a brother and sister with PHP1a with transient neonatal diarrhea and pancreatic insufficiency who inherited the insertion from their unaffected mother, who had germline mosaicism [
## Clinical Description
Disorders of
The term pseudohypoparathyroidism (PHP) refers to disorders with hypocalcemia and hyperphosphatemia (which are typical of hypoparathyroidism) that result from end-organ resistance to ‒ rather than deficiency of ‒ parathyroid hormone (PTH).
PHP-Ia and PHP-Ic have a similar phenotype and are distinguished only by
The development of the endocrine features occurs over time. The earliest manifestation of hormone resistance is usually mild hypothyroidism, which is often discovered during newborn screening as an elevated TSH with normal serum levels of thyroid hormones. The average age at diagnosis of PHP-Ia is around age seven years, when PTH resistance and hypocalcemia are recognized; however, individuals with milder manifestations may not be diagnosed until the third decade of life [
Occasionally, early PTH resistance is associated with hypercalcemia rather than hypocalcemia. Presumably, in these individuals the kidney retains the ability to increase production of 1,25(OH)
As in PTH-deficient hypoparathyroidism, protracted hypocalcemia and hyperphosphatemia lead to ectopic calcification, particularly in the brain at the grey-white cerebral intersection and the basal ganglia and ocular lenses, manifesting as posterior subcapsular cataracts.
Bone density is often increased [
Unrecognized hypocalcemia may present with tetany, seizures, or laryngeal spasm; seizures appear to be more common, independent of hypocalcemia [
Sleep apnea is also common (45% of individuals), but is only partly explained by obesity, as individuals with PHP-Ia have a fourfold increased risk for sleep apnea compared to similarly obese individuals. This increase may be due to hypotonia as well as the effects of Gsα inactivation on the normal sleep cycle [
Linear growth may initially be normal or advanced due to obesity; bone age is frequently advanced beyond chronologic age [
Affected individuals display clinical features of Albright hereditary osteodystrophy (AHO) comprising a round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification of the dermis and subcutaneous tissues. Macrocephaly relative to height is typical: 40% have a head circumference above the 90th percentile [
The most common musculoskeletal feature is brachydactyly; brachydactyly type E is manifest as shortened metacarpals (particularly 4th and 5th) and metatarsals (particularly 3rd and 4th) plus brachydactyly type D, manifest as shortening of the distal phalanx of the thumb.
Even in the absence of brachymetacarpia, individuals with AHO usually have brachydactyly type D, a shortened distal thumb phalanx and short, broad thumbnails, associated radiographically with cone-shaped epiphyses [
Brachydactyly may lead to carpal tunnel syndrome with symptomatic paresthesia, which may be confused with the symptoms of hypocalcemia [
Other reported musculoskeletal features include craniosynostosis, hyperostosis of the cranial vault, absence of normal caudal widening of the lumbar interpedicular distances (associated with spinal stenosis), ossification of paravertebral ligaments, shortened distal ulnas, bowing of the tibia and radius, small capital femoral epiphyses, coxa vara, coxa valga, increased prevalence of bony exostoses, and carpal tunnel syndrome [
Ectopic ossifications are most commonly cutaneous, either within subdermal fat or in the dermis. They are located most commonly in the scalp and extremities (particularly the periarticular areas of the hands and feet). These lesions may be very small and asymptomatic, or painful; occasionally lesions can extrude a chalky material. Removal of ectopic ossifications does not result in progression or exacerbation although they may recur if removal is incomplete [
Other areas of ectopic ossification include the sclera and choroid of the eye and cardiac ventricular septum. Visceral involvement is rare [
Dental changes such as enamel hypoplasia, widened root canals, shortened roots with open apices, thickened laminar dura, and delayed dental eruption have been noted in more than 30% of affected individuals, often with impacted second molars [
PHP-Ib consists of PTH resistance with partial resistance to TSH in some affected individuals. Partial TSH resistance manifests as slightly elevated serum TSH levels with generally normal (or low) serum concentrations of thyroid hormones [
Poorly treated PTH resistance can lead to hyperparathyroid bone disease or tertiary hyperparathyroidism. Very rarely bone density can be elevated [
Patterns of excessive growth or weight gain have been described in newborns or during early infancy and childhood.
Individuals with PHP-Ib may have growth-plate defects such as mild brachydactyly or a Madelung deformity-like defect [
The average age of diagnosis for symptomatic individuals is age ten to 12 years [
The phenotype is heterogeneous with a wide differential diagnosis (see
Intrauterine growth restriction is common.
Ectopic ossifications are frequent and almost pathognomonic of Gsα deficiency.
Individuals with PPHP have normocalcemia and no endocrine defects, but have the physical phenotype of Albright hereditary osteodystrophy.
Obesity and intellectual disabilities (10%) are less prevalent than in PHP-Ia [
Individuals with POH have no endocrine defects or features of AHO, but have progressive ectopic ossification that extends to deep connective tissues, often with debilitating effects [
Of note, POH-like ossifications have been observed rarely in individuals with AHO or PHP-1a.
Individuals with OC develop ossification limited to the dermis and subcutaneous tissues.
• Occasionally, early PTH resistance is associated with hypercalcemia rather than hypocalcemia. Presumably, in these individuals the kidney retains the ability to increase production of 1,25(OH)
• As in PTH-deficient hypoparathyroidism, protracted hypocalcemia and hyperphosphatemia lead to ectopic calcification, particularly in the brain at the grey-white cerebral intersection and the basal ganglia and ocular lenses, manifesting as posterior subcapsular cataracts.
• Bone density is often increased [
• Unrecognized hypocalcemia may present with tetany, seizures, or laryngeal spasm; seizures appear to be more common, independent of hypocalcemia [
## Pseudohypoparathyroidism Ia (PHP-Ia) and PHP-Ic
PHP-Ia and PHP-Ic have a similar phenotype and are distinguished only by
The development of the endocrine features occurs over time. The earliest manifestation of hormone resistance is usually mild hypothyroidism, which is often discovered during newborn screening as an elevated TSH with normal serum levels of thyroid hormones. The average age at diagnosis of PHP-Ia is around age seven years, when PTH resistance and hypocalcemia are recognized; however, individuals with milder manifestations may not be diagnosed until the third decade of life [
Occasionally, early PTH resistance is associated with hypercalcemia rather than hypocalcemia. Presumably, in these individuals the kidney retains the ability to increase production of 1,25(OH)
As in PTH-deficient hypoparathyroidism, protracted hypocalcemia and hyperphosphatemia lead to ectopic calcification, particularly in the brain at the grey-white cerebral intersection and the basal ganglia and ocular lenses, manifesting as posterior subcapsular cataracts.
Bone density is often increased [
Unrecognized hypocalcemia may present with tetany, seizures, or laryngeal spasm; seizures appear to be more common, independent of hypocalcemia [
Sleep apnea is also common (45% of individuals), but is only partly explained by obesity, as individuals with PHP-Ia have a fourfold increased risk for sleep apnea compared to similarly obese individuals. This increase may be due to hypotonia as well as the effects of Gsα inactivation on the normal sleep cycle [
Linear growth may initially be normal or advanced due to obesity; bone age is frequently advanced beyond chronologic age [
Affected individuals display clinical features of Albright hereditary osteodystrophy (AHO) comprising a round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification of the dermis and subcutaneous tissues. Macrocephaly relative to height is typical: 40% have a head circumference above the 90th percentile [
The most common musculoskeletal feature is brachydactyly; brachydactyly type E is manifest as shortened metacarpals (particularly 4th and 5th) and metatarsals (particularly 3rd and 4th) plus brachydactyly type D, manifest as shortening of the distal phalanx of the thumb.
Even in the absence of brachymetacarpia, individuals with AHO usually have brachydactyly type D, a shortened distal thumb phalanx and short, broad thumbnails, associated radiographically with cone-shaped epiphyses [
Brachydactyly may lead to carpal tunnel syndrome with symptomatic paresthesia, which may be confused with the symptoms of hypocalcemia [
Other reported musculoskeletal features include craniosynostosis, hyperostosis of the cranial vault, absence of normal caudal widening of the lumbar interpedicular distances (associated with spinal stenosis), ossification of paravertebral ligaments, shortened distal ulnas, bowing of the tibia and radius, small capital femoral epiphyses, coxa vara, coxa valga, increased prevalence of bony exostoses, and carpal tunnel syndrome [
Ectopic ossifications are most commonly cutaneous, either within subdermal fat or in the dermis. They are located most commonly in the scalp and extremities (particularly the periarticular areas of the hands and feet). These lesions may be very small and asymptomatic, or painful; occasionally lesions can extrude a chalky material. Removal of ectopic ossifications does not result in progression or exacerbation although they may recur if removal is incomplete [
Other areas of ectopic ossification include the sclera and choroid of the eye and cardiac ventricular septum. Visceral involvement is rare [
Dental changes such as enamel hypoplasia, widened root canals, shortened roots with open apices, thickened laminar dura, and delayed dental eruption have been noted in more than 30% of affected individuals, often with impacted second molars [
• Occasionally, early PTH resistance is associated with hypercalcemia rather than hypocalcemia. Presumably, in these individuals the kidney retains the ability to increase production of 1,25(OH)
• As in PTH-deficient hypoparathyroidism, protracted hypocalcemia and hyperphosphatemia lead to ectopic calcification, particularly in the brain at the grey-white cerebral intersection and the basal ganglia and ocular lenses, manifesting as posterior subcapsular cataracts.
• Bone density is often increased [
• Unrecognized hypocalcemia may present with tetany, seizures, or laryngeal spasm; seizures appear to be more common, independent of hypocalcemia [
## Pseudohypoparathyroidism Ib (PHP-Ib)
PHP-Ib consists of PTH resistance with partial resistance to TSH in some affected individuals. Partial TSH resistance manifests as slightly elevated serum TSH levels with generally normal (or low) serum concentrations of thyroid hormones [
Poorly treated PTH resistance can lead to hyperparathyroid bone disease or tertiary hyperparathyroidism. Very rarely bone density can be elevated [
Patterns of excessive growth or weight gain have been described in newborns or during early infancy and childhood.
Individuals with PHP-Ib may have growth-plate defects such as mild brachydactyly or a Madelung deformity-like defect [
The average age of diagnosis for symptomatic individuals is age ten to 12 years [
## Pseudopseudohypoparathyroidism (PPHP)
The phenotype is heterogeneous with a wide differential diagnosis (see
Intrauterine growth restriction is common.
Ectopic ossifications are frequent and almost pathognomonic of Gsα deficiency.
Individuals with PPHP have normocalcemia and no endocrine defects, but have the physical phenotype of Albright hereditary osteodystrophy.
Obesity and intellectual disabilities (10%) are less prevalent than in PHP-Ia [
## Progressive Osseous Heteroplasia (POH)
Individuals with POH have no endocrine defects or features of AHO, but have progressive ectopic ossification that extends to deep connective tissues, often with debilitating effects [
Of note, POH-like ossifications have been observed rarely in individuals with AHO or PHP-1a.
## Osteoma Cutis (OC)
Individuals with OC develop ossification limited to the dermis and subcutaneous tissues.
## Phenotypes and Genetic Mechanisms of Disorders of
Phenotypes and Genetic Mechanisms of Disorders of
From
AHO = Albright hereditary osteodystrophy; DMR = differentially methylated region; IUGR = intrauterine growth restriction; PHP = pseudohypoparathyroidism; PTH = parathyroid hormone; TSH = thyroid-stimulating hormone
See
Multiple hormone resistance, resistance to PTH, TSH, and GHRH; often gonadotropins (LH and FSH) as well
AHO comprising round face, short stature, brachydactyly/brachymetacarpia, and heterotopic ossification
Chromosome abnormalities of
Impairs coupling of Gsα to heptahelical receptors. See
Associated mainly with pathogenic variants in
## Genotype-Phenotype Correlations
No clear correlation appears to exist between the type and location of
However, two unique variants affecting both the stability and the activity of Gsα have been described in three unrelated individuals with PHP1a who presented with additional clinical features reflecting enhanced Gsα activity:
A missense variant associated with typical PHP1a features as well as testotoxicosis [
A four amino-acid insertion within the Gsα GDP/GTP-binding site identified in a brother and sister with PHP1a with transient neonatal diarrhea and pancreatic insufficiency who inherited the insertion from their unaffected mother, who had germline mosaicism [
• A missense variant associated with typical PHP1a features as well as testotoxicosis [
• A four amino-acid insertion within the Gsα GDP/GTP-binding site identified in a brother and sister with PHP1a with transient neonatal diarrhea and pancreatic insufficiency who inherited the insertion from their unaffected mother, who had germline mosaicism [
## Penetrance
Disorders of
## Prevalence
The estimated prevalence for pseudohypoparathyroidism (PHP) and Albright hereditary osteodystrophy (AHO) is approximately 0.79 per 100,000 (according to the Orphanet Report Series, November 2008).
A Japanese study estimated the prevalence of PHP at 3.4 per 1 million individuals [
The prevalence of POH has never been estimated. It is likely extremely rare: fewer than 60 clinically confirmed individuals worldwide have been reported [
## Genetically Related (Allelic) Disorders
Postzygotic
Isolated features of McCune-Albright syndrome (e.g., monostotic or polyostotic fibrous dysplasia), ovarian cysts and testicular sex cord tumors, acromegaly due to sporadic growth hormone-secreting adenomas in the pituitary, and ACTH-independent macronodular adrenal hyperplasia (none of which show other features of McCune-Albright syndrome); as well as intraductal papillary mucinous neoplasms of the pancreas [
Note that heterozygous germline activating
• Isolated features of McCune-Albright syndrome (e.g., monostotic or polyostotic fibrous dysplasia), ovarian cysts and testicular sex cord tumors, acromegaly due to sporadic growth hormone-secreting adenomas in the pituitary, and ACTH-independent macronodular adrenal hyperplasia (none of which show other features of McCune-Albright syndrome); as well as intraductal papillary mucinous neoplasms of the pancreas [
## Differential Diagnosis
Conditions to be considered in the differential diagnosis include the following:
## Management
To establish the extent of disease and needs in an individual diagnosed with a disorder of
Assessment of height, weight, body mass index, growth velocity, and pubertal development
X-ray of hands and feet to classify the type and extent of brachydactyly; bone age study to determine whether skeletal maturation is advanced
Endocrinology evaluation, with studies that may include the following:
Serum concentration of calcium and phosphorous
Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism
Parathyroid hormone (PTH)
Thyroid-stimulating hormone (TSH) and free T4
Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)
Urinary calcium excretion and tubular reabsorption of phosphorus
Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.
Psychoeducational profile/developmental assessment
Ophthalmologic examination for cataracts
Consultation with nutritionist when obesity is present
Consultation with a clinical geneticist and/or genetic counselor
For all forms of PHP-I, calcium and activated vitamin D doses should be adjusted to try to maintain PTH levels at the upper limit of normal or even slightly higher (e.g., 50-150 pg/mL) to avoid secondary complications of chronic hyperparathyroidism. Urinary calcium excretion should be monitored to detect hypercalciuria; however, because calcium reabsorption in the thick ascending limb of the kidney remains responsive to PTH, hypercalciuria in these individuals is very rare as long as PTH is not suppressed.
Rarely thiazide diuretics can be considered in individuals who develop hypercalciuria.
Maintenance of a normal serum calcium-phosphorus product is recommended to minimize the risk of cataract formation and intracerebral calcification. Oral calcium supplements should be taken with meals to reduce serum phosphorus levels. Occasionally, phosphate-binding resins may be required.
Note: Because individuals with PHP-I do not respond to PTH, there is no role for PTH therapy in these individuals.
Surveillance includes the following:
Once the diagnosis is established, annual monitoring for endocrine abnormalities with measurement of serum concentration of PTH, calcium, and phosphate; TSH and free T4, and urinary calcium excretion (either 24-hour urine collection or random urine collections for determination of the calcium/creatinine ratio). These studies should be begun as soon an individual begins treatment, and may be performed more frequently in growing children who may experience increasing requirements for thyroid hormone and/or activated forms of vitamin D.
Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing) should be evaluated annually. Individuals who receive growth hormone replacement should be monitored every three to four months per customary protocols.
Routine physical examination including assessment of: (1) height to identify changes in growth velocity; (2) the hands and feet for evidence of brachydactyly; and (3) new and/or enlarging ectopic ossifications
Annual examination by an ophthalmologist to monitor development of and/or progression of cataracts
Periodic assessment of psychoeducational needs regarding school assistance/educational support and developmental therapies (e.g., physical, occupational, and speech therapy)
Monitoring of post-pubertal females for disturbances in hypothalamic-pituitary-ovarian function
Limit dietary intake of phosphorus (dairy products and meats) in persons with persistently elevated serum levels of phosphate.
It is appropriate to evaluate apparently asymptomatic first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment. Evaluations can include:
Molecular genetic testing if the genetic mechanism of
If the genetic mechanism of
See
Serum concentration of calcium and thyroid studies (TSH and free T4) should be monitored throughout pregnancy, labor, and the postpartum period.
Calcium, vitamin D, and thyroid hormone should be supplemented as needed [
Because breastfeeding can significantly reduce requirements for activated vitamin D, mothers should be monitored for this during lactation and after weaning.
Dr Emily Germain-Lee at the University of Connecticut is recruiting individuals with PHP-Ia and AHO to determine whether growth hormone therapy can improve short stature and obesity.
Researchers at Vanderbilt University Medical Center are investigating whether theophylline treatment promotes weight loss, improves glucose tolerance, and slows growth plate closure in children and young adults.
Search
• Assessment of height, weight, body mass index, growth velocity, and pubertal development
• X-ray of hands and feet to classify the type and extent of brachydactyly; bone age study to determine whether skeletal maturation is advanced
• Endocrinology evaluation, with studies that may include the following:
• Serum concentration of calcium and phosphorous
• Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism
• Parathyroid hormone (PTH)
• Thyroid-stimulating hormone (TSH) and free T4
• Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)
• Urinary calcium excretion and tubular reabsorption of phosphorus
• Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.
• Serum concentration of calcium and phosphorous
• Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism
• Parathyroid hormone (PTH)
• Thyroid-stimulating hormone (TSH) and free T4
• Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)
• Urinary calcium excretion and tubular reabsorption of phosphorus
• Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.
• Psychoeducational profile/developmental assessment
• Ophthalmologic examination for cataracts
• Consultation with nutritionist when obesity is present
• Consultation with a clinical geneticist and/or genetic counselor
• Serum concentration of calcium and phosphorous
• Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism
• Parathyroid hormone (PTH)
• Thyroid-stimulating hormone (TSH) and free T4
• Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)
• Urinary calcium excretion and tubular reabsorption of phosphorus
• Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.
• Once the diagnosis is established, annual monitoring for endocrine abnormalities with measurement of serum concentration of PTH, calcium, and phosphate; TSH and free T4, and urinary calcium excretion (either 24-hour urine collection or random urine collections for determination of the calcium/creatinine ratio). These studies should be begun as soon an individual begins treatment, and may be performed more frequently in growing children who may experience increasing requirements for thyroid hormone and/or activated forms of vitamin D.
• Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing) should be evaluated annually. Individuals who receive growth hormone replacement should be monitored every three to four months per customary protocols.
• Routine physical examination including assessment of: (1) height to identify changes in growth velocity; (2) the hands and feet for evidence of brachydactyly; and (3) new and/or enlarging ectopic ossifications
• Annual examination by an ophthalmologist to monitor development of and/or progression of cataracts
• Periodic assessment of psychoeducational needs regarding school assistance/educational support and developmental therapies (e.g., physical, occupational, and speech therapy)
• Monitoring of post-pubertal females for disturbances in hypothalamic-pituitary-ovarian function
• Molecular genetic testing if the genetic mechanism of
• If the genetic mechanism of
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a disorder of
Assessment of height, weight, body mass index, growth velocity, and pubertal development
X-ray of hands and feet to classify the type and extent of brachydactyly; bone age study to determine whether skeletal maturation is advanced
Endocrinology evaluation, with studies that may include the following:
Serum concentration of calcium and phosphorous
Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism
Parathyroid hormone (PTH)
Thyroid-stimulating hormone (TSH) and free T4
Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)
Urinary calcium excretion and tubular reabsorption of phosphorus
Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.
Psychoeducational profile/developmental assessment
Ophthalmologic examination for cataracts
Consultation with nutritionist when obesity is present
Consultation with a clinical geneticist and/or genetic counselor
• Assessment of height, weight, body mass index, growth velocity, and pubertal development
• X-ray of hands and feet to classify the type and extent of brachydactyly; bone age study to determine whether skeletal maturation is advanced
• Endocrinology evaluation, with studies that may include the following:
• Serum concentration of calcium and phosphorous
• Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism
• Parathyroid hormone (PTH)
• Thyroid-stimulating hormone (TSH) and free T4
• Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)
• Urinary calcium excretion and tubular reabsorption of phosphorus
• Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.
• Serum concentration of calcium and phosphorous
• Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism
• Parathyroid hormone (PTH)
• Thyroid-stimulating hormone (TSH) and free T4
• Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)
• Urinary calcium excretion and tubular reabsorption of phosphorus
• Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.
• Psychoeducational profile/developmental assessment
• Ophthalmologic examination for cataracts
• Consultation with nutritionist when obesity is present
• Consultation with a clinical geneticist and/or genetic counselor
• Serum concentration of calcium and phosphorous
• Serum concentration of 25-hydroxyvitamin D and magnesium to evaluate respectively for severe vitamin D deficiency and hypomagnesemia, either of which can cause decreased responsiveness to PTH or secondary hyperparathyroidism
• Parathyroid hormone (PTH)
• Thyroid-stimulating hormone (TSH) and free T4
• Growth hormone evaluation (IGF1, IGFBP3, stimulated GH testing)
• Urinary calcium excretion and tubular reabsorption of phosphorus
• Note: Renal responsiveness to PTH (via measurement of the serum or urinary nephrogenous cyclic AMP response to administered PTH) is rarely indicated.
## Treatment of Manifestations
For all forms of PHP-I, calcium and activated vitamin D doses should be adjusted to try to maintain PTH levels at the upper limit of normal or even slightly higher (e.g., 50-150 pg/mL) to avoid secondary complications of chronic hyperparathyroidism. Urinary calcium excretion should be monitored to detect hypercalciuria; however, because calcium reabsorption in the thick ascending limb of the kidney remains responsive to PTH, hypercalciuria in these individuals is very rare as long as PTH is not suppressed.
Rarely thiazide diuretics can be considered in individuals who develop hypercalciuria.
Maintenance of a normal serum calcium-phosphorus product is recommended to minimize the risk of cataract formation and intracerebral calcification. Oral calcium supplements should be taken with meals to reduce serum phosphorus levels. Occasionally, phosphate-binding resins may be required.
Note: Because individuals with PHP-I do not respond to PTH, there is no role for PTH therapy in these individuals.
## Surveillance
Surveillance includes the following:
Once the diagnosis is established, annual monitoring for endocrine abnormalities with measurement of serum concentration of PTH, calcium, and phosphate; TSH and free T4, and urinary calcium excretion (either 24-hour urine collection or random urine collections for determination of the calcium/creatinine ratio). These studies should be begun as soon an individual begins treatment, and may be performed more frequently in growing children who may experience increasing requirements for thyroid hormone and/or activated forms of vitamin D.
Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing) should be evaluated annually. Individuals who receive growth hormone replacement should be monitored every three to four months per customary protocols.
Routine physical examination including assessment of: (1) height to identify changes in growth velocity; (2) the hands and feet for evidence of brachydactyly; and (3) new and/or enlarging ectopic ossifications
Annual examination by an ophthalmologist to monitor development of and/or progression of cataracts
Periodic assessment of psychoeducational needs regarding school assistance/educational support and developmental therapies (e.g., physical, occupational, and speech therapy)
Monitoring of post-pubertal females for disturbances in hypothalamic-pituitary-ovarian function
• Once the diagnosis is established, annual monitoring for endocrine abnormalities with measurement of serum concentration of PTH, calcium, and phosphate; TSH and free T4, and urinary calcium excretion (either 24-hour urine collection or random urine collections for determination of the calcium/creatinine ratio). These studies should be begun as soon an individual begins treatment, and may be performed more frequently in growing children who may experience increasing requirements for thyroid hormone and/or activated forms of vitamin D.
• Growth velocity and growth hormone status (serum IGF1 and/or stimulated growth hormone testing) should be evaluated annually. Individuals who receive growth hormone replacement should be monitored every three to four months per customary protocols.
• Routine physical examination including assessment of: (1) height to identify changes in growth velocity; (2) the hands and feet for evidence of brachydactyly; and (3) new and/or enlarging ectopic ossifications
• Annual examination by an ophthalmologist to monitor development of and/or progression of cataracts
• Periodic assessment of psychoeducational needs regarding school assistance/educational support and developmental therapies (e.g., physical, occupational, and speech therapy)
• Monitoring of post-pubertal females for disturbances in hypothalamic-pituitary-ovarian function
## Agents/Circumstances to Avoid
Limit dietary intake of phosphorus (dairy products and meats) in persons with persistently elevated serum levels of phosphate.
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic first-degree relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment. Evaluations can include:
Molecular genetic testing if the genetic mechanism of
If the genetic mechanism of
See
• Molecular genetic testing if the genetic mechanism of
• If the genetic mechanism of
## Pregnancy Management
Serum concentration of calcium and thyroid studies (TSH and free T4) should be monitored throughout pregnancy, labor, and the postpartum period.
Calcium, vitamin D, and thyroid hormone should be supplemented as needed [
Because breastfeeding can significantly reduce requirements for activated vitamin D, mothers should be monitored for this during lactation and after weaning.
## Therapies Under Investigation
Dr Emily Germain-Lee at the University of Connecticut is recruiting individuals with PHP-Ia and AHO to determine whether growth hormone therapy can improve short stature and obesity.
Researchers at Vanderbilt University Medical Center are investigating whether theophylline treatment promotes weight loss, improves glucose tolerance, and slows growth plate closure in children and young adults.
Search
## Genetic Counseling
Disorders of
An inactivating
A genetic alteration in the imprinting regulatory elements in the
Isolated epimutations
Paternal 20q disomy
Of individuals with a disorder of
Disorders of
Paternal germline mosaicism
Isolated epimutation in proband
Maternal germline mosaicism
OC = osteoma cutis; PHP-Ia = pseudohypoparathyroidism Ia; PHP-Ib = pseudohypoparathyroidism Ib; PHP-Ic = pseudohypoparathyroidism Ic; POH = progressive osseous heteroplasia; PPHP = pseudopseudohypoparathyroidism; PTH = parathyroid hormone
Although some probands diagnosed with a disorder of
If the parent is the individual in the family in whom the genetic alteration first occurred, the parent may have somatic mosaicism and may be mildly/minimally affected.
The endocrine features of PHP-1a may in some cases become apparent after the development of findings of AHO, suggesting that an individual may be incorrectly diagnosed initially as PPHP if an AHO phenotype occurs prior to the onset of endocrine abnormalities. In this case, maternal testing may identify a genetic or epigenetic cause.
POH/OC is more often inherited from the father; however, features of POH/OC are on occasion due to maternal inheritance.
Disorder of
PHP type depends on the maternal genotype.
Note regarding inheritance of PHP-Ib: Although females who inherit a PHP-Ib-related genetic alteration from their father (i.e., a paternally imprinted PHP-Ib-related genetic alteration) will be unaffected, their offspring have a 50% risk of inheriting the now maternally imprinted PHP-Ib-related genetic alteration and being affected.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the mechanism of
The phenotype in offspring who inherit a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• An inactivating
• A genetic alteration in the imprinting regulatory elements in the
• Isolated epimutations
• Paternal 20q disomy
• Paternal germline mosaicism
• Isolated epimutation in proband
• Maternal germline mosaicism
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Disorders of
An inactivating
A genetic alteration in the imprinting regulatory elements in the
Isolated epimutations
Paternal 20q disomy
• An inactivating
• A genetic alteration in the imprinting regulatory elements in the
• Isolated epimutations
• Paternal 20q disomy
## Risk to Family Members
Of individuals with a disorder of
Disorders of
Paternal germline mosaicism
Isolated epimutation in proband
Maternal germline mosaicism
OC = osteoma cutis; PHP-Ia = pseudohypoparathyroidism Ia; PHP-Ib = pseudohypoparathyroidism Ib; PHP-Ic = pseudohypoparathyroidism Ic; POH = progressive osseous heteroplasia; PPHP = pseudopseudohypoparathyroidism; PTH = parathyroid hormone
Although some probands diagnosed with a disorder of
If the parent is the individual in the family in whom the genetic alteration first occurred, the parent may have somatic mosaicism and may be mildly/minimally affected.
The endocrine features of PHP-1a may in some cases become apparent after the development of findings of AHO, suggesting that an individual may be incorrectly diagnosed initially as PPHP if an AHO phenotype occurs prior to the onset of endocrine abnormalities. In this case, maternal testing may identify a genetic or epigenetic cause.
POH/OC is more often inherited from the father; however, features of POH/OC are on occasion due to maternal inheritance.
Disorder of
PHP type depends on the maternal genotype.
Note regarding inheritance of PHP-Ib: Although females who inherit a PHP-Ib-related genetic alteration from their father (i.e., a paternally imprinted PHP-Ib-related genetic alteration) will be unaffected, their offspring have a 50% risk of inheriting the now maternally imprinted PHP-Ib-related genetic alteration and being affected.
• Paternal germline mosaicism
• Isolated epimutation in proband
• Maternal germline mosaicism
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the mechanism of
The phenotype in offspring who inherit a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
• United Kingdom
•
•
•
## Molecular Genetics
Disorders of GNAS Inactivation: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Disorders of GNAS Inactivation (
An inactivating
A genetic alteration in the imprinting regulatory elements in the
Isolated epimutations
Paternal 20q disomy
Gsα is encoded by
PHP-Ia and PHP-Ic result from lack of expression of the maternal allele
PPHP result from lack of expression of the paternal allele.
POH and OC can be associated with pathogenic variants in either the maternal or paternal allele; however, paternal pathogenic variants are more common.
Familial PHP-Ib genetic alterations include:
A pathogenic
Loss of imprinting (methylation) at the maternal GNAS exon A/B DMR (also referred to as exon 1A or
Deletion of maternal
Deletion of maternal NESP and/or NESP-AS [
Deletion of maternal
Simplex PHP-Ib genetic alterations include:
GNAS imprinting abnormalities that involve multiple DMRs [
Paternal uniparental disomy for all or part of chromosome 20 [
Heterozygous
Individuals with pathogenic variants in exon 1 of
Variants listed in the table have been provided by the authors.
Variant descriptions are based on the RefSeq
Haploinsufficiency of Gsα results in PHP-Ia and PHP-Ic (lack of expression of the maternal
In PHP-Ib, the imprinting defects lead to reduced expression of Gsα in a tissue-specific manner.
In PHP-Ic heterozygous
• An inactivating
• A genetic alteration in the imprinting regulatory elements in the
• Isolated epimutations
• Paternal 20q disomy
• PHP-Ia and PHP-Ic result from lack of expression of the maternal allele
• PPHP result from lack of expression of the paternal allele.
• POH and OC can be associated with pathogenic variants in either the maternal or paternal allele; however, paternal pathogenic variants are more common.
• A pathogenic
• Loss of imprinting (methylation) at the maternal GNAS exon A/B DMR (also referred to as exon 1A or
• Deletion of maternal
• Deletion of maternal NESP and/or NESP-AS [
• Deletion of maternal
• GNAS imprinting abnormalities that involve multiple DMRs [
• Paternal uniparental disomy for all or part of chromosome 20 [
## Molecular Pathogenesis
An inactivating
A genetic alteration in the imprinting regulatory elements in the
Isolated epimutations
Paternal 20q disomy
Gsα is encoded by
PHP-Ia and PHP-Ic result from lack of expression of the maternal allele
PPHP result from lack of expression of the paternal allele.
POH and OC can be associated with pathogenic variants in either the maternal or paternal allele; however, paternal pathogenic variants are more common.
Familial PHP-Ib genetic alterations include:
A pathogenic
Loss of imprinting (methylation) at the maternal GNAS exon A/B DMR (also referred to as exon 1A or
Deletion of maternal
Deletion of maternal NESP and/or NESP-AS [
Deletion of maternal
Simplex PHP-Ib genetic alterations include:
GNAS imprinting abnormalities that involve multiple DMRs [
Paternal uniparental disomy for all or part of chromosome 20 [
Heterozygous
Individuals with pathogenic variants in exon 1 of
Variants listed in the table have been provided by the authors.
Variant descriptions are based on the RefSeq
Haploinsufficiency of Gsα results in PHP-Ia and PHP-Ic (lack of expression of the maternal
In PHP-Ib, the imprinting defects lead to reduced expression of Gsα in a tissue-specific manner.
In PHP-Ic heterozygous
• An inactivating
• A genetic alteration in the imprinting regulatory elements in the
• Isolated epimutations
• Paternal 20q disomy
• PHP-Ia and PHP-Ic result from lack of expression of the maternal allele
• PPHP result from lack of expression of the paternal allele.
• POH and OC can be associated with pathogenic variants in either the maternal or paternal allele; however, paternal pathogenic variants are more common.
• A pathogenic
• Loss of imprinting (methylation) at the maternal GNAS exon A/B DMR (also referred to as exon 1A or
• Deletion of maternal
• Deletion of maternal NESP and/or NESP-AS [
• Deletion of maternal
• GNAS imprinting abnormalities that involve multiple DMRs [
• Paternal uniparental disomy for all or part of chromosome 20 [
## Gene Structure
Gsα is encoded by
## Pathogenic Variants
PHP-Ia and PHP-Ic result from lack of expression of the maternal allele
PPHP result from lack of expression of the paternal allele.
POH and OC can be associated with pathogenic variants in either the maternal or paternal allele; however, paternal pathogenic variants are more common.
Familial PHP-Ib genetic alterations include:
A pathogenic
Loss of imprinting (methylation) at the maternal GNAS exon A/B DMR (also referred to as exon 1A or
Deletion of maternal
Deletion of maternal NESP and/or NESP-AS [
Deletion of maternal
Simplex PHP-Ib genetic alterations include:
GNAS imprinting abnormalities that involve multiple DMRs [
Paternal uniparental disomy for all or part of chromosome 20 [
Heterozygous
Individuals with pathogenic variants in exon 1 of
Variants listed in the table have been provided by the authors.
Variant descriptions are based on the RefSeq
• PHP-Ia and PHP-Ic result from lack of expression of the maternal allele
• PPHP result from lack of expression of the paternal allele.
• POH and OC can be associated with pathogenic variants in either the maternal or paternal allele; however, paternal pathogenic variants are more common.
• A pathogenic
• Loss of imprinting (methylation) at the maternal GNAS exon A/B DMR (also referred to as exon 1A or
• Deletion of maternal
• Deletion of maternal NESP and/or NESP-AS [
• Deletion of maternal
• GNAS imprinting abnormalities that involve multiple DMRs [
• Paternal uniparental disomy for all or part of chromosome 20 [
## Normal Gene Product
## Abnormal Gene Product
Haploinsufficiency of Gsα results in PHP-Ia and PHP-Ic (lack of expression of the maternal
In PHP-Ib, the imprinting defects lead to reduced expression of Gsα in a tissue-specific manner.
In PHP-Ic heterozygous
## Chapter Notes
Dr Levine's
26 October 2017 (bp) Review posted live
15 April 2015 (mal) Original submission
• 26 October 2017 (bp) Review posted live
• 15 April 2015 (mal) Original submission
## Author Notes
Dr Levine's
## Revision History
26 October 2017 (bp) Review posted live
15 April 2015 (mal) Original submission
• 26 October 2017 (bp) Review posted live
• 15 April 2015 (mal) Original submission
## References
## Literature Cited
Schematic of the
|
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"N Makita, J Sato, P Rondard, H Fukamachi, Y Yuasa, MA Aldred, M Hashimoto, T Fujita, T Iiri. Human G(salpha) mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle.. Proc Natl Acad Sci U S A. 2007;104:17424-9",
"G Mantovani, FM Elli, A Spada. GNAS epigenetic defects and pseudohypoparathyroidism: time for a new classification?. Horm Metab Res. 2012;44:716-23",
"G Mantovani, E Ferrante, C Giavoli, A Linglart, M Cappa, M Cisternino, M Maghnie, L Ghizzoni, L de Sanctis, AG Lania, P Beck-Peccoz, A Spada. Recombinant human GH replacement therapy in children with pseudohypoparathyroidism type 1a: first study on the effect on growth.. J Clin Endocrinol Metab. 2010;95:5011-7",
"G Mantovani, A Spada, FM Elli. Pseudohypoparathyroidism and Gsα–cAMP-linked disorders: current view and open issues.. Nat Rev Endocrinol. 2016;12:347-56",
"T Mitsui, K Naaki, M Takagi, S Narumi, T Ishii, T. Hasegawa. A family of pseudohypoparathyroidism type Ia with an 850-kb submicroscopic deletion encompassing the whole GNAS locus.. Am J Med Genet A. 2012;158A:261-4",
"M Mouallem, M Shaharabany, N Weintrob, S Shalitin, N Nagelberg, H Shapira, Z Zadik, Z Farfel. Cognitive impairment is prevalent in pseudohypoparathyroidism type 1a, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha.. Clin Endocrinol (Oxf) 2008;68:233-9",
"JM Nakamoto, D Zimmerman, EA Jones, KY Loke, K Siddiq, MA Donlan, AS Brickman, C Van Dop. Concurrent hormone resistance (pseudohypoparathyroidism type Ia) and hormone independence (testotoxicosis) caused by a unique mutation in the G alpha s gene.. Biochem Mol Med. 1996;58:18-24",
"Y Nakamura, T Matsumoto, A Tamakoshi, T Kawamura, Y Seino, M Kasuga, H Yanagawa, Y Ohno. Prevalence of idiopathic hypoparathyroidism and pseudohypoparathyroidism in Japan.. J Epidemiol. 2000;10:29-33",
"YF Ngai, C Chijiwa, S Mercimek-Mahmutoglu, L Stewart, SL Yong, WP Robinson, WT Gibson. Pseudohypoparathyroidism type 1a and the GNAS p.R231H mutation: Somatic mosaicism in a mother with two affected sons.. Am J Med Genet A. 2010;152A:2784-90",
"RJ Pignolo, G Ramaswamy, JT Fong, EM Shore, FS Kaplan. Progressive osseous heteroplasia: diagnosis, treatment, and prognosis.. Appl Clin Genet. 2015;8:37-48",
"JS Prendiville, AW Lucky, SB Mallory, Z Mughal, F Mimouni, CB Langman. Osteoma cutis as a presenting sign of pseudohypoparathyroidism.. Pediatr Dermatol. 1992;9:11-8",
"FI Rezwan, RL Poole, T Prescott, JM Walker, I Karen Temple, DJ Mackay. Very small deletions within the NESP55 gene in pseudohypoparathyroidism type 1b.. Eur J Hum Genet. 2015;23:494-9",
"N Richard, G Abeguilé, N Coudray, H Mittre, N Gruchy, J Andrieux, P Cathebras, ML Kottler. A new deletion ablating NESP55 causes loss of maternal imprint of A/B GNAS and autosomal dominant pseudohypoparathyroidism type Ib.. J Clin Endocrinol Metab. 2012;97:E863-7",
"N Richard, A Molin, N Coudray, P Rault-Guillaume, H Jüppner, ML Kottler. Paternal GNAS mutations lead to severe intrauterine growth retardation (IUGR) and provide evidence for a role of XLαs in fetal development.. J Clin Endocrinol Metab. 2013;98:E1549-56",
"GM Ritchie. Dental manifestations of pseudohypoparathyroidism.. Arch Dis Child. 1965;40:565-72",
"JD Roizen, J Danzig, V Groleau, S McCormack, A Casella, J Harrington, E Sochett, A Tershakovec, BS Zemel, VA Stallings, MA Levine. Resting energy expenditure is decreased in pseudohypoparathyroidism type 1A.. J Clin Endocrinol Metab. 2016;101:880-8",
"J Sanchez, E Perera, S Jan de Beur, C Ding, A Dang, GD Berkovitz, MA Levine. Madelung-like deformity in pseudohypoparathyroidism type 1b.. J Clin Endocrinol Metab. 2011;96:E1507-11",
"AM Sbrocchi, F Rauch, ML Lawson, S Hadjiyannakis, S Lawrence, M Bastepe, H Jüppner, LM Ward. Osteosclerosis in two brothers with autosomal dominant pseudohypoparathyroidism type 1b: bone histomorphometric analysis.. Eur J Endocrinol. 2011;164:295-301",
"EM Shore, J Ahn, S Jan de Beur, M Li, M Xu, RJ Gardner, MA Zasloff, MP Whyte, MA Levine, FS Kaplan. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia.. N Engl J Med. 2002;346:99-106",
"EM Shore, FS Kaplan. Inherited human diseases of heterotopic bone formation.. Nat Rev Rheumatol. 2010;6:518-27",
"A Singh, N Agarwal, S Chopra, P Sikka, V Suri, B Kumar, P Dutta. Management of pseudohypoparathyroidism type 1a during pregnancy and labor: a case report.. Case Rep Obstet Gynecol. 2012;2012",
"O Tafaj, H. Jüppner. Pseudohypoparathyroidism: one gene, several syndromes.. J Endocrinol Invest. 2017;40:347-56",
"R Takatani, M Minagawa, A Molinaro, M Reyes, K Kinoshita, T Takatani, I Kazukawa, M Nagatsuma, K Kashimada, K Sato, K Matsushita, F Nomura, N Shimojo, H Jüppner. Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B).. Bone. 2015;79:15-20",
"S Thiele, R Werner, W Ahrens, U Hoppe, C Marschke, P Staedt, O. Hiort. A disruptive mutation in exon 3 of the GNAS gene with Albright hereditary osteodystrophy, normocalcemic pseudohypoparathyroidism, and selective long transcript variant Gsalpha-l deficiency.. J Clin Endocrinol Metab 2007;92:1764-8",
"S Thiele, R Werner, J Grötzinger, B Brix, P Staedt, D Struve, B Reiz, J Farida, O. Hiort. A positive genotype-phenotype correlation in a large cohort of patients with pseudohypoparathyroidism type ia and pseudo-pseudohypoparathyroidism and 33 newly identified mutations in the GNAS gene.. Mol Genet Genomic Med. 2015;3:111-20",
"S Turan, M. Bastepe. GNAS spectrum of disorders.. Curr Osteoporos Rep. 2015;13:146-58",
"EJ van Lindert, RH Bartels, K Noordam. Spinal stenosis with paraparesis in albright hereditary osteodystrophy. Case report and review of the literature.. Pediatr Neurosurg. 2008;44:337-40",
"LC Wilson. Albright's hereditary osteodystrophy.. J Pediatr Endocrinol Metab. 2006;19:671-3",
"LC Wilson, CM Hall. Albright's hereditary osteodystrophy and pseudohypoparathyroidism.. Semin Musculoskelet Radiol. 2002;6:273-83"
] |
26/10/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
gnb1-e
|
gnb1-e
|
[
"Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1",
"GNB1",
"GNB1 Encephalopathy"
] |
Anya Revah-Politi, Tristan T Sands, Sophie Colombo, David B Goldstein, Kwame Anyane-Yeboa
|
Summary The diagnosis of
|
## Diagnosis
Formal diagnostic criteria for
Moderate to profound developmental delay (DD) or intellectual disability (ID); AND
One or more of the following features presenting in infancy or childhood:
Generalized hypotonia of infancy that can evolve to hypertonia and spasticity
Feeding disorder and difficulties with weight gain in infancy
Movement disorder (dystonia, tics, ataxia, and chorea)
Epilepsy (including generalized, focal, and mixed epilepsy and infantile spasms)
Behavior problems (repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder [ADHD], and/or autism spectrum disorder [ASD])
Macrocephaly
Slow growth
Vision impairment (optic atrophy and cortical visual impairment) and/or abnormal eye movements (strabismus, nystagmus)
Gastrointestinal issues (chronic constipation, cyclic vomiting, gastroesophageal reflux disease [GERD], and/or abdominal distention with cramps)
Craniofacial anomalies (cleft palate, craniosynostosis)
Note: When present, dysmorphic features are nonspecific.
The diagnosis of
Molecular genetic testing in any child with DD or an older individual with ID typically begins with chromosomal microarray analysis (CMA), which uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis.
If CMA is not diagnostic, the next step is typically either a multigene panel or comprehensive genomic testing (exome sequencing or genome sequencing). Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Individuals with contiguous gene deletions, including 1p36 microdeletion, are not included in these calculations (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One individual with an intragenic deletion spanning exons 2-5 of
• Moderate to profound developmental delay (DD) or intellectual disability (ID); AND
• One or more of the following features presenting in infancy or childhood:
• Generalized hypotonia of infancy that can evolve to hypertonia and spasticity
• Feeding disorder and difficulties with weight gain in infancy
• Movement disorder (dystonia, tics, ataxia, and chorea)
• Epilepsy (including generalized, focal, and mixed epilepsy and infantile spasms)
• Behavior problems (repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder [ADHD], and/or autism spectrum disorder [ASD])
• Macrocephaly
• Slow growth
• Vision impairment (optic atrophy and cortical visual impairment) and/or abnormal eye movements (strabismus, nystagmus)
• Gastrointestinal issues (chronic constipation, cyclic vomiting, gastroesophageal reflux disease [GERD], and/or abdominal distention with cramps)
• Craniofacial anomalies (cleft palate, craniosynostosis)
• Note: When present, dysmorphic features are nonspecific.
• Generalized hypotonia of infancy that can evolve to hypertonia and spasticity
• Feeding disorder and difficulties with weight gain in infancy
• Movement disorder (dystonia, tics, ataxia, and chorea)
• Epilepsy (including generalized, focal, and mixed epilepsy and infantile spasms)
• Behavior problems (repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder [ADHD], and/or autism spectrum disorder [ASD])
• Macrocephaly
• Slow growth
• Vision impairment (optic atrophy and cortical visual impairment) and/or abnormal eye movements (strabismus, nystagmus)
• Gastrointestinal issues (chronic constipation, cyclic vomiting, gastroesophageal reflux disease [GERD], and/or abdominal distention with cramps)
• Craniofacial anomalies (cleft palate, craniosynostosis)
• Generalized hypotonia of infancy that can evolve to hypertonia and spasticity
• Feeding disorder and difficulties with weight gain in infancy
• Movement disorder (dystonia, tics, ataxia, and chorea)
• Epilepsy (including generalized, focal, and mixed epilepsy and infantile spasms)
• Behavior problems (repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder [ADHD], and/or autism spectrum disorder [ASD])
• Macrocephaly
• Slow growth
• Vision impairment (optic atrophy and cortical visual impairment) and/or abnormal eye movements (strabismus, nystagmus)
• Gastrointestinal issues (chronic constipation, cyclic vomiting, gastroesophageal reflux disease [GERD], and/or abdominal distention with cramps)
• Craniofacial anomalies (cleft palate, craniosynostosis)
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Moderate to profound developmental delay (DD) or intellectual disability (ID); AND
One or more of the following features presenting in infancy or childhood:
Generalized hypotonia of infancy that can evolve to hypertonia and spasticity
Feeding disorder and difficulties with weight gain in infancy
Movement disorder (dystonia, tics, ataxia, and chorea)
Epilepsy (including generalized, focal, and mixed epilepsy and infantile spasms)
Behavior problems (repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder [ADHD], and/or autism spectrum disorder [ASD])
Macrocephaly
Slow growth
Vision impairment (optic atrophy and cortical visual impairment) and/or abnormal eye movements (strabismus, nystagmus)
Gastrointestinal issues (chronic constipation, cyclic vomiting, gastroesophageal reflux disease [GERD], and/or abdominal distention with cramps)
Craniofacial anomalies (cleft palate, craniosynostosis)
Note: When present, dysmorphic features are nonspecific.
• Moderate to profound developmental delay (DD) or intellectual disability (ID); AND
• One or more of the following features presenting in infancy or childhood:
• Generalized hypotonia of infancy that can evolve to hypertonia and spasticity
• Feeding disorder and difficulties with weight gain in infancy
• Movement disorder (dystonia, tics, ataxia, and chorea)
• Epilepsy (including generalized, focal, and mixed epilepsy and infantile spasms)
• Behavior problems (repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder [ADHD], and/or autism spectrum disorder [ASD])
• Macrocephaly
• Slow growth
• Vision impairment (optic atrophy and cortical visual impairment) and/or abnormal eye movements (strabismus, nystagmus)
• Gastrointestinal issues (chronic constipation, cyclic vomiting, gastroesophageal reflux disease [GERD], and/or abdominal distention with cramps)
• Craniofacial anomalies (cleft palate, craniosynostosis)
• Note: When present, dysmorphic features are nonspecific.
• Generalized hypotonia of infancy that can evolve to hypertonia and spasticity
• Feeding disorder and difficulties with weight gain in infancy
• Movement disorder (dystonia, tics, ataxia, and chorea)
• Epilepsy (including generalized, focal, and mixed epilepsy and infantile spasms)
• Behavior problems (repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder [ADHD], and/or autism spectrum disorder [ASD])
• Macrocephaly
• Slow growth
• Vision impairment (optic atrophy and cortical visual impairment) and/or abnormal eye movements (strabismus, nystagmus)
• Gastrointestinal issues (chronic constipation, cyclic vomiting, gastroesophageal reflux disease [GERD], and/or abdominal distention with cramps)
• Craniofacial anomalies (cleft palate, craniosynostosis)
• Generalized hypotonia of infancy that can evolve to hypertonia and spasticity
• Feeding disorder and difficulties with weight gain in infancy
• Movement disorder (dystonia, tics, ataxia, and chorea)
• Epilepsy (including generalized, focal, and mixed epilepsy and infantile spasms)
• Behavior problems (repetitive and stereotypic behaviors, attention-deficit/hyperactivity disorder [ADHD], and/or autism spectrum disorder [ASD])
• Macrocephaly
• Slow growth
• Vision impairment (optic atrophy and cortical visual impairment) and/or abnormal eye movements (strabismus, nystagmus)
• Gastrointestinal issues (chronic constipation, cyclic vomiting, gastroesophageal reflux disease [GERD], and/or abdominal distention with cramps)
• Craniofacial anomalies (cleft palate, craniosynostosis)
## Establishing the Diagnosis
The diagnosis of
Molecular genetic testing in any child with DD or an older individual with ID typically begins with chromosomal microarray analysis (CMA), which uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis.
If CMA is not diagnostic, the next step is typically either a multigene panel or comprehensive genomic testing (exome sequencing or genome sequencing). Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Individuals with contiguous gene deletions, including 1p36 microdeletion, are not included in these calculations (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One individual with an intragenic deletion spanning exons 2-5 of
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Step 1
Molecular genetic testing in any child with DD or an older individual with ID typically begins with chromosomal microarray analysis (CMA), which uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications that cannot be detected by sequence analysis.
## Step 2
If CMA is not diagnostic, the next step is typically either a multigene panel or comprehensive genomic testing (exome sequencing or genome sequencing). Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Individuals with contiguous gene deletions, including 1p36 microdeletion, are not included in these calculations (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One individual with an intragenic deletion spanning exons 2-5 of
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date, 58 individuals have been identified with
Selected Clinical Manifestations of
OFC = occipital frontal circumference
Frequency = # of persons with the manifestation / # of persons examined for this specific manifestation
Speech delay is common; about 40% of individuals are nonverbal. Of note, in two individuals with normal hearing, alternative means of communication (such as sign language) improved communication.
Developmental regression was documented in three individuals. One became visually inattentive, hypotonic, and lethargic at age eight weeks, and had further developmental regression with the onset of infantile spasms at age seven months. Two others had regression of verbal skills by age three years [
ID, ranging from mild to severe, has been reported in about 74% of individuals. ID was not reported in two individuals older than age six years [
The presence or absence of DD and ID was not documented in one individual in the DECIPHER database [
EEG may be normal in the first years of life. Hypsarrhythmia, generalized epileptiform discharges or multifocal epileptiform discharges (especially from the temporal regions) may develop and become abundant in sleep.
Abnormal vision due to cortical visual impairment or optic atrophy has been reported in 11% of individuals, including one individual considered to be legally blind. Ocular albinism and possible rod-cone dystrophy were each observed once [
Although an increased risk for malignancies has been suggested [
The absence of congenital anomalies associated with high morbidity and mortality suggests a favorable long-term prognosis with appropriate support and management. The authors are aware of three individuals with
Many recurrent
Fifty-five percent of individuals with dystonia had a p.Ile80 substitution (
Three of the four individuals with cutaneous mastocytosis had the p.Ile80Thr variant [
A genotype-phenotype correlation between the p.Ile80Thr variant and severe axial hypotonia or hypotonic quadriplegia has been suggested [
Most probands reported to date with
Fifty-eight individuals with
No increased prevalence of
• Abnormal vision due to cortical visual impairment or optic atrophy has been reported in 11% of individuals, including one individual considered to be legally blind. Ocular albinism and possible rod-cone dystrophy were each observed once [
• Fifty-five percent of individuals with dystonia had a p.Ile80 substitution (
• Three of the four individuals with cutaneous mastocytosis had the p.Ile80Thr variant [
• A genotype-phenotype correlation between the p.Ile80Thr variant and severe axial hypotonia or hypotonic quadriplegia has been suggested [
## Clinical Description
To date, 58 individuals have been identified with
Selected Clinical Manifestations of
OFC = occipital frontal circumference
Frequency = # of persons with the manifestation / # of persons examined for this specific manifestation
Speech delay is common; about 40% of individuals are nonverbal. Of note, in two individuals with normal hearing, alternative means of communication (such as sign language) improved communication.
Developmental regression was documented in three individuals. One became visually inattentive, hypotonic, and lethargic at age eight weeks, and had further developmental regression with the onset of infantile spasms at age seven months. Two others had regression of verbal skills by age three years [
ID, ranging from mild to severe, has been reported in about 74% of individuals. ID was not reported in two individuals older than age six years [
The presence or absence of DD and ID was not documented in one individual in the DECIPHER database [
EEG may be normal in the first years of life. Hypsarrhythmia, generalized epileptiform discharges or multifocal epileptiform discharges (especially from the temporal regions) may develop and become abundant in sleep.
Abnormal vision due to cortical visual impairment or optic atrophy has been reported in 11% of individuals, including one individual considered to be legally blind. Ocular albinism and possible rod-cone dystrophy were each observed once [
Although an increased risk for malignancies has been suggested [
The absence of congenital anomalies associated with high morbidity and mortality suggests a favorable long-term prognosis with appropriate support and management. The authors are aware of three individuals with
• Abnormal vision due to cortical visual impairment or optic atrophy has been reported in 11% of individuals, including one individual considered to be legally blind. Ocular albinism and possible rod-cone dystrophy were each observed once [
## Genotype-Phenotype Correlations
Many recurrent
Fifty-five percent of individuals with dystonia had a p.Ile80 substitution (
Three of the four individuals with cutaneous mastocytosis had the p.Ile80Thr variant [
A genotype-phenotype correlation between the p.Ile80Thr variant and severe axial hypotonia or hypotonic quadriplegia has been suggested [
• Fifty-five percent of individuals with dystonia had a p.Ile80 substitution (
• Three of the four individuals with cutaneous mastocytosis had the p.Ile80Thr variant [
• A genotype-phenotype correlation between the p.Ile80Thr variant and severe axial hypotonia or hypotonic quadriplegia has been suggested [
## Penetrance
Most probands reported to date with
## Prevalence
Fifty-eight individuals with
No increased prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because the phenotypic features associated with
•
•
•
•
•
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Brain MRI
EEG incl sleep study to characterize any recurrent abnormal episodes & to evaluate for subtle or subclinical seizures & epileptic encephalopathy
To incl:
Motor, adaptive, cognitive, & speech/language evaluation
Evaluation for early intervention / special education
Gross motor & fine motor skills
Mobility & activities of daily living & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl evaluation of aspiration risk & nutritional status
Assess for history of recurrent constipation, cyclic vomiting, gastroesophageal reflux disease, & distended abdomen w/cramps.
Consider evaluation for gastric tube placement in those w/dysphagia &/or aspiration risk.
Confirmation of diagnosis
Recommendations for trigger avoidance
Photographs for serial monitoring
Treatment recommendations
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CBC = complete blood count; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Avoid substances & environments that may provoke mast cell activation.
Standard treatment, incl non-sedating & longer-acting histamine (H1)-receptor antagonists to treat common symptoms
Ensure appropriate social work involvement to connect families w/local resources, respite, & support
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
Ongoing assessment for need of palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
Measurement of growth parameters
Evaluation of nutritional status & safety of oral intake
At each visit
Monitor for recurrent constipation, cyclic vomiting, gastroesophageal reflux, & distended abdomen w/cramps.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
Monitor developmental progress & educational needs.
Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior
Physical medicine, OT/PT assessment of mobility, self-help skills
CBC to monitor for hematologic malignancies
Education of family re early clinical signs of hematologic malignancies (e.g., easy bruising due to thrombocytopenia)
Every 6 mos - yr
At each visit
CBC = complete blood count; OT = occupational therapy; PT = physical therapy
See
Search
• Brain MRI
• EEG incl sleep study to characterize any recurrent abnormal episodes & to evaluate for subtle or subclinical seizures & epileptic encephalopathy
• Motor, adaptive, cognitive, & speech/language evaluation
• Evaluation for early intervention / special education
• Gross motor & fine motor skills
• Mobility & activities of daily living & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl evaluation of aspiration risk & nutritional status
• Assess for history of recurrent constipation, cyclic vomiting, gastroesophageal reflux disease, & distended abdomen w/cramps.
• Consider evaluation for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Confirmation of diagnosis
• Recommendations for trigger avoidance
• Photographs for serial monitoring
• Treatment recommendations
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Avoid substances & environments that may provoke mast cell activation.
• Standard treatment, incl non-sedating & longer-acting histamine (H1)-receptor antagonists to treat common symptoms
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support
• Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
• Ongoing assessment for need of palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Measurement of growth parameters
• Evaluation of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
• CBC to monitor for hematologic malignancies
• Education of family re early clinical signs of hematologic malignancies (e.g., easy bruising due to thrombocytopenia)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Brain MRI
EEG incl sleep study to characterize any recurrent abnormal episodes & to evaluate for subtle or subclinical seizures & epileptic encephalopathy
To incl:
Motor, adaptive, cognitive, & speech/language evaluation
Evaluation for early intervention / special education
Gross motor & fine motor skills
Mobility & activities of daily living & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl evaluation of aspiration risk & nutritional status
Assess for history of recurrent constipation, cyclic vomiting, gastroesophageal reflux disease, & distended abdomen w/cramps.
Consider evaluation for gastric tube placement in those w/dysphagia &/or aspiration risk.
Confirmation of diagnosis
Recommendations for trigger avoidance
Photographs for serial monitoring
Treatment recommendations
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CBC = complete blood count; OT = occupational therapy; PT = physical therapy
• Brain MRI
• EEG incl sleep study to characterize any recurrent abnormal episodes & to evaluate for subtle or subclinical seizures & epileptic encephalopathy
• Motor, adaptive, cognitive, & speech/language evaluation
• Evaluation for early intervention / special education
• Gross motor & fine motor skills
• Mobility & activities of daily living & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl evaluation of aspiration risk & nutritional status
• Assess for history of recurrent constipation, cyclic vomiting, gastroesophageal reflux disease, & distended abdomen w/cramps.
• Consider evaluation for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Confirmation of diagnosis
• Recommendations for trigger avoidance
• Photographs for serial monitoring
• Treatment recommendations
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Avoid substances & environments that may provoke mast cell activation.
Standard treatment, incl non-sedating & longer-acting histamine (H1)-receptor antagonists to treat common symptoms
Ensure appropriate social work involvement to connect families w/local resources, respite, & support
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
Ongoing assessment for need of palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Avoid substances & environments that may provoke mast cell activation.
• Standard treatment, incl non-sedating & longer-acting histamine (H1)-receptor antagonists to treat common symptoms
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support
• Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
• Ongoing assessment for need of palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
Measurement of growth parameters
Evaluation of nutritional status & safety of oral intake
At each visit
Monitor for recurrent constipation, cyclic vomiting, gastroesophageal reflux, & distended abdomen w/cramps.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
Monitor developmental progress & educational needs.
Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior
Physical medicine, OT/PT assessment of mobility, self-help skills
CBC to monitor for hematologic malignancies
Education of family re early clinical signs of hematologic malignancies (e.g., easy bruising due to thrombocytopenia)
Every 6 mos - yr
At each visit
CBC = complete blood count; OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Evaluation of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations (e.g., seizures, changes in tone, movement disorders).
• CBC to monitor for hematologic malignancies
• Education of family re early clinical signs of hematologic malignancies (e.g., easy bruising due to thrombocytopenia)
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most probands reported to date with
Rarely, individuals diagnosed with
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Note: A parent with somatic and germline mosaicism for a
If a parent of the proband has the
If the proband represents a simplex case (i.e., the only affected family member) and the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
If neither parent has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most probands reported to date with
• Rarely, individuals diagnosed with
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Note: A parent with somatic and germline mosaicism for a
• If a parent of the proband has the
• If the proband represents a simplex case (i.e., the only affected family member) and the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Most probands reported to date with
Rarely, individuals diagnosed with
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Note: A parent with somatic and germline mosaicism for a
If a parent of the proband has the
If the proband represents a simplex case (i.e., the only affected family member) and the
• Most probands reported to date with
• Rarely, individuals diagnosed with
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Note: A parent with somatic and germline mosaicism for a
• If a parent of the proband has the
• If the proband represents a simplex case (i.e., the only affected family member) and the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
If neither parent has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
Speaking out for People with Intellectual and Developmental Disabilities
Parents and physicians can submit clinical information on newly diagnosed individuals to the GNB1 Human Disease Genes Website.
This resource was established to clarify the clinical phenotype associated with pathogenic variants in the complete coding region of GNB1 and to facilitate research into the underlying mechanism of GNB1 encephalopathy.
•
•
•
•
•
•
•
• Canada
•
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
•
• Parents and physicians can submit clinical information on newly diagnosed individuals to the GNB1 Human Disease Genes Website.
• This resource was established to clarify the clinical phenotype associated with pathogenic variants in the complete coding region of GNB1 and to facilitate research into the underlying mechanism of GNB1 encephalopathy.
•
## Molecular Genetics
GNB1 Encephalopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GNB1 Encephalopathy (
Heterotrimeric G protein complexes function as cellular signal transducers for G protein-coupled receptors (GPCRs). They are composed of an alpha (Gα), a beta (Gβ), and a gamma subunit (Gγ). GPCR activation catalyzes a GDP-to-GTP exchange on the Gα subunit, leading to the dissociation of Gα from the obligate dimer Gβγ. Both Gα and Gβγ then bind and regulate a wide variety of downstream effectors.
Recurrent missense changes
The vast majority of those tested occurred
Thirty different missense variants have been reported so far, with 73% of these occurring in exons 6 and 7 (NM_002074.4). The most common variant reported to date is Ile80Thr in exon 6 (seen in 20% of affected individuals).
Many reported germline missense variants occurred at the same codons and/or were identical to somatic missense variants identified in tumor samples [
In functional studies, the abnormal Gβ1 protein impaired function of the G protein heterotrimer [
Because most pathogenic variants appear to occur at the surface of interaction between the Gβ1 and Gα subunits or downstream effectors, it is believed that perturbation of this interaction will affect the regulation of the downstream signaling pathways. This may have gain-of-function, dominant-negative, or loss-of-function consequences on the regulation of these pathways.
Research on
Notable
Variants listed in the table have been provided by the authors.
Acute lymphoblastic leukemia has been reported in one individual with a
Recurrent somatic
• Recurrent missense changes
• The vast majority of those tested occurred
• Thirty different missense variants have been reported so far, with 73% of these occurring in exons 6 and 7 (NM_002074.4). The most common variant reported to date is Ile80Thr in exon 6 (seen in 20% of affected individuals).
• Many reported germline missense variants occurred at the same codons and/or were identical to somatic missense variants identified in tumor samples [
• In functional studies, the abnormal Gβ1 protein impaired function of the G protein heterotrimer [
## Molecular Pathogenesis
Heterotrimeric G protein complexes function as cellular signal transducers for G protein-coupled receptors (GPCRs). They are composed of an alpha (Gα), a beta (Gβ), and a gamma subunit (Gγ). GPCR activation catalyzes a GDP-to-GTP exchange on the Gα subunit, leading to the dissociation of Gα from the obligate dimer Gβγ. Both Gα and Gβγ then bind and regulate a wide variety of downstream effectors.
Recurrent missense changes
The vast majority of those tested occurred
Thirty different missense variants have been reported so far, with 73% of these occurring in exons 6 and 7 (NM_002074.4). The most common variant reported to date is Ile80Thr in exon 6 (seen in 20% of affected individuals).
Many reported germline missense variants occurred at the same codons and/or were identical to somatic missense variants identified in tumor samples [
In functional studies, the abnormal Gβ1 protein impaired function of the G protein heterotrimer [
Because most pathogenic variants appear to occur at the surface of interaction between the Gβ1 and Gα subunits or downstream effectors, it is believed that perturbation of this interaction will affect the regulation of the downstream signaling pathways. This may have gain-of-function, dominant-negative, or loss-of-function consequences on the regulation of these pathways.
Research on
Notable
Variants listed in the table have been provided by the authors.
• Recurrent missense changes
• The vast majority of those tested occurred
• Thirty different missense variants have been reported so far, with 73% of these occurring in exons 6 and 7 (NM_002074.4). The most common variant reported to date is Ile80Thr in exon 6 (seen in 20% of affected individuals).
• Many reported germline missense variants occurred at the same codons and/or were identical to somatic missense variants identified in tumor samples [
• In functional studies, the abnormal Gβ1 protein impaired function of the G protein heterotrimer [
## Cancer and Benign Tumors
Acute lymphoblastic leukemia has been reported in one individual with a
Recurrent somatic
## Chapter Notes
Anya Revah-Politi is a certified genetic counselor at the Institute for Genomic Medicine and at the Precision Genomics Laboratory at Columbia University Irving Medical Center. She holds a faculty appointment as Assistant Professor of Genetic Counseling in Pathology and Cell Biology and in the Institute for Genomic Medicine at Columbia University Irving Medical Center.
Tristan T Sands is an Assistant Professor of Neurology in the Division of Child Neurology and at the Institute for Genomic Medicine at Columbia University Irving Medical Center.
Sophie Colombo is an Associate Research Scientist in the Goldstein Laboratory at the Institute for Genomic Medicine at Columbia University Irving Medical Center.
David B Goldstein is the John E Borne Professor of Medical and Surgical Research (in Genetics and Development, in the Institute for Genomic Medicine, and in Neurology), Professor of Medical Sciences (in Medicine), and Director of Institute for Genomic Medicine, at Columbia University Irving Medical Center.
Kwame Anyane-Yeboa is a Professor of Pediatrics and serves as Chief at the Division of Clinical Genetics at Columbia University Irving Medical Center. He is a frequent collaborator in the Institute for Genomic Medicine.
Columbia University Institute for Genomic Medicine website:
We acknowledge the contribution of the DECIPHER Consortium. The DECIPHER study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from
15 April 2021 (aa) Revision: incorporated data from
5 March 2020 (bp) Review posted live
28 June 2019 (kay) Original submission
• 15 April 2021 (aa) Revision: incorporated data from
• 5 March 2020 (bp) Review posted live
• 28 June 2019 (kay) Original submission
## Author Notes
Anya Revah-Politi is a certified genetic counselor at the Institute for Genomic Medicine and at the Precision Genomics Laboratory at Columbia University Irving Medical Center. She holds a faculty appointment as Assistant Professor of Genetic Counseling in Pathology and Cell Biology and in the Institute for Genomic Medicine at Columbia University Irving Medical Center.
Tristan T Sands is an Assistant Professor of Neurology in the Division of Child Neurology and at the Institute for Genomic Medicine at Columbia University Irving Medical Center.
Sophie Colombo is an Associate Research Scientist in the Goldstein Laboratory at the Institute for Genomic Medicine at Columbia University Irving Medical Center.
David B Goldstein is the John E Borne Professor of Medical and Surgical Research (in Genetics and Development, in the Institute for Genomic Medicine, and in Neurology), Professor of Medical Sciences (in Medicine), and Director of Institute for Genomic Medicine, at Columbia University Irving Medical Center.
Kwame Anyane-Yeboa is a Professor of Pediatrics and serves as Chief at the Division of Clinical Genetics at Columbia University Irving Medical Center. He is a frequent collaborator in the Institute for Genomic Medicine.
Columbia University Institute for Genomic Medicine website:
## Acknowledgments
We acknowledge the contribution of the DECIPHER Consortium. The DECIPHER study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from
## Revision History
15 April 2021 (aa) Revision: incorporated data from
5 March 2020 (bp) Review posted live
28 June 2019 (kay) Original submission
• 15 April 2021 (aa) Revision: incorporated data from
• 5 March 2020 (bp) Review posted live
• 28 June 2019 (kay) Original submission
## References
## Literature Cited
|
[
"M Brett, AH Lai, TW Ting, AM Tan, R Foo, S Jamuar, EC Tan. Acute lymphoblastic leukemia in a child with a de novo germline gnb1 mutation.. Am J Med Genet A. 2017;173:550-2",
"W Endo, S Ikemoto, N Togashi, T Miyabayashi, E Nakajima, S Hamano, M Shibuya, S Sato, Y Takezawa, Y Okubo, T Inui, M Kato, T Sengoku, K Ogata, K Hamanaka, T Mizuguchi, S Miyatake, M Nakashima, N Matsumoto, K Haginoya. Phenotype-genotype correlations in patients with GNB1 gene variants, including the first three reported Japanese patients to exhibit spastic diplegia, dyskinetic quadriplegia, and infantile spasms.. Brain Dev. 2020;42:199-204",
"HV Firth, SM Richards, AP Bevan, S Clayton, M Corpas, D Rajan, S Van Vooren, Y Moreau, RM Pettett, NP Carter. DECIPHER: Database of chromosomal imbalance and phenotype in humans using Ensembl resources.. Am J Hum Genet. 2009;84:524-33",
"P Hemati, A Revah-Politi, H Bassan, S Petrovski, CG Bilancia, K Ramsey, NG Griffin, L Bier, MT Cho, M Rosello, SA Lynch, S Colombo, A Weber, M Haug, EL Heinzen, TT Sands, V Narayanan, M Primiano, VS Aggarwal, F Millan, SG Sattler-Holtrop, A Caro-Llopis, N Pillar, J Baker, R Freedman, HY Kroes, S Sacharow, N Stong, P Lapunzina, MC Schneider, NJ Mendelsohn, A Singleton, VL Ramey, K Wou, A Kuzminsky, S Monfort, M Weisz Hubshman, S Doyle, A Iglesias, F Martinez, D Mckenzie, C Orellana, KLI van Gassen, M Palomares, L Bazak, A Lee, A Bircher, L Basel-Vanagaite, M Hafström, G Houge. C4RCD Research Group, DDD study, Goldstein DB, Anyane-Yeboa K. Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature.. Am J Med Genet A. 2018;176:2259-75",
"HF Jones, H Morales-Briceño, K Barwick, J Lewis, A Sanchis-Juan, FL Raymond, K Stewart, MC Waugh, N Mahant, MA Kurian, RC Dale, SS Mohammad. Myoclonus-dystonia caused by GNB1 mutation responsive to deep brain stimulation.. Mov Disord. 2019;34:1079-80",
"SM Khan, R Sleno, S Gora, P Zylbergold, JP Laverdure, JC Labbé, GJ Miller, TE Hébert. The expanding roles of Gβγ subunits in G protein-coupled receptor signaling and drug action.. Pharmacol Rev. 2013;65:545-77",
"SM Khan, JY Sung, TE Hébert. Gβγ subunits-Different spaces, different faces.. Pharmacol Res. 2016;111:434-41",
"K Lohmann, I Masuho, DN Patil, H Baumann, E Hebert, S Steinrucke, D Trujillano, NK Skamangas, V Dobricic, I Huning, G Gillessen-Kaesbach, A Westenberger, D Savic-Pavicevic, A Munchau, G Oprea, C Klein, A Rolfs, KA Martemyanov. Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans.. Hum Mol Genet. 2017;26:1078-86",
"CT Myers, G Hollingsworth, AM Muir, AL Schneider, Z Thuesmunn, A Knupp, C King, A Lacroix, MG Mehaffey, SF Berkovic, GL Carvill, LG Sadleir, IE Scheffer, HC Mefford. Parental mosaicism in \"de novo\" epileptic encephalopathies.. N Engl J Med. 2018;378:1646-8",
"H Okae, Y Iwakura. Neural tube defects and impaired neural progenitor cell proliferation in Gbeta1-deficient mice.. Dev Dyn. 2010;239:1089-101",
"J Peng, Y Wang, F He, C Chen, LW Wu, LF Yang, YP Ma, W Zhang, ZQ Shi, C Chen, K Xia, H Guo, F Yin, N Pang. Novel West syndrome candidate genes in a Chinese cohort.. CNS Neurosci Ther. 2018;24:1196-206",
"S Petrovski, S Kury, CT Myers, K Anyane-Yeboa, B Cogne, M Bialer, F Xia, P Hemati, J Riviello, M Mehaffey, T Besnard, E Becraft, A Wadley, A Revah Politi, S Colombo, X Zhu, Z Ren, I Andrews, T Dudding-Byth, AL Schneider, G Wallace. University of Washington Center for Mendelian Genomics, Rosen ABI, Schelley S, Enns GM, Corre P, Dalton J, Mercier S, Latypova X, Schmitt S, Guzman E, Moore C, Bier L, Heinzen EL, Karachunski P, Shur N, Grebe T, Basinger A, Nguyen JM, Bezieau S, Wierenga K, Bernstein JA, Scheffer IE, Rosenfeld JA, Mefford HC, Isidor B, Goldstein DB. Germline de novo mutations in GNB1 cause severe neurodevelopmental disability, hypotonia, and seizures.. Am J Hum Genet. 2016;98:1001-10",
"L Schultz-Rogers, I Masuho, FPE Vairo, CT Schmitz, TL Schwab, KJ Clark, L Gunderson, PN Pichurin, K Wierenga, KA Martemyanov, EW Klee. Haploinsufficiency as a disease mechanism in GNB1-associated neurodevelopmental disorder.. Mol Genet Genomic Med. 2020;8",
"AV Smrcka. G protein βγ subunits: central mediators of G protein-coupled receptor signaling.. Cell Mol Life Sci. 2008;65:2191-4",
"S Steinrücke, K Lohmann, A Domingo, A Rolfs, T Bäumer, J Spiegler, C Hartmann, A. Münchau. Novel GNB1 missense mutation in a patient with generalized dystonia, hypotonia, and intellectual disability.. Neurol Genet. 2016;2",
"K Szczałuba, A Biernacka, K Szymańska, P Gasperowicz, J Kosińska, M Rydzanicz, R. Płoski. Novel GNB1 de novo mutation in a patient with neurodevelopmental disorder and cutaneous mastocytosis: Clinical report and literature review.. Eur J Med Genet. 2018;61:157-60",
"TC Theoharides, P Valent, C Akin. Mast cells, mastocytosis, and related disorders.. N Engl J Med. 2015;373:1885-6",
"A Yoda, G Adelmant, J Tamburini, B Chapuy, N Shindoh, Y Yoda, O Weigert, N Kopp, SC Wu, SS Kim, H Liu, T Tivey, AL Christie, KG Elpek, J Card, K Gritsman, J Gotlib, MW Deininger, H Makishima, SJ Turley, N Javidi-Sharifi, JP Maciejewski, S Jaiswal, BL Ebert, SJ Rodig, JW Tyner, JA Marto, DM Weinstock, AA Lane. Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.. Nat. Med. 2015;21:71-5"
] |
5/3/2020
|
15/4/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
gnb5-ndd
|
gnb5-ndd
|
[
"Intellectual Developmental Disorder with Cardiac Arrhythmia (IDDCA) Syndrome",
"Language Delay and ADHD / Cognitive Impairment with or without Cardiac Arrhythmia (LADCI)",
"Intellectual Developmental Disorder with Cardiac Arrhythmia (IDDCA) Syndrome",
"Language Delay and ADHD / Cognitive Impairment with or without Cardiac Arrhythmia (LADCI)",
"Guanine nucleotide-binding protein subunit beta-5",
"GNB5",
"GNB5-Related Neurodevelopmental Disorder"
] |
Gemma Poke, Lynette Grant Sadleir, Giuseppe Merla, Guillem de Valles-Ibáñez, Jonathan Robert Skinner
|
Summary The diagnosis of
|
This chapter reviews the entire spectrum of neurodevelopmental and arrhythmia phenotypes associated with biallelic
## Diagnosis
No consensus clinical diagnostic criteria for
Developmental delay
Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
Hypotonia
Visual impairment with nystagmus
Seizures (focal seizures, epileptic spasms)
Developmental delay / intellectual disability and severe language delay. One exception appears to be an extended family in which severe language delay is not accompanied by intellectual deficits [
Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
The diagnosis of
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
One additional individual with homozygous contiguous gene deletions (not included in these calculations) has been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Developmental delay
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Hypotonia
• Visual impairment with nystagmus
• Seizures (focal seizures, epileptic spasms)
• Developmental delay
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Hypotonia
• Visual impairment with nystagmus
• Seizures (focal seizures, epileptic spasms)
• Developmental delay / intellectual disability and severe language delay. One exception appears to be an extended family in which severe language delay is not accompanied by intellectual deficits [
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Developmental delay / intellectual disability and severe language delay. One exception appears to be an extended family in which severe language delay is not accompanied by intellectual deficits [
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Developmental delay
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Hypotonia
• Visual impairment with nystagmus
• Seizures (focal seizures, epileptic spasms)
• Developmental delay / intellectual disability and severe language delay. One exception appears to be an extended family in which severe language delay is not accompanied by intellectual deficits [
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
## Suggestive Findings
Developmental delay
Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
Hypotonia
Visual impairment with nystagmus
Seizures (focal seizures, epileptic spasms)
Developmental delay / intellectual disability and severe language delay. One exception appears to be an extended family in which severe language delay is not accompanied by intellectual deficits [
Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Developmental delay
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Hypotonia
• Visual impairment with nystagmus
• Seizures (focal seizures, epileptic spasms)
• Developmental delay
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Hypotonia
• Visual impairment with nystagmus
• Seizures (focal seizures, epileptic spasms)
• Developmental delay / intellectual disability and severe language delay. One exception appears to be an extended family in which severe language delay is not accompanied by intellectual deficits [
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Developmental delay / intellectual disability and severe language delay. One exception appears to be an extended family in which severe language delay is not accompanied by intellectual deficits [
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Developmental delay
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
• Hypotonia
• Visual impairment with nystagmus
• Seizures (focal seizures, epileptic spasms)
• Developmental delay / intellectual disability and severe language delay. One exception appears to be an extended family in which severe language delay is not accompanied by intellectual deficits [
• Bradycardia due to sinoatrial node dysfunction (sick sinus syndrome)
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
One additional individual with homozygous contiguous gene deletions (not included in these calculations) has been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
One additional individual with homozygous contiguous gene deletions (not included in these calculations) has been reported (see
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
To date, 41 individuals with biallelic
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ERG = electroretinogram; GERD = gastroesophageal reflux disease; ID = intellectual disability
Number of persons with feature out of number of persons assessed for feature
Five members of a single family [
Cognitive outcome is variable. Severe-to-profound ID is seen in ~75%, mild-to-moderate ID in ~12%, and normal intellect with a severe language disorder in ~12% (one family).
Of the three individuals reported by
Hypotonia and hyporeflexia are common initially and are near universal in children with severe or profound ID. Hypertonia, spasticity, and joint contractures develop in a minority. At least one individual required surgery for hamstring contractures [Author, personal observation].
Attention-deficit/hyperactivity disorder (ADHD) was reported in 3/5 children with language delay but normal IQ; ADHD as assessed by DSM-IV criteria was either hyperactive or inattentive [
The presence or absence of cardiac involvement does not correlate with the level of developmental impairment.
Bradycardia due to sinus node dysfunction (sick sinus syndrome), the most common arrhythmia, may present with cyanosis or apnea, or be asymptomatic and incidentally picked up on EKG. Bradycardia may be identified prenatally [
Animal models suggest that
Other arrhythmias rarely reported [
AV block (2 individuals)
Atrial tachycardia (1 individual)
Atrial fibrillation (1 individual)
Sinus tachycardia (1 individual)
Six children had a pacemaker inserted; four had profound ID and two had mild-to-moderate ID [
Twenty-six individuals had a developmental and epileptic encephalopathy, presenting with developmental delay prior to seizure onset [
The median age at seizure onset was six months (range: 1 week to 3 years).
In the 16 individuals for whom detailed seizure semiology (i.e., seizure type) was provided, the first seizure type was epileptic spasms in seven, focal motor seizures in seven, and tonic-clonic seizures in two. The most common seizure type overall was epileptic spasms (onset age: 2 months to 3 years), which can occur either at seizure presentation or later.
While EEGs may be normal in the first weeks of life, by age three to six months there is burst suppression or hypsarrhythmia, and by age three years multifocal discharges with background slowing [
Visual impairment is common in children with severe-to-profound ID; it has not been reported in children with mild ID.
Nystagmus affects nearly all children with severe-to-profound ID. Both upbeat nystagmus [
Retinopathy in
Strabismus is described in six individuals with severe-to-profound ID and one with moderate ID [
Myopic refractive errors, described in two children ages two and three years with severe-to-profound ID, measured -1.5 diopters in the younger child [
Pathologic gastric reflux disease (common in children with severe-to-profound ID) may be severe, resulting in hospitalization and/or bleeding [
Birth weight is usually normal. Postnatal microcephaly or macrocephaly are uncommon. Limited data on other postnatal growth parameters are available.
Brain imaging is usually normal. Occasionally nonspecific changes including prominent cerebrospinal fluid spaces, cerebral or cerebellar atrophy, and/or a thin corpus callosum are noted [
Three individuals with confirmed pathogenic variants in
Age at death, reported in 7/8 individuals, ranged from five months to 13 years; all had severe or profound developmental impairment and epilepsy. Circumstances of death were reported in six of the eight:
In one family [
A girl age five months died during severe acute gastroenteritis.
Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
A girl age 13 years died in her sleep, possibly from a cardiac arrhythmia or SUDEP [
In another child, age not specified, death was attributed to cardiac arrest [
No publications mentioned coroners' reports.
Existing literature supports a genotype-phenotype correlation.
Variants predicted to cause protein truncation are associated with a severe neurodevelopmental phenotype. Of 31 individuals with severe or profound ID, 26 were homozygous or compound homozygous for nonsense, frameshift, or splice site variants [
Nine individuals from four families who are homozygous for a recurrent missense variant affecting residue 123 (
Three individuals homozygous for other missense variants have severe ID [
Three individuals who are compound heterozygous for a missense variant and a truncating variant have moderate-to-profound ID at age ≤2 years [
Parental consanguinity is commonly observed.
Of the 25 reported families, nine (36%) are from India or Pakistan and five (20%) are from northern Africa [
• AV block (2 individuals)
• Atrial tachycardia (1 individual)
• Atrial fibrillation (1 individual)
• Sinus tachycardia (1 individual)
• In one family [
• A girl age five months died during severe acute gastroenteritis.
• Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
• Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
• A girl age five months died during severe acute gastroenteritis.
• Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
• Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
• A girl age 13 years died in her sleep, possibly from a cardiac arrhythmia or SUDEP [
• In another child, age not specified, death was attributed to cardiac arrest [
• A girl age five months died during severe acute gastroenteritis.
• Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
• Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
• Nine individuals from four families who are homozygous for a recurrent missense variant affecting residue 123 (
• Three individuals homozygous for other missense variants have severe ID [
• Three individuals who are compound heterozygous for a missense variant and a truncating variant have moderate-to-profound ID at age ≤2 years [
## Clinical Description
To date, 41 individuals with biallelic
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ERG = electroretinogram; GERD = gastroesophageal reflux disease; ID = intellectual disability
Number of persons with feature out of number of persons assessed for feature
Five members of a single family [
Cognitive outcome is variable. Severe-to-profound ID is seen in ~75%, mild-to-moderate ID in ~12%, and normal intellect with a severe language disorder in ~12% (one family).
Of the three individuals reported by
Hypotonia and hyporeflexia are common initially and are near universal in children with severe or profound ID. Hypertonia, spasticity, and joint contractures develop in a minority. At least one individual required surgery for hamstring contractures [Author, personal observation].
Attention-deficit/hyperactivity disorder (ADHD) was reported in 3/5 children with language delay but normal IQ; ADHD as assessed by DSM-IV criteria was either hyperactive or inattentive [
The presence or absence of cardiac involvement does not correlate with the level of developmental impairment.
Bradycardia due to sinus node dysfunction (sick sinus syndrome), the most common arrhythmia, may present with cyanosis or apnea, or be asymptomatic and incidentally picked up on EKG. Bradycardia may be identified prenatally [
Animal models suggest that
Other arrhythmias rarely reported [
AV block (2 individuals)
Atrial tachycardia (1 individual)
Atrial fibrillation (1 individual)
Sinus tachycardia (1 individual)
Six children had a pacemaker inserted; four had profound ID and two had mild-to-moderate ID [
Twenty-six individuals had a developmental and epileptic encephalopathy, presenting with developmental delay prior to seizure onset [
The median age at seizure onset was six months (range: 1 week to 3 years).
In the 16 individuals for whom detailed seizure semiology (i.e., seizure type) was provided, the first seizure type was epileptic spasms in seven, focal motor seizures in seven, and tonic-clonic seizures in two. The most common seizure type overall was epileptic spasms (onset age: 2 months to 3 years), which can occur either at seizure presentation or later.
While EEGs may be normal in the first weeks of life, by age three to six months there is burst suppression or hypsarrhythmia, and by age three years multifocal discharges with background slowing [
Visual impairment is common in children with severe-to-profound ID; it has not been reported in children with mild ID.
Nystagmus affects nearly all children with severe-to-profound ID. Both upbeat nystagmus [
Retinopathy in
Strabismus is described in six individuals with severe-to-profound ID and one with moderate ID [
Myopic refractive errors, described in two children ages two and three years with severe-to-profound ID, measured -1.5 diopters in the younger child [
Pathologic gastric reflux disease (common in children with severe-to-profound ID) may be severe, resulting in hospitalization and/or bleeding [
Birth weight is usually normal. Postnatal microcephaly or macrocephaly are uncommon. Limited data on other postnatal growth parameters are available.
Brain imaging is usually normal. Occasionally nonspecific changes including prominent cerebrospinal fluid spaces, cerebral or cerebellar atrophy, and/or a thin corpus callosum are noted [
Three individuals with confirmed pathogenic variants in
Age at death, reported in 7/8 individuals, ranged from five months to 13 years; all had severe or profound developmental impairment and epilepsy. Circumstances of death were reported in six of the eight:
In one family [
A girl age five months died during severe acute gastroenteritis.
Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
A girl age 13 years died in her sleep, possibly from a cardiac arrhythmia or SUDEP [
In another child, age not specified, death was attributed to cardiac arrest [
No publications mentioned coroners' reports.
• AV block (2 individuals)
• Atrial tachycardia (1 individual)
• Atrial fibrillation (1 individual)
• Sinus tachycardia (1 individual)
• In one family [
• A girl age five months died during severe acute gastroenteritis.
• Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
• Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
• A girl age five months died during severe acute gastroenteritis.
• Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
• Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
• A girl age 13 years died in her sleep, possibly from a cardiac arrhythmia or SUDEP [
• In another child, age not specified, death was attributed to cardiac arrest [
• A girl age five months died during severe acute gastroenteritis.
• Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
• Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
## Neurodevelopmental Disorder
Cognitive outcome is variable. Severe-to-profound ID is seen in ~75%, mild-to-moderate ID in ~12%, and normal intellect with a severe language disorder in ~12% (one family).
Of the three individuals reported by
## Other Neurodevelopmental Features
Hypotonia and hyporeflexia are common initially and are near universal in children with severe or profound ID. Hypertonia, spasticity, and joint contractures develop in a minority. At least one individual required surgery for hamstring contractures [Author, personal observation].
Attention-deficit/hyperactivity disorder (ADHD) was reported in 3/5 children with language delay but normal IQ; ADHD as assessed by DSM-IV criteria was either hyperactive or inattentive [
## Sinus Node Dysfunction
The presence or absence of cardiac involvement does not correlate with the level of developmental impairment.
Bradycardia due to sinus node dysfunction (sick sinus syndrome), the most common arrhythmia, may present with cyanosis or apnea, or be asymptomatic and incidentally picked up on EKG. Bradycardia may be identified prenatally [
Animal models suggest that
Other arrhythmias rarely reported [
AV block (2 individuals)
Atrial tachycardia (1 individual)
Atrial fibrillation (1 individual)
Sinus tachycardia (1 individual)
Six children had a pacemaker inserted; four had profound ID and two had mild-to-moderate ID [
• AV block (2 individuals)
• Atrial tachycardia (1 individual)
• Atrial fibrillation (1 individual)
• Sinus tachycardia (1 individual)
## Epilepsy
Twenty-six individuals had a developmental and epileptic encephalopathy, presenting with developmental delay prior to seizure onset [
The median age at seizure onset was six months (range: 1 week to 3 years).
In the 16 individuals for whom detailed seizure semiology (i.e., seizure type) was provided, the first seizure type was epileptic spasms in seven, focal motor seizures in seven, and tonic-clonic seizures in two. The most common seizure type overall was epileptic spasms (onset age: 2 months to 3 years), which can occur either at seizure presentation or later.
While EEGs may be normal in the first weeks of life, by age three to six months there is burst suppression or hypsarrhythmia, and by age three years multifocal discharges with background slowing [
## Visual Impairment
Visual impairment is common in children with severe-to-profound ID; it has not been reported in children with mild ID.
Nystagmus affects nearly all children with severe-to-profound ID. Both upbeat nystagmus [
Retinopathy in
Strabismus is described in six individuals with severe-to-profound ID and one with moderate ID [
Myopic refractive errors, described in two children ages two and three years with severe-to-profound ID, measured -1.5 diopters in the younger child [
## Gastroesophageal Reflux Disease
Pathologic gastric reflux disease (common in children with severe-to-profound ID) may be severe, resulting in hospitalization and/or bleeding [
## Other
Birth weight is usually normal. Postnatal microcephaly or macrocephaly are uncommon. Limited data on other postnatal growth parameters are available.
Brain imaging is usually normal. Occasionally nonspecific changes including prominent cerebrospinal fluid spaces, cerebral or cerebellar atrophy, and/or a thin corpus callosum are noted [
## Mortality
Three individuals with confirmed pathogenic variants in
Age at death, reported in 7/8 individuals, ranged from five months to 13 years; all had severe or profound developmental impairment and epilepsy. Circumstances of death were reported in six of the eight:
In one family [
A girl age five months died during severe acute gastroenteritis.
Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
A girl age 13 years died in her sleep, possibly from a cardiac arrhythmia or SUDEP [
In another child, age not specified, death was attributed to cardiac arrest [
No publications mentioned coroners' reports.
• In one family [
• A girl age five months died during severe acute gastroenteritis.
• Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
• Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
• A girl age five months died during severe acute gastroenteritis.
• Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
• Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
• A girl age 13 years died in her sleep, possibly from a cardiac arrhythmia or SUDEP [
• In another child, age not specified, death was attributed to cardiac arrest [
• A girl age five months died during severe acute gastroenteritis.
• Her brother and sister died at seven and eight months, respectively, during sleep; death was attributed to sudden unexpected death in epilepsy (SUDEP).
• Another brother presented to hospital with sinus bradycardia and died with multiorgan failure at age seven years.
## Genotype-Phenotype Correlations
Existing literature supports a genotype-phenotype correlation.
Variants predicted to cause protein truncation are associated with a severe neurodevelopmental phenotype. Of 31 individuals with severe or profound ID, 26 were homozygous or compound homozygous for nonsense, frameshift, or splice site variants [
Nine individuals from four families who are homozygous for a recurrent missense variant affecting residue 123 (
Three individuals homozygous for other missense variants have severe ID [
Three individuals who are compound heterozygous for a missense variant and a truncating variant have moderate-to-profound ID at age ≤2 years [
• Nine individuals from four families who are homozygous for a recurrent missense variant affecting residue 123 (
• Three individuals homozygous for other missense variants have severe ID [
• Three individuals who are compound heterozygous for a missense variant and a truncating variant have moderate-to-profound ID at age ≤2 years [
## Prevalence
Parental consanguinity is commonly observed.
Of the 25 reported families, nine (36%) are from India or Pakistan and five (20%) are from northern Africa [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
One child was reported with an approximately 193-kb homozygous contiguous gene deletion of chromosome 15q21.2, involving
## Differential Diagnosis
Because the phenotypic features associated with
For children with a phenotype consistent with infantile-onset epileptic encephalopathy, all genes known to be associated with early-infantile epileptic encephalopathy (see
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Full neurologic exam
Brain MRI (if not performed at time of initial eval)
EEG if seizures suspected
To examine age-appropriate motor, adaptive, cognitive, & speech/language abilities
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl 12-lead EKG & 24-hr ambulatory (Holter) EKG
Consider implantation of digital EKG loop recorder, or prolonged event monitor recordings to document or exclude assoc of asystole or other arrhythmias w/seizures.
EKG to exclude structural heart disease (not found to date in this condition)
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy; MOI = mode of inheritance; SLP = speech-language pathology
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Management by multidisciplinary specialists, including a general pediatrician, developmental pediatrician, pediatric neurologist, speech-language pathologist, orthopedist, physical medicine and rehabilitation specialist, physical therapist, occupational therapist, pediatric ophthalmologist, and pediatric cardiologist is recommended.
Treatment of Manifestations in Individuals with
Treat epileptic encephalopathy per local guidelines specific for seizure type & epilepsy syndrome.
Education of parents/caregivers
To incl stretching to help avoid contractures & falls
Consider need for positioning & mobility devices, disability parking placard.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ADL = activities of daily living; ASMs = anti-seizure medications; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. Augmentative and alternative communication (AAC) devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Recommended Surveillance for Individuals with
Seizure type & frequency;
ASM side effects.
Monitor for history suggestive of arrhythmic syncope.
EKG & Holter recordings
Use of event monitors incl implantable loop recorders may help establish whether or not pauses are assoc w/or causative of syncope or seizure activity.
AAC = augmentative and alternative communication; ADL = activities of daily living; ASM = anti-seizure medication
Parasympathomimetics, which should be used with extreme caution because of the potential to cause asystole, are generally only used in the context of general anesthesia or treatment of glaucoma. Access to possible emergent pacing during general anesthesia would be advisable; however, a favorable response to isoprotenerol or epinephrine would be expected [
Other drugs that can potentiate bradycardia, particularly beta blockers, are best avoided.
It is appropriate to clarify the genetic status of at-risk neonates (if prenatal testing was not performed) in order to identify as early as possible those with biallelic
Undergo developmental assessment and monitoring;
Be referred to a pediatric cardiologist.
Screening in the first days should at least include an EKG and 24-hour Holter recording, repeated periodically thereafter during childhood unless molecular genetic testing demonstrates that the individual has not inherited the biallelic
Likewise, it is appropriate to clarify the genetic status of sibs of a proband with mild developmental delay in order to identify as early as possible those with biallelic
Clarification of genetic status is presumed to be unnecessary for older developmentally normal sibs of a proband with a severe neurodevelopmental phenotype because of phenotypic similarity in affected sibs in all multiplex families reported to date: older developmentally normal sibs of severely affected probands are unlikely to be affected. However, genetic testing for confirmation and reassurance may be offered.
See
Search
• Full neurologic exam
• Brain MRI (if not performed at time of initial eval)
• EEG if seizures suspected
• To examine age-appropriate motor, adaptive, cognitive, & speech/language abilities
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl 12-lead EKG & 24-hr ambulatory (Holter) EKG
• Consider implantation of digital EKG loop recorder, or prolonged event monitor recordings to document or exclude assoc of asystole or other arrhythmias w/seizures.
• EKG to exclude structural heart disease (not found to date in this condition)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Treat epileptic encephalopathy per local guidelines specific for seizure type & epilepsy syndrome.
• Education of parents/caregivers
• To incl stretching to help avoid contractures & falls
• Consider need for positioning & mobility devices, disability parking placard.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Seizure type & frequency;
• ASM side effects.
• Monitor for history suggestive of arrhythmic syncope.
• EKG & Holter recordings
• Use of event monitors incl implantable loop recorders may help establish whether or not pauses are assoc w/or causative of syncope or seizure activity.
• Undergo developmental assessment and monitoring;
• Be referred to a pediatric cardiologist.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Full neurologic exam
Brain MRI (if not performed at time of initial eval)
EEG if seizures suspected
To examine age-appropriate motor, adaptive, cognitive, & speech/language abilities
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl 12-lead EKG & 24-hr ambulatory (Holter) EKG
Consider implantation of digital EKG loop recorder, or prolonged event monitor recordings to document or exclude assoc of asystole or other arrhythmias w/seizures.
EKG to exclude structural heart disease (not found to date in this condition)
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy; MOI = mode of inheritance; SLP = speech-language pathology
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Full neurologic exam
• Brain MRI (if not performed at time of initial eval)
• EEG if seizures suspected
• To examine age-appropriate motor, adaptive, cognitive, & speech/language abilities
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl 12-lead EKG & 24-hr ambulatory (Holter) EKG
• Consider implantation of digital EKG loop recorder, or prolonged event monitor recordings to document or exclude assoc of asystole or other arrhythmias w/seizures.
• EKG to exclude structural heart disease (not found to date in this condition)
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Management by multidisciplinary specialists, including a general pediatrician, developmental pediatrician, pediatric neurologist, speech-language pathologist, orthopedist, physical medicine and rehabilitation specialist, physical therapist, occupational therapist, pediatric ophthalmologist, and pediatric cardiologist is recommended.
Treatment of Manifestations in Individuals with
Treat epileptic encephalopathy per local guidelines specific for seizure type & epilepsy syndrome.
Education of parents/caregivers
To incl stretching to help avoid contractures & falls
Consider need for positioning & mobility devices, disability parking placard.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
ADL = activities of daily living; ASMs = anti-seizure medications; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. Augmentative and alternative communication (AAC) devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Treat epileptic encephalopathy per local guidelines specific for seizure type & epilepsy syndrome.
• Education of parents/caregivers
• To incl stretching to help avoid contractures & falls
• Consider need for positioning & mobility devices, disability parking placard.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language pathology (SLP) services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
Recommended Surveillance for Individuals with
Seizure type & frequency;
ASM side effects.
Monitor for history suggestive of arrhythmic syncope.
EKG & Holter recordings
Use of event monitors incl implantable loop recorders may help establish whether or not pauses are assoc w/or causative of syncope or seizure activity.
AAC = augmentative and alternative communication; ADL = activities of daily living; ASM = anti-seizure medication
• Seizure type & frequency;
• ASM side effects.
• Monitor for history suggestive of arrhythmic syncope.
• EKG & Holter recordings
• Use of event monitors incl implantable loop recorders may help establish whether or not pauses are assoc w/or causative of syncope or seizure activity.
## Agents/Circumstances to Avoid
Parasympathomimetics, which should be used with extreme caution because of the potential to cause asystole, are generally only used in the context of general anesthesia or treatment of glaucoma. Access to possible emergent pacing during general anesthesia would be advisable; however, a favorable response to isoprotenerol or epinephrine would be expected [
Other drugs that can potentiate bradycardia, particularly beta blockers, are best avoided.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of at-risk neonates (if prenatal testing was not performed) in order to identify as early as possible those with biallelic
Undergo developmental assessment and monitoring;
Be referred to a pediatric cardiologist.
Screening in the first days should at least include an EKG and 24-hour Holter recording, repeated periodically thereafter during childhood unless molecular genetic testing demonstrates that the individual has not inherited the biallelic
Likewise, it is appropriate to clarify the genetic status of sibs of a proband with mild developmental delay in order to identify as early as possible those with biallelic
Clarification of genetic status is presumed to be unnecessary for older developmentally normal sibs of a proband with a severe neurodevelopmental phenotype because of phenotypic similarity in affected sibs in all multiplex families reported to date: older developmentally normal sibs of severely affected probands are unlikely to be affected. However, genetic testing for confirmation and reassurance may be offered.
See
• Undergo developmental assessment and monitoring;
• Be referred to a pediatric cardiologist.
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.
## Mode of Inheritance
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
Canada
•
•
•
•
•
•
•
• Canada
•
•
•
•
• Canada
•
•
•
•
•
•
•
## Molecular Genetics
GNB5-Related Neurodevelopmental Disorder : Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GNB5-Related Neurodevelopmental Disorder (
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
LG Sadleir, G de Valles-Ibáñez, and G Poke are members of the Epilepsy Research Group at the University of Otago, Wellington (
Jonathan R Skinner is a paediatric electrophysiologist and genetic cardiologist. His main research interests include a focus on preventing young sudden death through the detection and management of – and translational research into – inherited cardiac conditions. See
We thank the generosity of our patients in sharing their clinical information, as well as our colleagues who have supported research into this disorder. We thank Li Feng for providing a translation of
9 September 2021 (gp) Revision: nucleotide variant correction: c.348_352delTAAGA
26 August 2021 (bp) Review posted live
19 March 2021 (gp) Initial submission
• 9 September 2021 (gp) Revision: nucleotide variant correction: c.348_352delTAAGA
• 26 August 2021 (bp) Review posted live
• 19 March 2021 (gp) Initial submission
## Author Notes
LG Sadleir, G de Valles-Ibáñez, and G Poke are members of the Epilepsy Research Group at the University of Otago, Wellington (
Jonathan R Skinner is a paediatric electrophysiologist and genetic cardiologist. His main research interests include a focus on preventing young sudden death through the detection and management of – and translational research into – inherited cardiac conditions. See
## Acknowledgments
We thank the generosity of our patients in sharing their clinical information, as well as our colleagues who have supported research into this disorder. We thank Li Feng for providing a translation of
## Revision History
9 September 2021 (gp) Revision: nucleotide variant correction: c.348_352delTAAGA
26 August 2021 (bp) Review posted live
19 March 2021 (gp) Initial submission
• 9 September 2021 (gp) Revision: nucleotide variant correction: c.348_352delTAAGA
• 26 August 2021 (bp) Review posted live
• 19 March 2021 (gp) Initial submission
## References
## Literature Cited
|
[
"P De Nittis, S Efthymiou, A Sarre, N Guex, J Chrast, A Putoux, T Sultan, J Raza Alvi, Z Ur Rahman, F Zafar, N Rana, F Rahman, N Anwar, S Maqbool, MS Zaki, JG Gleeson, D Murphy, H Galehdari, G Shariati, N Mazaheri, A Sedaghat, G Lesca, N Chatron, V Salpietro, M Christoforou, H Houlden, WF Simonds, T Pedrazzini, R Maroofian, A Reymond. Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome.. J Med Genet. 2021;58:815-31",
"PG Jones, SJ Lombardi, MI Cockett. Cloning and tissue distribution of the human G protein β5 cDNA.. Biochim Biophys Acta. 1998;1402:288-91",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"EM Lodder, P De Nittis, CD Koopman, W Wiszniewski, CF Moura de Souza, N Lahrouchi, N Guex, V Napolioni, F Tessadori, L Beekman, EA Nannenberg, L Boualla, NA Blom, W de Graaff, M Kamermans, D Cocciadiferro, N Malerba, B Mandriani, ZHC Akdemir, RJ Fish, MK Eldomery, I Ratbi, AAM Wilde, T de Boer, WF Simonds, M Neerman-Arbez, VR Sutton, F Kok, JR Lupski, A Reymond, CR Bezzina, J Bakkers, G Merla. GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.. Am J Hum Genet. 2016;99:704-10",
"JH Mai, ZH Ou, L Chen, J Duan, JX Liao, CX Han. Intellectual developmental disorder with cardiac arrhythmia syndrome in a family caused by GNB5 variation and literature review.. Zhonghua Er Ke Za Zhi. 2020;58:833-7",
"N Malerba, S Towner, K Keating, GM Squeo, W Wilson, G Merla. A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.. Front Genet. 2018;9:626",
"G Poke, C King, A Muir, G de Valles-Ibanez, M Germano, CF Moura de Souza, J Fung, B Chung, CW Fung, C Mignot, A Ilea, B Keren, AI Vermersch, S Davis, T Stanley, M Moharir, P Kannu, Z Shao, N Malerba, G Merla, HC Mefford, IE Scheffer, LG Sadleir. The epileptology of GNB5 encephalopathy.. Epilepsia. 2019;60:e121-e7",
"FL Sciacca, C Ciaccio, F Fontana, C Strano, F Gilardoni, C Pantaleoni, S D'Arrigo. Severe Phenotype in a patient with homozygous 15q21.2 microdeletion involving BCL2L10, GNB5, and MYO5C genes, resembling infantile developmental disorder with cardiac arrhythmias (IDDCA).. Front Genet. 2020;11:399",
"HE Shamseldin, I Masuho, A Alenizi, S Alyamani, DN Patil, N Ibrahim, KA Martemyanov, FS Alkuraya. GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.. Genome Biol. 2016;17:195",
"Z Shao, A Tumber, J Maynes, E Tavares, P Kannu, E Heon, A Vincent. Unique retinal signaling defect in GNB5-related disease.. Doc Ophthalmol. 2020;140:273-7",
"J Sondek, DP Siderovski. Gγ-like (GGL) domains: new frontiers in G-protein signaling and β-propeller scaffolding.. Biochem Pharmacol. 2001;61:1329-37",
"M Tang, Y Wang, Y Xu, W Tong, D Jin, XA Yang. IDDCA syndrome in a Chinese infant due to GNB5 biallelic mutations.. J Hum Genet. 2020;65:627-31",
"D Turkdogan, S Usluer, F Akalin, U Agyuz, ES Aslan. Familial early infantile epileptic encephalopathy and cardiac conduction disorder: a rare cause of SUDEP in infancy.. Seizure. 2017;50:171-2",
"H Vernon, J Cohen, P De Nittis, A Fatemi, R McClellan, A Goldstein, N Malerba, N Guex, A Reymond, G Merla. Intellectual developmental disorder with cardiac arrhythmia syndrome in a child with compound heterozygous GNB5 variants.. Clin Genet. 2018;93:1254-6",
"K Xie, S Ge, VE Collins, CL Haynes, KJ Renner, RL Meisel, R Lujan, KA Martemyanov. Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.. Psychopharmacology. 2012;219:823-34",
"S Yazdani, A Badjatiya, N Dorrani, H Lee, WW Grody, SF Nelson, KM Dipple. Genetic characterization and long-term management of severely affected siblings with intellectual developmental disorder with cardiac arrhythmia syndrome.. Mol Genet Metab Rep. 2020;23"
] |
26/8/2021
|
9/9/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
gonad-dys-46xy
|
gonad-dys-46xy
|
[
"46,XY Disorder of Sex Development (DSD)",
"46,XY Complete Gonadal Dysgenesis (CGD)",
"Desert hedgehog protein",
"Doublesex- and mab-3-related transcription factor 1",
"Mitogen-activated protein kinase kinase kinase 1",
"Probable ATP-dependent RNA helicase DHX37",
"Sex-determining region Y protein",
"Steroidogenic factor 1",
"Transcription factor SOX-8",
"Transcription factor SOX-9",
"DHH",
"DHX37",
"DMRT1",
"MAP3K1",
"NR5A1",
"SOX8",
"SOX9",
"SRY",
"Nonsyndromic Disorders of Testicular Development Overview",
"Overview"
] |
Nonsyndromic Disorders of Testicular Development Overview
|
Lauren Mohnach, Patricia Y Fechner, Catherine E Keegan
|
Summary The purpose of this overview is to: To describe the To review the To provide an To inform To inform
|
46,XY disorder of sex development (DSD)
46,XY complete gonadal dysgenesis (CGD)
For synonyms and outdated names see
• 46,XY disorder of sex development (DSD)
• 46,XY complete gonadal dysgenesis (CGD)
## Clinical Characteristics of Nonsyndromic Disorders of Testicular Development
Nonsyndromic disorders of testicular development are a group of disorders characterized by:
Normal general physical examination
Clinical and gonadal findings of a
A normal 46,XY karyotype by conventional staining (see
Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee
Microphallus
Abnormalities of scrotal formation
Normal-appearing female
Absent
Fully developed uterus and fallopian tubes
Normal testis
Ovotestis
Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells)
Streak gonad
Clinical manifestations of nonsynromic 46,XY CGD include:
The nomenclature for disorders of sex development (DSD) was revised in 2006 to reflect the genetic causes and pathogenesis of these conditions [
The term "differences of sex development" is often used to replace "disorders of sex development," although "disorders of sex development" is still appropriate to use among medical providers.
The term "disorders of sex development" has replaced the term "intersex."
The term "46,XY DSD" has replaced the following terms:
Male pseudohermaphrodite
Undervirilization of an XY male
Undermasculinization of an XY male
Mixed gonadal dysgenesis
Partial gonadal dysgenesis
The term "46,XY CGD" has replaced the terms "46,XY sex reversal" and "46,XY female."
The term "46,XY ovotesticular DSD" has replaced "46,XY true hermaphrodite."
• Normal general physical examination
• Clinical and gonadal findings of a
• A normal 46,XY karyotype by conventional staining (see
• Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee
• Microphallus
• Abnormalities of scrotal formation
• Normal-appearing female
• Absent
• Fully developed uterus and fallopian tubes
• Normal testis
• Ovotestis
• Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells)
• Streak gonad
• The term "differences of sex development" is often used to replace "disorders of sex development," although "disorders of sex development" is still appropriate to use among medical providers.
• The term "disorders of sex development" has replaced the term "intersex."
• The term "46,XY DSD" has replaced the following terms:
• Male pseudohermaphrodite
• Undervirilization of an XY male
• Undermasculinization of an XY male
• Mixed gonadal dysgenesis
• Partial gonadal dysgenesis
• Male pseudohermaphrodite
• Undervirilization of an XY male
• Undermasculinization of an XY male
• Mixed gonadal dysgenesis
• Partial gonadal dysgenesis
• The term "46,XY CGD" has replaced the terms "46,XY sex reversal" and "46,XY female."
• The term "46,XY ovotesticular DSD" has replaced "46,XY true hermaphrodite."
• Male pseudohermaphrodite
• Undervirilization of an XY male
• Undermasculinization of an XY male
• Mixed gonadal dysgenesis
• Partial gonadal dysgenesis
## Clinical Manifestations of Nonsyndromic 46,XY DSD
Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee
Microphallus
Abnormalities of scrotal formation
Normal-appearing female
Absent
Fully developed uterus and fallopian tubes
Normal testis
Ovotestis
Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells)
Streak gonad
• Ambiguous with mild-to-severe penoscrotal hypospadias with or without chordee
• Microphallus
• Abnormalities of scrotal formation
• Normal-appearing female
• Absent
• Fully developed uterus and fallopian tubes
• Normal testis
• Ovotestis
• Dysgenetic testis (decreased size and number of seminiferous tubules, reduced number or absence of germ cells, peritubular fibrosis, and hyperplasia of Leydig cells)
• Streak gonad
## Clinical Manifestations of Nonsyndromic 46,XY CGD
Clinical manifestations of nonsynromic 46,XY CGD include:
## Nomenclature
The nomenclature for disorders of sex development (DSD) was revised in 2006 to reflect the genetic causes and pathogenesis of these conditions [
The term "differences of sex development" is often used to replace "disorders of sex development," although "disorders of sex development" is still appropriate to use among medical providers.
The term "disorders of sex development" has replaced the term "intersex."
The term "46,XY DSD" has replaced the following terms:
Male pseudohermaphrodite
Undervirilization of an XY male
Undermasculinization of an XY male
Mixed gonadal dysgenesis
Partial gonadal dysgenesis
The term "46,XY CGD" has replaced the terms "46,XY sex reversal" and "46,XY female."
The term "46,XY ovotesticular DSD" has replaced "46,XY true hermaphrodite."
• The term "differences of sex development" is often used to replace "disorders of sex development," although "disorders of sex development" is still appropriate to use among medical providers.
• The term "disorders of sex development" has replaced the term "intersex."
• The term "46,XY DSD" has replaced the following terms:
• Male pseudohermaphrodite
• Undervirilization of an XY male
• Undermasculinization of an XY male
• Mixed gonadal dysgenesis
• Partial gonadal dysgenesis
• Male pseudohermaphrodite
• Undervirilization of an XY male
• Undermasculinization of an XY male
• Mixed gonadal dysgenesis
• Partial gonadal dysgenesis
• The term "46,XY CGD" has replaced the terms "46,XY sex reversal" and "46,XY female."
• The term "46,XY ovotesticular DSD" has replaced "46,XY true hermaphrodite."
• Male pseudohermaphrodite
• Undervirilization of an XY male
• Undermasculinization of an XY male
• Mixed gonadal dysgenesis
• Partial gonadal dysgenesis
## Causes of Nonsyndromic Disorders of Testicular Development
Many genetic causes of nonsyndromic disorders of testicular development are not known. Approximately 60% of affected individuals will have an underlying genetic etiology identified through molecular genetic testing (
Molecular Genetics of Nonsyndromic Disorders of Testicular Development
AD = autosomal dominant; AR = autosomal recessive; CGD = complete gonadal dysgenesis; DSD = differences/disorders of sex development; MOI = mode of inheritance; XL = X-linked; YL = Y-linked
Genes are listed in alphabetic order.
Biallelic pathogenic variants in
Pathogenic variants may include heterozygous complete or partial deletions of
Deletions of 9p24 are a recurrent cause of 46,XY DSD and 46,XY CGD. While most reports are of individuals who have larger deletions of this chromosome region leading to syndromic features (see
Disruption of the
Deletion of
Hemizygous pathogenic variants in
Genes involved in the duplications include
Hemizygous deletions and pathogenic variants in
Disorders to consider in the differential diagnosis for apparent nonsyndromic disorders of testicular development are listed in
Additional Nonsyndromic DSD Conditions to Consider in the Differential Diagnosis of Ambiguous Genitalia and/or Sex Chromosome-Phenotype Discordance
ACTH = adrenocorticotropic hormone; DHT = dihydrotestosterone; FSH = follicle stimulating hormone; GnRH = gonadotropin-releasing hormone; hCG = human chorionic gonadotropin; LH = luteinizing hormone; MOI = mode of inheritance; T = testosterone
Typical MOI; exceptions occur.
The majority of the conditions in
The phenotype was proposed to be caused by biallelic pathogenic variants in
Syndromic conditions to consider in the differential diagnosis of ambiguous genitalia and/or sex chromosome/phenotype discordance are listed in
Syndromic DSD Conditions to Consider in the Differential Diagnosis of Ambiguous Genitalia and/or Sex Chromosome-Phenotype Discordance
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
Typical MOI; exceptions occur
Deletions of 9p24 vary in size, including large, cytogenetically visible deletions or smaller deletions. None of these 9p24 deletions (including those that lead to apparently nonsyndromic 46,XY disorders of testicular development) is recurrent. See also
Eye anomalies, including high hyperopia and nanophthalmos, have also been described in individuals with pathogenic variants in
WAGR syndrome is associated with contiguous gene deletions including
## Evaluation Strategies to Identify the Genetic Cause of Nonsyndromic Disorders of Testicular Development
The initial evaluation of an individual suspected of having a nonsyndromic disorder of sex development is to determine the chromosome complement.
Note: (1) If the individual has a 46,XY chromosome complement but is
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which genes are likely involved, whereas genomic testing does not. Individuals with distinctive hormonal, gonadal, and/or imaging findings described in
When the phenotypic, laboratory, and imaging findings suggest the diagnosis of nonsyndromic disorders of testicular development, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by 46,XY DSD, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
## Chromosome Analysis
Note: (1) If the individual has a 46,XY chromosome complement but is
## Molecular Genetic Testing
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which genes are likely involved, whereas genomic testing does not. Individuals with distinctive hormonal, gonadal, and/or imaging findings described in
When the phenotypic, laboratory, and imaging findings suggest the diagnosis of nonsyndromic disorders of testicular development, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by 46,XY DSD, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
## Option 1
When the phenotypic, laboratory, and imaging findings suggest the diagnosis of nonsyndromic disorders of testicular development, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by 46,XY DSD, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
## Management
A consensus statement on the management of disorders of sex development (DSD) was developed under the sponsorship of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pædiatric Endocrinology [
Evaluation and long-term management should be provided at a center with an interdisciplinary care team (including clinical geneticists, endocrinologists, surgeons, and mental health professionals) experienced in the diagnosis and management of DSD conditions.
The general concepts of care include the following.
All individuals should receive a sex of rearing.
Sex assignment in newborns with ambiguous genitalia should not be decided prior to an evaluation by experts.
The choice of sex of rearing for individuals with 46,XY DSD is based on the underlying diagnosis, expert opinion, and parental beliefs [
Surgical intervention in minors with DSD is controversial, particularly in those being reared female. Surgical intervention should focus on functionality; whenever possible, removal of tissue and irreversible procedures should be avoided.
When
When
Note: (1) No controlled clinical trials of the efficacy of different surgical techniques have been conducted. The long-term data regarding the quality of life and sexual function among those assigned male and female sex vary. (2) There is no consensus on the appropriate timing of the surgical procedures listed.
Streak gonads and dysgenetic gonads are at increased risk for the development of gonadoblastoma and should be surgically removed if nonfunctional.
In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life.
Nonfunctional gonads typically do not make hormones that can be detected in infancy and childhood, such as anti-müllerian hormone and inhibin B.
A human chorionic gonadotropin stimulation test will not detect an increase in testosterone level; this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional.
A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads.
Note: Hormonal evaluation cannot distinguish between one versus two functioning gonads.
If a dysgenetic gonad is located in the inguinal canal, it may be placed into the scrotum if results indicate some testicular function. However, this gonad will need to undergo surveillance for gonadoblastoma. There are no current guidelines on surveillance; one option would be yearly ultrasound of the gonad.
Removal of gonads that are not consistent with the assigned sex of rearing is controversial.
Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development.
Routine surveillance for the development of contrasexual puberty is warranted in those whose sex of rearing is discordant with gonadal sex.
If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent.
In some states, removal of potentially functional gonads in a minor requires a court order.
If an individual is given a
A short course of testosterone therapy may be used in infancy for treatment of micropenis (stretched penile length that is 2.5 SD below the mean for age).
Testosterone therapy is typically required to initiate and sustain puberty.
If an individual is given a
Estrogen therapy is used to initiate breast development and puberty.
If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles.
46,XY individuals with a heterozygous pathogenic variant in
Open communication with affected individuals and families, including their active participation in the decision-making process, is critical.
Providers need to address the concerns of the affected individual and family respectfully and in strict confidence.
Assigned sex of rearing may not be congruent with gender identity, which is determined by the individual over time.
Most individuals with a nonsyndromic DSD are infertile due to dysgenetic or streak gonads. Some pathogenic variants in
Women with 46,XY DSD or 46,XY CGD with müllerian structures may become pregnant through oocyte donation.
Regular follow up with an interdisciplinary DSD team including endocrinology, medical genetics, obstetrics/gynecology, psychology, and urology is indicated.
See
Search
• All individuals should receive a sex of rearing.
• Sex assignment in newborns with ambiguous genitalia should not be decided prior to an evaluation by experts.
• The choice of sex of rearing for individuals with 46,XY DSD is based on the underlying diagnosis, expert opinion, and parental beliefs [
• Surgical intervention in minors with DSD is controversial, particularly in those being reared female. Surgical intervention should focus on functionality; whenever possible, removal of tissue and irreversible procedures should be avoided.
• When
• When
• Streak gonads and dysgenetic gonads are at increased risk for the development of gonadoblastoma and should be surgically removed if nonfunctional.
• In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life.
• Nonfunctional gonads typically do not make hormones that can be detected in infancy and childhood, such as anti-müllerian hormone and inhibin B.
• A human chorionic gonadotropin stimulation test will not detect an increase in testosterone level; this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional.
• A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads.
• Note: Hormonal evaluation cannot distinguish between one versus two functioning gonads.
• In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life.
• Nonfunctional gonads typically do not make hormones that can be detected in infancy and childhood, such as anti-müllerian hormone and inhibin B.
• A human chorionic gonadotropin stimulation test will not detect an increase in testosterone level; this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional.
• A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads.
• If a dysgenetic gonad is located in the inguinal canal, it may be placed into the scrotum if results indicate some testicular function. However, this gonad will need to undergo surveillance for gonadoblastoma. There are no current guidelines on surveillance; one option would be yearly ultrasound of the gonad.
• Removal of gonads that are not consistent with the assigned sex of rearing is controversial.
• Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development.
• Routine surveillance for the development of contrasexual puberty is warranted in those whose sex of rearing is discordant with gonadal sex.
• If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent.
• In some states, removal of potentially functional gonads in a minor requires a court order.
• Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development.
• Routine surveillance for the development of contrasexual puberty is warranted in those whose sex of rearing is discordant with gonadal sex.
• If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent.
• In some states, removal of potentially functional gonads in a minor requires a court order.
• In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life.
• Nonfunctional gonads typically do not make hormones that can be detected in infancy and childhood, such as anti-müllerian hormone and inhibin B.
• A human chorionic gonadotropin stimulation test will not detect an increase in testosterone level; this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional.
• A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads.
• Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development.
• Routine surveillance for the development of contrasexual puberty is warranted in those whose sex of rearing is discordant with gonadal sex.
• If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent.
• In some states, removal of potentially functional gonads in a minor requires a court order.
• If an individual is given a
• A short course of testosterone therapy may be used in infancy for treatment of micropenis (stretched penile length that is 2.5 SD below the mean for age).
• Testosterone therapy is typically required to initiate and sustain puberty.
• A short course of testosterone therapy may be used in infancy for treatment of micropenis (stretched penile length that is 2.5 SD below the mean for age).
• Testosterone therapy is typically required to initiate and sustain puberty.
• If an individual is given a
• Estrogen therapy is used to initiate breast development and puberty.
• If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles.
• Estrogen therapy is used to initiate breast development and puberty.
• If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles.
• 46,XY individuals with a heterozygous pathogenic variant in
• A short course of testosterone therapy may be used in infancy for treatment of micropenis (stretched penile length that is 2.5 SD below the mean for age).
• Testosterone therapy is typically required to initiate and sustain puberty.
• Estrogen therapy is used to initiate breast development and puberty.
• If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles.
• Open communication with affected individuals and families, including their active participation in the decision-making process, is critical.
• Providers need to address the concerns of the affected individual and family respectfully and in strict confidence.
• Assigned sex of rearing may not be congruent with gender identity, which is determined by the individual over time.
• Most individuals with a nonsyndromic DSD are infertile due to dysgenetic or streak gonads. Some pathogenic variants in
• Women with 46,XY DSD or 46,XY CGD with müllerian structures may become pregnant through oocyte donation.
## Treatment of Manifestations
A consensus statement on the management of disorders of sex development (DSD) was developed under the sponsorship of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pædiatric Endocrinology [
Evaluation and long-term management should be provided at a center with an interdisciplinary care team (including clinical geneticists, endocrinologists, surgeons, and mental health professionals) experienced in the diagnosis and management of DSD conditions.
The general concepts of care include the following.
All individuals should receive a sex of rearing.
Sex assignment in newborns with ambiguous genitalia should not be decided prior to an evaluation by experts.
The choice of sex of rearing for individuals with 46,XY DSD is based on the underlying diagnosis, expert opinion, and parental beliefs [
Surgical intervention in minors with DSD is controversial, particularly in those being reared female. Surgical intervention should focus on functionality; whenever possible, removal of tissue and irreversible procedures should be avoided.
When
When
Note: (1) No controlled clinical trials of the efficacy of different surgical techniques have been conducted. The long-term data regarding the quality of life and sexual function among those assigned male and female sex vary. (2) There is no consensus on the appropriate timing of the surgical procedures listed.
Streak gonads and dysgenetic gonads are at increased risk for the development of gonadoblastoma and should be surgically removed if nonfunctional.
In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life.
Nonfunctional gonads typically do not make hormones that can be detected in infancy and childhood, such as anti-müllerian hormone and inhibin B.
A human chorionic gonadotropin stimulation test will not detect an increase in testosterone level; this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional.
A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads.
Note: Hormonal evaluation cannot distinguish between one versus two functioning gonads.
If a dysgenetic gonad is located in the inguinal canal, it may be placed into the scrotum if results indicate some testicular function. However, this gonad will need to undergo surveillance for gonadoblastoma. There are no current guidelines on surveillance; one option would be yearly ultrasound of the gonad.
Removal of gonads that are not consistent with the assigned sex of rearing is controversial.
Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development.
Routine surveillance for the development of contrasexual puberty is warranted in those whose sex of rearing is discordant with gonadal sex.
If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent.
In some states, removal of potentially functional gonads in a minor requires a court order.
If an individual is given a
A short course of testosterone therapy may be used in infancy for treatment of micropenis (stretched penile length that is 2.5 SD below the mean for age).
Testosterone therapy is typically required to initiate and sustain puberty.
If an individual is given a
Estrogen therapy is used to initiate breast development and puberty.
If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles.
46,XY individuals with a heterozygous pathogenic variant in
Open communication with affected individuals and families, including their active participation in the decision-making process, is critical.
Providers need to address the concerns of the affected individual and family respectfully and in strict confidence.
Assigned sex of rearing may not be congruent with gender identity, which is determined by the individual over time.
Most individuals with a nonsyndromic DSD are infertile due to dysgenetic or streak gonads. Some pathogenic variants in
Women with 46,XY DSD or 46,XY CGD with müllerian structures may become pregnant through oocyte donation.
• All individuals should receive a sex of rearing.
• Sex assignment in newborns with ambiguous genitalia should not be decided prior to an evaluation by experts.
• The choice of sex of rearing for individuals with 46,XY DSD is based on the underlying diagnosis, expert opinion, and parental beliefs [
• Surgical intervention in minors with DSD is controversial, particularly in those being reared female. Surgical intervention should focus on functionality; whenever possible, removal of tissue and irreversible procedures should be avoided.
• When
• When
• Streak gonads and dysgenetic gonads are at increased risk for the development of gonadoblastoma and should be surgically removed if nonfunctional.
• In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life.
• Nonfunctional gonads typically do not make hormones that can be detected in infancy and childhood, such as anti-müllerian hormone and inhibin B.
• A human chorionic gonadotropin stimulation test will not detect an increase in testosterone level; this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional.
• A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads.
• Note: Hormonal evaluation cannot distinguish between one versus two functioning gonads.
• In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life.
• Nonfunctional gonads typically do not make hormones that can be detected in infancy and childhood, such as anti-müllerian hormone and inhibin B.
• A human chorionic gonadotropin stimulation test will not detect an increase in testosterone level; this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional.
• A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads.
• If a dysgenetic gonad is located in the inguinal canal, it may be placed into the scrotum if results indicate some testicular function. However, this gonad will need to undergo surveillance for gonadoblastoma. There are no current guidelines on surveillance; one option would be yearly ultrasound of the gonad.
• Removal of gonads that are not consistent with the assigned sex of rearing is controversial.
• Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development.
• Routine surveillance for the development of contrasexual puberty is warranted in those whose sex of rearing is discordant with gonadal sex.
• If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent.
• In some states, removal of potentially functional gonads in a minor requires a court order.
• Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development.
• Routine surveillance for the development of contrasexual puberty is warranted in those whose sex of rearing is discordant with gonadal sex.
• If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent.
• In some states, removal of potentially functional gonads in a minor requires a court order.
• In a 46,XY individual, absence of virilization and presence of müllerian structures implies that gonads are nonfunctional and were not making appropriate hormones, such as testosterone and anti-müllerian hormone, during fetal life and are unlikely to do so during postnatal life.
• Nonfunctional gonads typically do not make hormones that can be detected in infancy and childhood, such as anti-müllerian hormone and inhibin B.
• A human chorionic gonadotropin stimulation test will not detect an increase in testosterone level; this test is not always necessary, particularly if there is other evidence that a gonad is nonfunctional.
• A greatly elevated follicle-stimulating hormone and/or luteinizing hormone in infancy is usually associated with nonfunctional gonads.
• Depending on the specific diagnosis, potentially functional gonads may be retained with appropriate surveillance for tumor development.
• Routine surveillance for the development of contrasexual puberty is warranted in those whose sex of rearing is discordant with gonadal sex.
• If contrasexual puberty occurs, hormonal suppression with replacement of the desired sex hormone can be used to avoid gonadectomy until the individual is of age of consent.
• In some states, removal of potentially functional gonads in a minor requires a court order.
• If an individual is given a
• A short course of testosterone therapy may be used in infancy for treatment of micropenis (stretched penile length that is 2.5 SD below the mean for age).
• Testosterone therapy is typically required to initiate and sustain puberty.
• A short course of testosterone therapy may be used in infancy for treatment of micropenis (stretched penile length that is 2.5 SD below the mean for age).
• Testosterone therapy is typically required to initiate and sustain puberty.
• If an individual is given a
• Estrogen therapy is used to initiate breast development and puberty.
• If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles.
• Estrogen therapy is used to initiate breast development and puberty.
• If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles.
• 46,XY individuals with a heterozygous pathogenic variant in
• A short course of testosterone therapy may be used in infancy for treatment of micropenis (stretched penile length that is 2.5 SD below the mean for age).
• Testosterone therapy is typically required to initiate and sustain puberty.
• Estrogen therapy is used to initiate breast development and puberty.
• If the affected individual has a uterus, progesterone will be added once puberty has progressed in order to promote menstrual cycles.
• Open communication with affected individuals and families, including their active participation in the decision-making process, is critical.
• Providers need to address the concerns of the affected individual and family respectfully and in strict confidence.
• Assigned sex of rearing may not be congruent with gender identity, which is determined by the individual over time.
• Most individuals with a nonsyndromic DSD are infertile due to dysgenetic or streak gonads. Some pathogenic variants in
• Women with 46,XY DSD or 46,XY CGD with müllerian structures may become pregnant through oocyte donation.
## Surveillance
Regular follow up with an interdisciplinary DSD team including endocrinology, medical genetics, obstetrics/gynecology, psychology, and urology is indicated.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Risk Assessment
Nonsyndromic disorders of testicular development can be inherited in a sex-limited autosomal recessive, sex-limited autosomal dominant, Y-linked, or X-linked manner depending on the causative genetic alteration.
Sex-limited autosomal recessive inheritance: mutation of
Sex-limited autosomal dominant inheritance: intragenic mutation of
Y-linked inheritance: mutation of
X-linked inheritance: duplication at Xp21
The parents of an individual with a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are usually asymptomatic.
If both parents are known to be heterozygous for a
XY sibs who inherit biallelic pathogenic variants will have clinical features.
Heterozygotes (carriers) are usually asymptomatic.
Individuals with sex-limited autosomal recessive 46,XY nonsyndromic disorder of testicular development are frequently unable to reproduce.
If assisted reproductive technology enables an individual with a sex-limited autosomal recessive nonsyndromic disorder of testicular development to have children, all offspring will be heterozygous for a pathogenic variant in
An individual with a sex-limited autosomal dominant disorder of testicular development caused by a
Some individuals with a sex-limited autosomal dominant disorder of testicular development have a
Testing of the parents for the genetic alteration identified in the proband is recommended to allow reliable recurrence risk counseling.
If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological relatedness, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with a sex-limited autosomal dominant nonsyndromic disorder of testicular development may appear to be negative because of a milder phenotypic presentation in a parent or the appearance of reduced penetrance due to the sex-limited expression of the genetic variant. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
If a parent of the proband has the genetic alteration identified in the proband, the risk to sibs of inheriting the genetic alteration is 50%.
46,XY sibs who inherit the genetic alteration will have clinical features.
In general, individuals with a 46,XX chromosome complement and a heterozygous
If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism.
Individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development are frequently unable to reproduce. Some pathogenic variants in
If assisted reproductive technology enables individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development to have children, each child would have a 50% chance of inheriting the genetic alteration. 46,XY offspring would show clinical features. 46,XX offspring would generally be unaffected, although some 46,XX individuals with a heterozygous
Most individuals with an
Rarely, individuals with an
Somatic (and presumably germline) mosaicism for an
OR
Reduced penetrance of an
The frequency of paternal mosaicism and
The mother of an individual with an
Because probands with an
If the father of the proband has germline mosaicism or an
Individuals with an
If assisted reproductive technologies can enable individuals with an
In a family with more than one individual with an Xp21 duplication-related nonsyndromic disorder of testicular development, the mother of an affected individual is an obligate heterozygote (carrier) of the duplication. Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her DNA, she most likely has germline mosaicism.
If only one family member is affected (i.e., a simplex case), the mother may be a heterozygote (carrier), the proband may have a
Too few affected individuals have been reported to provide an accurate rate of
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
The father of an affected male will not have the disorder nor will he be hemizygous for the
If the mother of the proband has an Xp21 duplication, the chance of transmitting it in each pregnancy is 50%. 46,XY sibs who inherit the duplication will be affected; 46,XX sibs who inherit the duplication will be heterozygous and will usually not be affected.
If the proband represents a simplex case and if the Xp21 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
Individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development are unlikely to reproduce.
If assisted reproductive technology enables individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development to have children, such individuals will pass the duplication to all of their XX offspring and none of their XY offspring.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers), or who are at increased risk of being heterozygotes (carriers) or affected.
Once the genetic cause of a nonsyndromic disorder of testicular development has been identified in an affected family member, prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Sex-limited autosomal recessive inheritance: mutation of
• Sex-limited autosomal dominant inheritance: intragenic mutation of
• Y-linked inheritance: mutation of
• X-linked inheritance: duplication at Xp21
• The parents of an individual with a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are usually asymptomatic.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• XY sibs who inherit biallelic pathogenic variants will have clinical features.
• Heterozygotes (carriers) are usually asymptomatic.
• Individuals with sex-limited autosomal recessive 46,XY nonsyndromic disorder of testicular development are frequently unable to reproduce.
• If assisted reproductive technology enables an individual with a sex-limited autosomal recessive nonsyndromic disorder of testicular development to have children, all offspring will be heterozygous for a pathogenic variant in
• An individual with a sex-limited autosomal dominant disorder of testicular development caused by a
• Some individuals with a sex-limited autosomal dominant disorder of testicular development have a
• Testing of the parents for the genetic alteration identified in the proband is recommended to allow reliable recurrence risk counseling.
• If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological relatedness, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with a sex-limited autosomal dominant nonsyndromic disorder of testicular development may appear to be negative because of a milder phenotypic presentation in a parent or the appearance of reduced penetrance due to the sex-limited expression of the genetic variant. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• The proband has a
• The proband inherited a pathogenic variant from a parent with mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the genetic alteration identified in the proband, the risk to sibs of inheriting the genetic alteration is 50%.
• 46,XY sibs who inherit the genetic alteration will have clinical features.
• In general, individuals with a 46,XX chromosome complement and a heterozygous
• 46,XY sibs who inherit the genetic alteration will have clinical features.
• In general, individuals with a 46,XX chromosome complement and a heterozygous
• If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism.
• 46,XY sibs who inherit the genetic alteration will have clinical features.
• In general, individuals with a 46,XX chromosome complement and a heterozygous
• Individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development are frequently unable to reproduce. Some pathogenic variants in
• If assisted reproductive technology enables individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development to have children, each child would have a 50% chance of inheriting the genetic alteration. 46,XY offspring would show clinical features. 46,XX offspring would generally be unaffected, although some 46,XX individuals with a heterozygous
• Most individuals with an
• Rarely, individuals with an
• Somatic (and presumably germline) mosaicism for an
• OR
• Reduced penetrance of an
• Somatic (and presumably germline) mosaicism for an
• OR
• Reduced penetrance of an
• The frequency of paternal mosaicism and
• The mother of an individual with an
• Somatic (and presumably germline) mosaicism for an
• OR
• Reduced penetrance of an
• Because probands with an
• If the father of the proband has germline mosaicism or an
• Individuals with an
• If assisted reproductive technologies can enable individuals with an
• In a family with more than one individual with an Xp21 duplication-related nonsyndromic disorder of testicular development, the mother of an affected individual is an obligate heterozygote (carrier) of the duplication. Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her DNA, she most likely has germline mosaicism.
• If only one family member is affected (i.e., a simplex case), the mother may be a heterozygote (carrier), the proband may have a
• Too few affected individuals have been reported to provide an accurate rate of
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• If the mother of the proband has an Xp21 duplication, the chance of transmitting it in each pregnancy is 50%. 46,XY sibs who inherit the duplication will be affected; 46,XX sibs who inherit the duplication will be heterozygous and will usually not be affected.
• If the proband represents a simplex case and if the Xp21 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• Individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development are unlikely to reproduce.
• If assisted reproductive technology enables individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development to have children, such individuals will pass the duplication to all of their XX offspring and none of their XY offspring.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers), or who are at increased risk of being heterozygotes (carriers) or affected.
## Mode of Inheritance
Nonsyndromic disorders of testicular development can be inherited in a sex-limited autosomal recessive, sex-limited autosomal dominant, Y-linked, or X-linked manner depending on the causative genetic alteration.
Sex-limited autosomal recessive inheritance: mutation of
Sex-limited autosomal dominant inheritance: intragenic mutation of
Y-linked inheritance: mutation of
X-linked inheritance: duplication at Xp21
• Sex-limited autosomal recessive inheritance: mutation of
• Sex-limited autosomal dominant inheritance: intragenic mutation of
• Y-linked inheritance: mutation of
• X-linked inheritance: duplication at Xp21
## Sex-Limited Autosomal Recessive Inheritance – Risk to Family Members
The parents of an individual with a
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are usually asymptomatic.
If both parents are known to be heterozygous for a
XY sibs who inherit biallelic pathogenic variants will have clinical features.
Heterozygotes (carriers) are usually asymptomatic.
Individuals with sex-limited autosomal recessive 46,XY nonsyndromic disorder of testicular development are frequently unable to reproduce.
If assisted reproductive technology enables an individual with a sex-limited autosomal recessive nonsyndromic disorder of testicular development to have children, all offspring will be heterozygous for a pathogenic variant in
• The parents of an individual with a
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are usually asymptomatic.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• XY sibs who inherit biallelic pathogenic variants will have clinical features.
• Heterozygotes (carriers) are usually asymptomatic.
• Individuals with sex-limited autosomal recessive 46,XY nonsyndromic disorder of testicular development are frequently unable to reproduce.
• If assisted reproductive technology enables an individual with a sex-limited autosomal recessive nonsyndromic disorder of testicular development to have children, all offspring will be heterozygous for a pathogenic variant in
## Sex-Limited Autosomal Dominant Inheritance – Risk to Family Members
An individual with a sex-limited autosomal dominant disorder of testicular development caused by a
Some individuals with a sex-limited autosomal dominant disorder of testicular development have a
Testing of the parents for the genetic alteration identified in the proband is recommended to allow reliable recurrence risk counseling.
If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological relatedness, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with a sex-limited autosomal dominant nonsyndromic disorder of testicular development may appear to be negative because of a milder phenotypic presentation in a parent or the appearance of reduced penetrance due to the sex-limited expression of the genetic variant. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
If a parent of the proband has the genetic alteration identified in the proband, the risk to sibs of inheriting the genetic alteration is 50%.
46,XY sibs who inherit the genetic alteration will have clinical features.
In general, individuals with a 46,XX chromosome complement and a heterozygous
If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism.
Individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development are frequently unable to reproduce. Some pathogenic variants in
If assisted reproductive technology enables individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development to have children, each child would have a 50% chance of inheriting the genetic alteration. 46,XY offspring would show clinical features. 46,XX offspring would generally be unaffected, although some 46,XX individuals with a heterozygous
• An individual with a sex-limited autosomal dominant disorder of testicular development caused by a
• Some individuals with a sex-limited autosomal dominant disorder of testicular development have a
• Testing of the parents for the genetic alteration identified in the proband is recommended to allow reliable recurrence risk counseling.
• If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological relatedness, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with a sex-limited autosomal dominant nonsyndromic disorder of testicular development may appear to be negative because of a milder phenotypic presentation in a parent or the appearance of reduced penetrance due to the sex-limited expression of the genetic variant. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• The proband has a
• The proband inherited a pathogenic variant from a parent with mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband has the genetic alteration identified in the proband, the risk to sibs of inheriting the genetic alteration is 50%.
• 46,XY sibs who inherit the genetic alteration will have clinical features.
• In general, individuals with a 46,XX chromosome complement and a heterozygous
• 46,XY sibs who inherit the genetic alteration will have clinical features.
• In general, individuals with a 46,XX chromosome complement and a heterozygous
• If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the possibility of parental germline mosaicism.
• 46,XY sibs who inherit the genetic alteration will have clinical features.
• In general, individuals with a 46,XX chromosome complement and a heterozygous
• Individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development are frequently unable to reproduce. Some pathogenic variants in
• If assisted reproductive technology enables individuals with a sex-limited autosomal dominant nonsyndromic disorder of testicular development to have children, each child would have a 50% chance of inheriting the genetic alteration. 46,XY offspring would show clinical features. 46,XX offspring would generally be unaffected, although some 46,XX individuals with a heterozygous
## Y-Linked Inheritance – Risk to Family Members
Most individuals with an
Rarely, individuals with an
Somatic (and presumably germline) mosaicism for an
OR
Reduced penetrance of an
The frequency of paternal mosaicism and
The mother of an individual with an
Because probands with an
If the father of the proband has germline mosaicism or an
Individuals with an
If assisted reproductive technologies can enable individuals with an
• Most individuals with an
• Rarely, individuals with an
• Somatic (and presumably germline) mosaicism for an
• OR
• Reduced penetrance of an
• Somatic (and presumably germline) mosaicism for an
• OR
• Reduced penetrance of an
• The frequency of paternal mosaicism and
• The mother of an individual with an
• Somatic (and presumably germline) mosaicism for an
• OR
• Reduced penetrance of an
• Because probands with an
• If the father of the proband has germline mosaicism or an
• Individuals with an
• If assisted reproductive technologies can enable individuals with an
## X-Linked Inheritance – Risk to Family Members
In a family with more than one individual with an Xp21 duplication-related nonsyndromic disorder of testicular development, the mother of an affected individual is an obligate heterozygote (carrier) of the duplication. Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her DNA, she most likely has germline mosaicism.
If only one family member is affected (i.e., a simplex case), the mother may be a heterozygote (carrier), the proband may have a
Too few affected individuals have been reported to provide an accurate rate of
Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
The father of an affected male will not have the disorder nor will he be hemizygous for the
If the mother of the proband has an Xp21 duplication, the chance of transmitting it in each pregnancy is 50%. 46,XY sibs who inherit the duplication will be affected; 46,XX sibs who inherit the duplication will be heterozygous and will usually not be affected.
If the proband represents a simplex case and if the Xp21 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
Individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development are unlikely to reproduce.
If assisted reproductive technology enables individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development to have children, such individuals will pass the duplication to all of their XX offspring and none of their XY offspring.
• In a family with more than one individual with an Xp21 duplication-related nonsyndromic disorder of testicular development, the mother of an affected individual is an obligate heterozygote (carrier) of the duplication. Note: If a woman has more than one affected child and no other affected relatives and if the duplication cannot be detected in her DNA, she most likely has germline mosaicism.
• If only one family member is affected (i.e., a simplex case), the mother may be a heterozygote (carrier), the proband may have a
• Too few affected individuals have been reported to provide an accurate rate of
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.
• The father of an affected male will not have the disorder nor will he be hemizygous for the
• If the mother of the proband has an Xp21 duplication, the chance of transmitting it in each pregnancy is 50%. 46,XY sibs who inherit the duplication will be affected; 46,XX sibs who inherit the duplication will be heterozygous and will usually not be affected.
• If the proband represents a simplex case and if the Xp21 duplication cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• Individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development are unlikely to reproduce.
• If assisted reproductive technology enables individuals with an Xp21 duplication-related nonsyndromic disorder of testicular development to have children, such individuals will pass the duplication to all of their XX offspring and none of their XY offspring.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers), or who are at increased risk of being heterozygotes (carriers) or affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes (carriers), or who are at increased risk of being heterozygotes (carriers) or affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the genetic cause of a nonsyndromic disorder of testicular development has been identified in an affected family member, prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
InterNational Council on Infertility Information Dissemination
•
•
•
•
•
•
•
• United Kingdom
•
•
• InterNational Council on Infertility Information Dissemination
•
## Chapter Notes
Patricia Fechner, MD (2016-present)Catherine E Keegan, MD, PhD (2016-present)Lauren Mohnach, MS (2016-present)Harry Ostrer, MD; New York University School of Medicine (2008-2016)
Website:
18 August 2022 (ma) Comprehensive update posted live
2 June 2016 (ma) Comprehensive update posted live; reconfigured as an overview
21 May 2008 (me) Review posted live
19 December 2007 (ho) Original submission
• 18 August 2022 (ma) Comprehensive update posted live
• 2 June 2016 (ma) Comprehensive update posted live; reconfigured as an overview
• 21 May 2008 (me) Review posted live
• 19 December 2007 (ho) Original submission
## Author History
Patricia Fechner, MD (2016-present)Catherine E Keegan, MD, PhD (2016-present)Lauren Mohnach, MS (2016-present)Harry Ostrer, MD; New York University School of Medicine (2008-2016)
## Author Notes
Website:
## Revision History
18 August 2022 (ma) Comprehensive update posted live
2 June 2016 (ma) Comprehensive update posted live; reconfigured as an overview
21 May 2008 (me) Review posted live
19 December 2007 (ho) Original submission
• 18 August 2022 (ma) Comprehensive update posted live
• 2 June 2016 (ma) Comprehensive update posted live; reconfigured as an overview
• 21 May 2008 (me) Review posted live
• 19 December 2007 (ho) Original submission
## References
Accord Alliance. DSD Guidelines. Available
Houk CP, Hughes IA, Ahmed SF, Lee PA; Writing Committee for the International Intersex Consensus Conference Participants. Summary of consensus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics. 2006;118:753-7. [
Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus Statement on Management of Intersex Disorders. Pediatrics. 2006;118:e488-500. [
León NY, Reyes AP, Harley VR. A clinical algorithm to diagnose differences of sex development. Lancet Diabetes Endocrinol. 2019;7:560-74. [
Wisniewski AB, Batista RL, Costa EM, Finlayson C, Sircili MHP, Dénes FT, Domenice S, Mendonca BB. Management of 46,XY differences/disorders of sex development (DSD) throughout life. Endocr Rev. 2019;40:1547-72. [
• Accord Alliance. DSD Guidelines. Available
• Houk CP, Hughes IA, Ahmed SF, Lee PA; Writing Committee for the International Intersex Consensus Conference Participants. Summary of consensus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics. 2006;118:753-7. [
• Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus Statement on Management of Intersex Disorders. Pediatrics. 2006;118:e488-500. [
• León NY, Reyes AP, Harley VR. A clinical algorithm to diagnose differences of sex development. Lancet Diabetes Endocrinol. 2019;7:560-74. [
• Wisniewski AB, Batista RL, Costa EM, Finlayson C, Sircili MHP, Dénes FT, Domenice S, Mendonca BB. Management of 46,XY differences/disorders of sex development (DSD) throughout life. Endocr Rev. 2019;40:1547-72. [
## Published Guidelines / Consensus Statements
Accord Alliance. DSD Guidelines. Available
Houk CP, Hughes IA, Ahmed SF, Lee PA; Writing Committee for the International Intersex Consensus Conference Participants. Summary of consensus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics. 2006;118:753-7. [
Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus Statement on Management of Intersex Disorders. Pediatrics. 2006;118:e488-500. [
León NY, Reyes AP, Harley VR. A clinical algorithm to diagnose differences of sex development. Lancet Diabetes Endocrinol. 2019;7:560-74. [
Wisniewski AB, Batista RL, Costa EM, Finlayson C, Sircili MHP, Dénes FT, Domenice S, Mendonca BB. Management of 46,XY differences/disorders of sex development (DSD) throughout life. Endocr Rev. 2019;40:1547-72. [
• Accord Alliance. DSD Guidelines. Available
• Houk CP, Hughes IA, Ahmed SF, Lee PA; Writing Committee for the International Intersex Consensus Conference Participants. Summary of consensus statement on intersex disorders and their management. International Intersex Consensus Conference. Pediatrics. 2006;118:753-7. [
• Lee PA, Houk CP, Ahmed SF, Hughes IA; International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. Consensus Statement on Management of Intersex Disorders. Pediatrics. 2006;118:e488-500. [
• León NY, Reyes AP, Harley VR. A clinical algorithm to diagnose differences of sex development. Lancet Diabetes Endocrinol. 2019;7:560-74. [
• Wisniewski AB, Batista RL, Costa EM, Finlayson C, Sircili MHP, Dénes FT, Domenice S, Mendonca BB. Management of 46,XY differences/disorders of sex development (DSD) throughout life. Endocr Rev. 2019;40:1547-72. [
## Literature Cited
|
[] |
21/5/2008
|
18/8/2022
|
15/9/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
gria2-ndd
|
gria2-ndd
|
[
"Glutamate receptor 2",
"GRIA2",
"GRIA2-Related Neurodevelopmental Disorder"
] |
Stephanie Efthymiou, Elisa Rumbos Siurana, Vincenzo Salpietro, Allan Bayat, Henry Houlden
|
Summary The clinical phenotype of The diagnosis of
|
The scope table outlines the current understanding of the clustering of distinctive features in the four broad phenotypic spectra (abnormal body tone, epilepsy, movement disorder, and neurobehavioral and/or psychiatric disorders) of
ADHD = attention-deficit/hyperactivity disorder; ASD = autistic spectrum disorder
## Diagnosis
Formal diagnostic criteria for
AND any of the following features presenting in infancy or childhood:
Congenital-onset abnormal muscle tone (generalized hypotonia or hypertonia)
Feeding difficulties during infancy associated with abnormal muscle tone
Autism spectrum disorder, attention-deficit/hyperactivity disorder, repetitive behaviors, obsessive-compulsive findings, inappropriate laughing/screaming spells, aggressive or self-injurious behavior
Stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms)
Microcephaly (or deceleration of head growth)
Cerebral visual impairment, broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
Skeletal abnormalities (scoliosis, spinal fusion, femoral anteversion)
Hypothyroidism
Sleep apnea
Note: The constellation of findings may occasionally resemble
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Three individuals with contiguous gene deletions (not included in this table) have also been reported [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than that of gene-targeted deletion/duplication analysis.
•
• Congenital-onset abnormal muscle tone (generalized hypotonia or hypertonia)
• Feeding difficulties during infancy associated with abnormal muscle tone
• Congenital-onset abnormal muscle tone (generalized hypotonia or hypertonia)
• Feeding difficulties during infancy associated with abnormal muscle tone
•
• Autism spectrum disorder, attention-deficit/hyperactivity disorder, repetitive behaviors, obsessive-compulsive findings, inappropriate laughing/screaming spells, aggressive or self-injurious behavior
• Stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms)
• Autism spectrum disorder, attention-deficit/hyperactivity disorder, repetitive behaviors, obsessive-compulsive findings, inappropriate laughing/screaming spells, aggressive or self-injurious behavior
• Stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms)
•
• Microcephaly (or deceleration of head growth)
• Cerebral visual impairment, broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
• Skeletal abnormalities (scoliosis, spinal fusion, femoral anteversion)
• Hypothyroidism
• Sleep apnea
• Microcephaly (or deceleration of head growth)
• Cerebral visual impairment, broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
• Skeletal abnormalities (scoliosis, spinal fusion, femoral anteversion)
• Hypothyroidism
• Sleep apnea
• Congenital-onset abnormal muscle tone (generalized hypotonia or hypertonia)
• Feeding difficulties during infancy associated with abnormal muscle tone
• Autism spectrum disorder, attention-deficit/hyperactivity disorder, repetitive behaviors, obsessive-compulsive findings, inappropriate laughing/screaming spells, aggressive or self-injurious behavior
• Stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms)
• Microcephaly (or deceleration of head growth)
• Cerebral visual impairment, broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
• Skeletal abnormalities (scoliosis, spinal fusion, femoral anteversion)
• Hypothyroidism
• Sleep apnea
## Suggestive Findings
AND any of the following features presenting in infancy or childhood:
Congenital-onset abnormal muscle tone (generalized hypotonia or hypertonia)
Feeding difficulties during infancy associated with abnormal muscle tone
Autism spectrum disorder, attention-deficit/hyperactivity disorder, repetitive behaviors, obsessive-compulsive findings, inappropriate laughing/screaming spells, aggressive or self-injurious behavior
Stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms)
Microcephaly (or deceleration of head growth)
Cerebral visual impairment, broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
Skeletal abnormalities (scoliosis, spinal fusion, femoral anteversion)
Hypothyroidism
Sleep apnea
Note: The constellation of findings may occasionally resemble
•
• Congenital-onset abnormal muscle tone (generalized hypotonia or hypertonia)
• Feeding difficulties during infancy associated with abnormal muscle tone
• Congenital-onset abnormal muscle tone (generalized hypotonia or hypertonia)
• Feeding difficulties during infancy associated with abnormal muscle tone
•
• Autism spectrum disorder, attention-deficit/hyperactivity disorder, repetitive behaviors, obsessive-compulsive findings, inappropriate laughing/screaming spells, aggressive or self-injurious behavior
• Stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms)
• Autism spectrum disorder, attention-deficit/hyperactivity disorder, repetitive behaviors, obsessive-compulsive findings, inappropriate laughing/screaming spells, aggressive or self-injurious behavior
• Stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms)
•
• Microcephaly (or deceleration of head growth)
• Cerebral visual impairment, broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
• Skeletal abnormalities (scoliosis, spinal fusion, femoral anteversion)
• Hypothyroidism
• Sleep apnea
• Microcephaly (or deceleration of head growth)
• Cerebral visual impairment, broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
• Skeletal abnormalities (scoliosis, spinal fusion, femoral anteversion)
• Hypothyroidism
• Sleep apnea
• Congenital-onset abnormal muscle tone (generalized hypotonia or hypertonia)
• Feeding difficulties during infancy associated with abnormal muscle tone
• Autism spectrum disorder, attention-deficit/hyperactivity disorder, repetitive behaviors, obsessive-compulsive findings, inappropriate laughing/screaming spells, aggressive or self-injurious behavior
• Stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms)
• Microcephaly (or deceleration of head growth)
• Cerebral visual impairment, broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
• Skeletal abnormalities (scoliosis, spinal fusion, femoral anteversion)
• Hypothyroidism
• Sleep apnea
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Three individuals with contiguous gene deletions (not included in this table) have also been reported [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than that of gene-targeted deletion/duplication analysis.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Three individuals with contiguous gene deletions (not included in this table) have also been reported [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than that of gene-targeted deletion/duplication analysis.
## Clinical Characteristics
The clinical phenotype of
Some affected individuals have normal early development, followed by variable regression with impaired social and/or language skills. About half of individuals are nonverbal. Several individuals are unable to walk, and several have gait abnormalities, including gait dyspraxia and ataxia.
Nearly half of affected children develop seizures including early-onset tonic-clonic, focal, and focal to bilateral tonic-clonic seizures, most of which are refractory to treatment. Some children present with movement disorders, including chorea, dystonia, and dyskinesia.
Neurobehavioral and/or psychiatric disorders can include autism spectrum disorder, obsessive-compulsive findings, hyperactivity, inappropriate laughing/screaming spells, repetitive behaviors, and stereotypic movements.
Several individuals have either microcephaly or head growth deceleration during infancy.
To date, 33 individuals, ranging in age from three months to 31 years, have been reported with a pathogenic variant in
All affected individuals had delays (or regression) of speech and language development, and in most cases they could only speak a few intelligible words.
Among the 15 individuals with seizures, epilepsy could be classified as generalized onset in three, focal onset in five, and of unknown onset in seven. Known electroclinical epilepsy syndromes included epileptic spasms syndrome and developmental and epileptic encephalopathy.
Seizures were controlled with standard anti-seizure medications in only two of 12 individuals.
EEG features included polyspikes, slow spike-and-wave, and bilateral temporal non-synchronized epileptic activity.
Two infants died before age six months with sudden unexplained death in epilepsy (patients 17 and 20 in
One reported female with tonic seizures beginning at age eight years, moderate ID/DD, no Rett-like features, and normal brain imaging is alive at age 31 years (patient 23 in
No clear genotype-phenotype correlations have been identified to date in
The pathogenic variant
The pathogenic variant
Of note, the pathogenic variant
The prevalence of
To date, 33 individuals with
• Two infants died before age six months with sudden unexplained death in epilepsy (patients 17 and 20 in
• One reported female with tonic seizures beginning at age eight years, moderate ID/DD, no Rett-like features, and normal brain imaging is alive at age 31 years (patient 23 in
• The pathogenic variant
• The pathogenic variant
## Clinical Description
The clinical phenotype of
Some affected individuals have normal early development, followed by variable regression with impaired social and/or language skills. About half of individuals are nonverbal. Several individuals are unable to walk, and several have gait abnormalities, including gait dyspraxia and ataxia.
Nearly half of affected children develop seizures including early-onset tonic-clonic, focal, and focal to bilateral tonic-clonic seizures, most of which are refractory to treatment. Some children present with movement disorders, including chorea, dystonia, and dyskinesia.
Neurobehavioral and/or psychiatric disorders can include autism spectrum disorder, obsessive-compulsive findings, hyperactivity, inappropriate laughing/screaming spells, repetitive behaviors, and stereotypic movements.
Several individuals have either microcephaly or head growth deceleration during infancy.
To date, 33 individuals, ranging in age from three months to 31 years, have been reported with a pathogenic variant in
All affected individuals had delays (or regression) of speech and language development, and in most cases they could only speak a few intelligible words.
Among the 15 individuals with seizures, epilepsy could be classified as generalized onset in three, focal onset in five, and of unknown onset in seven. Known electroclinical epilepsy syndromes included epileptic spasms syndrome and developmental and epileptic encephalopathy.
Seizures were controlled with standard anti-seizure medications in only two of 12 individuals.
EEG features included polyspikes, slow spike-and-wave, and bilateral temporal non-synchronized epileptic activity.
Two infants died before age six months with sudden unexplained death in epilepsy (patients 17 and 20 in
One reported female with tonic seizures beginning at age eight years, moderate ID/DD, no Rett-like features, and normal brain imaging is alive at age 31 years (patient 23 in
• Two infants died before age six months with sudden unexplained death in epilepsy (patients 17 and 20 in
• One reported female with tonic seizures beginning at age eight years, moderate ID/DD, no Rett-like features, and normal brain imaging is alive at age 31 years (patient 23 in
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlations have been identified to date in
The pathogenic variant
The pathogenic variant
Of note, the pathogenic variant
• The pathogenic variant
• The pathogenic variant
## Prevalence
The prevalence of
To date, 33 individuals with
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because
In persons with abnormal developmental milestones, epilepsy, and features resembling
Selected Genes of Interest in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NDD = neurodevelopmental disorder; XL = X-linked
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Brain MRI
EEG if history of seizures
Eval for movement disorders
Eval for sleep apnea
Motor, adaptive, cognitive, & speech-language ability
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills
Early intervention / special education
Speech therapy
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
To incl eval of aspiration risk, nutritional status, & growth
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Eval for gastroesophageal reflux disease & constipation.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Consider perampanel for treatment of seizures, behavior, alertness, mood, & fine motor control affected by gain-of-function variants.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision service / OT / mobility services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
A published case study details success in perampanel treatment an individual with a
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Measurement of growth parameters (incl OFC)
Eval of nutritional status & safety of oral intake
Monitor for constipation & gastroesophageal reflux disease.
Monitor feeding needs, esp in early infancy.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, or movement disorders.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy
See
Search
• Brain MRI
• EEG if history of seizures
• Eval for movement disorders
• Eval for sleep apnea
• Motor, adaptive, cognitive, & speech-language ability
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills
• Early intervention / special education
• Speech therapy
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• To incl eval of aspiration risk, nutritional status, & growth
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Eval for gastroesophageal reflux disease & constipation.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Consider perampanel for treatment of seizures, behavior, alertness, mood, & fine motor control affected by gain-of-function variants.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision service / OT / mobility services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Measurement of growth parameters (incl OFC)
• Eval of nutritional status & safety of oral intake
• Monitor for constipation & gastroesophageal reflux disease.
• Monitor feeding needs, esp in early infancy.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, or movement disorders.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Brain MRI
EEG if history of seizures
Eval for movement disorders
Eval for sleep apnea
Motor, adaptive, cognitive, & speech-language ability
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills
Early intervention / special education
Speech therapy
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
To incl eval of aspiration risk, nutritional status, & growth
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Eval for gastroesophageal reflux disease & constipation.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Brain MRI
• EEG if history of seizures
• Eval for movement disorders
• Eval for sleep apnea
• Motor, adaptive, cognitive, & speech-language ability
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills
• Early intervention / special education
• Speech therapy
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• To incl eval of aspiration risk, nutritional status, & growth
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Eval for gastroesophageal reflux disease & constipation.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Consider perampanel for treatment of seizures, behavior, alertness, mood, & fine motor control affected by gain-of-function variants.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision service / OT / mobility services
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
A published case study details success in perampanel treatment an individual with a
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Consider perampanel for treatment of seizures, behavior, alertness, mood, & fine motor control affected by gain-of-function variants.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision service / OT / mobility services
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Measurement of growth parameters (incl OFC)
Eval of nutritional status & safety of oral intake
Monitor for constipation & gastroesophageal reflux disease.
Monitor feeding needs, esp in early infancy.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, or movement disorders.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters (incl OFC)
• Eval of nutritional status & safety of oral intake
• Monitor for constipation & gastroesophageal reflux disease.
• Monitor feeding needs, esp in early infancy.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, or movement disorders.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
All probands reported to date with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and germline mosaicism for a
If a parent of the proband is known to have the
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• All probands reported to date with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is known to have the
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
All probands reported to date with
Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and germline mosaicism for a
If a parent of the proband is known to have the
If the
• All probands reported to date with
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is known to have the
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Risk to future pregnancies is presumed to be low as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
•
•
•
•
• Canada
•
•
•
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
## Molecular Genetics
GRIA2-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GRIA2-Related Neurodevelopmental Disorder (
The AMPA-type glutamate receptors (AMPARs) are ligand-gated cation channels, expressed in both neurons and glia, that mediate most of the fast excitatory transmission in the central nervous system [
Missense
The specific
DEE = developmental and epileptic encephalopathy; SUDEP = sudden unexplained death in epilepsy
Variants listed in the table have been provided by the authors.
• Missense
• The specific
## Molecular Pathogenesis
The AMPA-type glutamate receptors (AMPARs) are ligand-gated cation channels, expressed in both neurons and glia, that mediate most of the fast excitatory transmission in the central nervous system [
Missense
The specific
DEE = developmental and epileptic encephalopathy; SUDEP = sudden unexplained death in epilepsy
Variants listed in the table have been provided by the authors.
• Missense
• The specific
## Chapter Notes
Contact information:
Web page:
The team led by
Their aims are to deep-phenotype
Dr Bayat would be happy to communicate with persons who have any questions regarding diagnosis of
Contact information: [email protected] or [email protected]
Web page:
Contact
This work was supported by the SYNAPS Study group funded by the Wellcome trust. Ms Elisa Rumbos Siurana's current functional investigations are funded by a Joint Sparks-Great Ormond Street Hospital for Children research program. Dr Allan Bayat is funded by a BRIDGE – Translational Excellence Programme grant funded by the Novo Nordisk Foundation, grant agreement number: NNF20SA0064340.
11 January 2024 (bp) Review posted live
5 July 2023 (ab) Original submission
• 11 January 2024 (bp) Review posted live
• 5 July 2023 (ab) Original submission
## Author Notes
Contact information:
Web page:
The team led by
Their aims are to deep-phenotype
Dr Bayat would be happy to communicate with persons who have any questions regarding diagnosis of
Contact information: [email protected] or [email protected]
Web page:
Contact
## Acknowledgments
This work was supported by the SYNAPS Study group funded by the Wellcome trust. Ms Elisa Rumbos Siurana's current functional investigations are funded by a Joint Sparks-Great Ormond Street Hospital for Children research program. Dr Allan Bayat is funded by a BRIDGE – Translational Excellence Programme grant funded by the Novo Nordisk Foundation, grant agreement number: NNF20SA0064340.
## Revision History
11 January 2024 (bp) Review posted live
5 July 2023 (ab) Original submission
• 11 January 2024 (bp) Review posted live
• 5 July 2023 (ab) Original submission
## References
## Literature Cited
|
[] |
11/1/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
grin1-ndd
|
grin1-ndd
|
[
"GRIN1-Related Developmental and Epileptic Encephalopathy",
"GRIN1-Related Developmental and Epileptic Encephalopathy",
"Glutamate receptor ionotropic, NMDA 1",
"GRIN1",
"GRIN1-Related Neurodevelopmental Disorder"
] |
Konrad Platzer, Johannes R Lemke
|
Summary The diagnosis of Once the
|
## Diagnosis
Formal diagnostic criteria for
Mild-to-profound developmental delay or intellectual disability
AND
Any of the following presenting in infancy or childhood:
Epilepsy
Muscular tone abnormalities such as hypotonia and spasticity
Dystonic, dyskinetic, or choreiform movement disorder
Autism spectrum disorder
Microcephaly
Cortical visual impairment
The diagnosis of
A heterozygous
Biallelic pathogenic (or likely pathogenic) missense or truncating variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the phenotype of
For an introduction to multigene panels click
A multigene panel may not include all rare genes recently identified as causing intellectual disability; and
Comprehensive genomic testing may be able to detect pathogenic variants in genes that – for technical reasons – do not sequence well.
Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Mild-to-profound developmental delay or intellectual disability
• AND
• Any of the following presenting in infancy or childhood:
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Microcephaly
• Cortical visual impairment
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Microcephaly
• Cortical visual impairment
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Microcephaly
• Cortical visual impairment
• A heterozygous
• Biallelic pathogenic (or likely pathogenic) missense or truncating variants in
• A multigene panel may not include all rare genes recently identified as causing intellectual disability; and
• Comprehensive genomic testing may be able to detect pathogenic variants in genes that – for technical reasons – do not sequence well.
## Suggestive Findings
Mild-to-profound developmental delay or intellectual disability
AND
Any of the following presenting in infancy or childhood:
Epilepsy
Muscular tone abnormalities such as hypotonia and spasticity
Dystonic, dyskinetic, or choreiform movement disorder
Autism spectrum disorder
Microcephaly
Cortical visual impairment
• Mild-to-profound developmental delay or intellectual disability
• AND
• Any of the following presenting in infancy or childhood:
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Microcephaly
• Cortical visual impairment
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Microcephaly
• Cortical visual impairment
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Microcephaly
• Cortical visual impairment
## Establishing the Diagnosis
The diagnosis of
A heterozygous
Biallelic pathogenic (or likely pathogenic) missense or truncating variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Because the phenotype of
For an introduction to multigene panels click
A multigene panel may not include all rare genes recently identified as causing intellectual disability; and
Comprehensive genomic testing may be able to detect pathogenic variants in genes that – for technical reasons – do not sequence well.
Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• A heterozygous
• Biallelic pathogenic (or likely pathogenic) missense or truncating variants in
• A multigene panel may not include all rare genes recently identified as causing intellectual disability; and
• Comprehensive genomic testing may be able to detect pathogenic variants in genes that – for technical reasons – do not sequence well.
## Option 1
For an introduction to multigene panels click
## Option 2
A multigene panel may not include all rare genes recently identified as causing intellectual disability; and
Comprehensive genomic testing may be able to detect pathogenic variants in genes that – for technical reasons – do not sequence well.
Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• A multigene panel may not include all rare genes recently identified as causing intellectual disability; and
• Comprehensive genomic testing may be able to detect pathogenic variants in genes that – for technical reasons – do not sequence well.
## Clinical Characteristics
To date, 72 individuals with
Onset of seizures ranged from birth to 11 years with a median onset of 22.5 months. In 27 individuals on whom follow up or outcome on treatment with anti-seizure medication was available, 17 had refractory seizures and ten were well controlled with standard anti-seizure medication.
Muscular hypotonia (in 66%)
Spasticity (40%)
Movement disorders (48%); where specified, affected individuals showed signs of dystonic (13%), dyskinetic (11%), and/or choreiform movements (15%).
Cortical visual impairment (34%)
Oculogyric crisis (11%)
Other signs repeatedly noted in individuals without an MCD were generalized volume loss or cerebral atrophy (23%).
Signs of a leukoencephalopathy have been noted in two individuals with nonspecific hyperintensities of the white matter [
Scoliosis has been seen in 11% of affected individuals.
No specific dysmorphic facial features have been observed. If present, dysmorphic features are nonspecific.
It is unknown if life span in
All three children from a family with a homozygous nonsense
Penetrance of
The prevalence of
• Muscular hypotonia (in 66%)
• Spasticity (40%)
• Movement disorders (48%); where specified, affected individuals showed signs of dystonic (13%), dyskinetic (11%), and/or choreiform movements (15%).
• Cortical visual impairment (34%)
• Oculogyric crisis (11%)
• Scoliosis has been seen in 11% of affected individuals.
• No specific dysmorphic facial features have been observed. If present, dysmorphic features are nonspecific.
## Clinical Description
To date, 72 individuals with
Onset of seizures ranged from birth to 11 years with a median onset of 22.5 months. In 27 individuals on whom follow up or outcome on treatment with anti-seizure medication was available, 17 had refractory seizures and ten were well controlled with standard anti-seizure medication.
Muscular hypotonia (in 66%)
Spasticity (40%)
Movement disorders (48%); where specified, affected individuals showed signs of dystonic (13%), dyskinetic (11%), and/or choreiform movements (15%).
Cortical visual impairment (34%)
Oculogyric crisis (11%)
Other signs repeatedly noted in individuals without an MCD were generalized volume loss or cerebral atrophy (23%).
Signs of a leukoencephalopathy have been noted in two individuals with nonspecific hyperintensities of the white matter [
Scoliosis has been seen in 11% of affected individuals.
No specific dysmorphic facial features have been observed. If present, dysmorphic features are nonspecific.
It is unknown if life span in
• Muscular hypotonia (in 66%)
• Spasticity (40%)
• Movement disorders (48%); where specified, affected individuals showed signs of dystonic (13%), dyskinetic (11%), and/or choreiform movements (15%).
• Cortical visual impairment (34%)
• Oculogyric crisis (11%)
• Scoliosis has been seen in 11% of affected individuals.
• No specific dysmorphic facial features have been observed. If present, dysmorphic features are nonspecific.
## Genotype-Phenotype Correlations
All three children from a family with a homozygous nonsense
## Penetrance
Penetrance of
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because the phenotypic features associated with
Intellectual disability without other distinctive findings (See
Early-onset epileptic encephalopathy (See
Polymicrogyria [
• Intellectual disability without other distinctive findings (See
• Early-onset epileptic encephalopathy (See
• Polymicrogyria [
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility & ADL & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Eval of motor, speech & language, general cognitive, & vocational skills
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
See
Search
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility & ADL & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Eval of motor, speech & language, general cognitive, & vocational skills
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility & ADL & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Eval of motor, speech & language, general cognitive, & vocational skills
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility & ADL & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Eval of motor, speech & language, general cognitive, & vocational skills
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
In an autosomal dominant manner, typically caused by a
In an autosomal recessive manner
All probands reported to date with autosomal dominant
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Theoretically, if the parent is the individual in whom the
The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the
In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was 10% [
Each child of an individual with a
Individuals with
The parents of a child with autosomal recessive
To date, heterozygous (carrier) parents have been asymptomatic and, thus, are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygous (carrier) sibs are asymptomatic and are not at risk of developing the disorder.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• In an autosomal dominant manner, typically caused by a
• In an autosomal recessive manner
• All probands reported to date with autosomal dominant
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Theoretically, if the parent is the individual in whom the
• The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the
• In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was 10% [
• Each child of an individual with a
• Individuals with
• The parents of a child with autosomal recessive
• To date, heterozygous (carrier) parents have been asymptomatic and, thus, are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygous (carrier) sibs are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
In an autosomal dominant manner, typically caused by a
In an autosomal recessive manner
• In an autosomal dominant manner, typically caused by a
• In an autosomal recessive manner
## Autosomal Dominant Inheritance – Risk to Family Members
All probands reported to date with autosomal dominant
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Theoretically, if the parent is the individual in whom the
The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the
In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was 10% [
Each child of an individual with a
Individuals with
• All probands reported to date with autosomal dominant
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Theoretically, if the parent is the individual in whom the
• The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the
• In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was 10% [
• Each child of an individual with a
• Individuals with
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with autosomal recessive
To date, heterozygous (carrier) parents have been asymptomatic and, thus, are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygous (carrier) sibs are asymptomatic and are not at risk of developing the disorder.
• The parents of a child with autosomal recessive
• To date, heterozygous (carrier) parents have been asymptomatic and, thus, are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygous (carrier) sibs are asymptomatic and are not at risk of developing the disorder.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
## Resources
Canada
•
•
•
•
•
• Canada
•
•
•
•
•
•
•
## Molecular Genetics
GRIN1-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GRIN1-Related Neurodevelopmental Disorder (
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels expressed throughout the brain mediating excitatory neurotransmission. Signaling via NMDAR plays an important role in brain development, learning, memory, and other higher cognitive functions. NMDARs are diheterotetramers or triheterotetramers composed of two glycine-binding GluN1subunits (encoded by
In autosomal recessive
## Molecular Pathogenesis
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels expressed throughout the brain mediating excitatory neurotransmission. Signaling via NMDAR plays an important role in brain development, learning, memory, and other higher cognitive functions. NMDARs are diheterotetramers or triheterotetramers composed of two glycine-binding GluN1subunits (encoded by
In autosomal recessive
## Chapter Notes
Konrad Platzer, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
Johannes R Lemke, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from
1 April 2021 (aa) Revision: incorporated parental mosaicism data from
20 June 2019 (bp) Review posted live
28 February 2019 (kp) Original submission
• 1 April 2021 (aa) Revision: incorporated parental mosaicism data from
• 20 June 2019 (bp) Review posted live
• 28 February 2019 (kp) Original submission
## Author Notes
Konrad Platzer, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
Johannes R Lemke, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
## Acknowledgments
This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from
## Revision History
1 April 2021 (aa) Revision: incorporated parental mosaicism data from
20 June 2019 (bp) Review posted live
28 February 2019 (kp) Original submission
• 1 April 2021 (aa) Revision: incorporated parental mosaicism data from
• 20 June 2019 (bp) Review posted live
• 28 February 2019 (kp) Original submission
## References
## Literature Cited
Brain MRI findings of polymicrogyria in children with
Note in most images (except I): Increased extra-axial spaces and enlarged lateral ventricles suggesting cerebral volume loss. Images B, C, and K are T
Reproduced from
|
[] |
20/6/2019
|
1/4/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
grin2a-dis
|
grin2a-dis
|
[
"Glutamate receptor ionotropic, NMDA 2A",
"GRIN2A",
"GRIN2A-Related Disorders"
] |
Vincent Strehlow, Kenneth A Myers, Angela T Morgan, Ingrid E Scheffer, Johannes R. Lemke
|
Summary The diagnosis of a
|
## Diagnosis
A
Mild-to-profound developmental delay / intellectual disability; some affected individuals may be of normal intellect.
Focal epilepsy
Self-limited epilepsy with centrotemporal spikes
Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)
Infantile-onset DEE, sometimes with epileptic spasms
Speech and language disorders including dysarthria, speech dyspraxia, aphasia, and nonverbal phenotypes
Movement disorders including ataxia, dystonia, or choreiform movements
Hypotonia
Neuropsychiatric features including behavioral issues, attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, anxiety disorders, and mood disorders
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches should include
Note: Single-gene testing (sequence analysis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. These methods will detect from single-exon to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
• Mild-to-profound developmental delay / intellectual disability; some affected individuals may be of normal intellect.
• Focal epilepsy
• Self-limited epilepsy with centrotemporal spikes
• Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)
• Infantile-onset DEE, sometimes with epileptic spasms
• Self-limited epilepsy with centrotemporal spikes
• Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)
• Infantile-onset DEE, sometimes with epileptic spasms
• Speech and language disorders including dysarthria, speech dyspraxia, aphasia, and nonverbal phenotypes
• Movement disorders including ataxia, dystonia, or choreiform movements
• Hypotonia
• Neuropsychiatric features including behavioral issues, attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, anxiety disorders, and mood disorders
• Self-limited epilepsy with centrotemporal spikes
• Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)
• Infantile-onset DEE, sometimes with epileptic spasms
## Suggestive Findings
A
Mild-to-profound developmental delay / intellectual disability; some affected individuals may be of normal intellect.
Focal epilepsy
Self-limited epilepsy with centrotemporal spikes
Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)
Infantile-onset DEE, sometimes with epileptic spasms
Speech and language disorders including dysarthria, speech dyspraxia, aphasia, and nonverbal phenotypes
Movement disorders including ataxia, dystonia, or choreiform movements
Hypotonia
Neuropsychiatric features including behavioral issues, attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, anxiety disorders, and mood disorders
• Mild-to-profound developmental delay / intellectual disability; some affected individuals may be of normal intellect.
• Focal epilepsy
• Self-limited epilepsy with centrotemporal spikes
• Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)
• Infantile-onset DEE, sometimes with epileptic spasms
• Self-limited epilepsy with centrotemporal spikes
• Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)
• Infantile-onset DEE, sometimes with epileptic spasms
• Speech and language disorders including dysarthria, speech dyspraxia, aphasia, and nonverbal phenotypes
• Movement disorders including ataxia, dystonia, or choreiform movements
• Hypotonia
• Neuropsychiatric features including behavioral issues, attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, anxiety disorders, and mood disorders
• Self-limited epilepsy with centrotemporal spikes
• Developmental and/or epileptic encephalopathy (DEE/EE) with spike-wave activation in sleep (DEE/EE-SWAS)
• Infantile-onset DEE, sometimes with epileptic spasms
## Establishing the Diagnosis
The diagnosis of a
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches should include
Note: Single-gene testing (sequence analysis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. These methods will detect from single-exon to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
## Clinical Characteristics
The clinical spectrum of
To date, about 400 individuals have been identified with a pathogenic variant in
Select Features of
Moderate speech and language impairment includes dysarthria, speech dyspraxia, dysphasia, speech regression with residual impairments, sometimes with additional impairments such as impaired pitch, hypernasality, or imprecise articulation [
Movement disorders include ataxia, dystonia, chorea, and complex movement disorders.
Several brain abnormalities have been reported including focal cortical dysplasia, dysplastic corpus callosum, hypoplasia of corpus callosum with midline lipoma, hippocampal hyperintensity, hippocampal sclerosis, heterotopia, subcortical lesion, hypoplastic olfactory bulb, cerebellar glioma, enlarged Virchow-Robin spaces, and delayed myelination; 11% of individuals (9/85) also had generalized cortical atrophy.
Seizure onset depends on the type of underlying
The predominant seizure type(s) in a given individual depends on the epilepsy syndrome. Broadly,
Specific epilepsy syndromes associated with
DEE/EE-SWAS with focal seizures, which may be drug-resistant. The electroencephalogram (EEG) shows marked activation in non-REM sleep of bilateral slow spike-and-wave discharges [
In LKS, a subtype of DEE/EE-SWAS, 30% of individuals do not have seizures.
Self-limited epilepsy with centrotemporal spikes (SeLECTS) with onset in childhood (usually age 3-6 years) with EEG showing centrotemporal discharges [
Infantile-onset DEE, with severe-to-profound impairment and sometimes epileptic spasms
Mildly affected individuals may display subtly impaired intelligibility of conversational speech, most characterized by dysarthric and dyspraxic features of hypernasality, imprecise consonant production, and impaired pitch and prosody [
Hypotonia (40/139; 29%)
Movement disorders, including dystonia, chorea, and ataxia (19/72; 26%)
Mental health disorders are relatively frequent in individuals with pathogenic null variants in
Several genotype-phenotype correlations have been observed.
Pathogenic
Individuals with pathogenic null variants have later mean seizure onset (age 4.5 ± 0.2 years) compared to those with pathogenic missense variants (age 3.1 ± 0.4 years), and individuals with pathogenic missense variants usually have drug-resistant seizures persisting throughout childhood and adolescence [
Mental health disorders are relatively frequent in individuals with pathogenic null variants in
In families of mildly affected individuals, carriers of the familial pathogenic
Epilepsy Syndrome Terminology Used in
Epileptic acquired aphasia
Continuous spike-wave during slow-wave sleep (CSWS)
Electrical status epilepticus in sleep (ESES)
Epilepsy aphasia spectrum disorders
Atypical childhood epilepsy with centrotemporal spikes (ACECTS)
Childhood epilepsy with centrotemporal spikes (CECTS)
Benign epilepsy with centrotemporal spikes (BECTS)
Benign rolandic epilepsy of childhood (BREC)
Benign focal epilepsy of childhood (BFEC)
ILAE = International League Against Epilepsy
See
The prevalence of
• DEE/EE-SWAS with focal seizures, which may be drug-resistant. The electroencephalogram (EEG) shows marked activation in non-REM sleep of bilateral slow spike-and-wave discharges [
• In LKS, a subtype of DEE/EE-SWAS, 30% of individuals do not have seizures.
• Self-limited epilepsy with centrotemporal spikes (SeLECTS) with onset in childhood (usually age 3-6 years) with EEG showing centrotemporal discharges [
• Infantile-onset DEE, with severe-to-profound impairment and sometimes epileptic spasms
• Hypotonia (40/139; 29%)
• Movement disorders, including dystonia, chorea, and ataxia (19/72; 26%)
• Epileptic acquired aphasia
• Continuous spike-wave during slow-wave sleep (CSWS)
• Electrical status epilepticus in sleep (ESES)
• Epilepsy aphasia spectrum disorders
• Atypical childhood epilepsy with centrotemporal spikes (ACECTS)
• Childhood epilepsy with centrotemporal spikes (CECTS)
• Benign epilepsy with centrotemporal spikes (BECTS)
• Benign rolandic epilepsy of childhood (BREC)
• Benign focal epilepsy of childhood (BFEC)
## Clinical Description
The clinical spectrum of
To date, about 400 individuals have been identified with a pathogenic variant in
Select Features of
Moderate speech and language impairment includes dysarthria, speech dyspraxia, dysphasia, speech regression with residual impairments, sometimes with additional impairments such as impaired pitch, hypernasality, or imprecise articulation [
Movement disorders include ataxia, dystonia, chorea, and complex movement disorders.
Several brain abnormalities have been reported including focal cortical dysplasia, dysplastic corpus callosum, hypoplasia of corpus callosum with midline lipoma, hippocampal hyperintensity, hippocampal sclerosis, heterotopia, subcortical lesion, hypoplastic olfactory bulb, cerebellar glioma, enlarged Virchow-Robin spaces, and delayed myelination; 11% of individuals (9/85) also had generalized cortical atrophy.
Seizure onset depends on the type of underlying
The predominant seizure type(s) in a given individual depends on the epilepsy syndrome. Broadly,
Specific epilepsy syndromes associated with
DEE/EE-SWAS with focal seizures, which may be drug-resistant. The electroencephalogram (EEG) shows marked activation in non-REM sleep of bilateral slow spike-and-wave discharges [
In LKS, a subtype of DEE/EE-SWAS, 30% of individuals do not have seizures.
Self-limited epilepsy with centrotemporal spikes (SeLECTS) with onset in childhood (usually age 3-6 years) with EEG showing centrotemporal discharges [
Infantile-onset DEE, with severe-to-profound impairment and sometimes epileptic spasms
Mildly affected individuals may display subtly impaired intelligibility of conversational speech, most characterized by dysarthric and dyspraxic features of hypernasality, imprecise consonant production, and impaired pitch and prosody [
Hypotonia (40/139; 29%)
Movement disorders, including dystonia, chorea, and ataxia (19/72; 26%)
Mental health disorders are relatively frequent in individuals with pathogenic null variants in
• DEE/EE-SWAS with focal seizures, which may be drug-resistant. The electroencephalogram (EEG) shows marked activation in non-REM sleep of bilateral slow spike-and-wave discharges [
• In LKS, a subtype of DEE/EE-SWAS, 30% of individuals do not have seizures.
• Self-limited epilepsy with centrotemporal spikes (SeLECTS) with onset in childhood (usually age 3-6 years) with EEG showing centrotemporal discharges [
• Infantile-onset DEE, with severe-to-profound impairment and sometimes epileptic spasms
• Hypotonia (40/139; 29%)
• Movement disorders, including dystonia, chorea, and ataxia (19/72; 26%)
## Genotype-Phenotype Correlations
Several genotype-phenotype correlations have been observed.
Pathogenic
Individuals with pathogenic null variants have later mean seizure onset (age 4.5 ± 0.2 years) compared to those with pathogenic missense variants (age 3.1 ± 0.4 years), and individuals with pathogenic missense variants usually have drug-resistant seizures persisting throughout childhood and adolescence [
Mental health disorders are relatively frequent in individuals with pathogenic null variants in
## Penetrance
In families of mildly affected individuals, carriers of the familial pathogenic
## Nomenclature
Epilepsy Syndrome Terminology Used in
Epileptic acquired aphasia
Continuous spike-wave during slow-wave sleep (CSWS)
Electrical status epilepticus in sleep (ESES)
Epilepsy aphasia spectrum disorders
Atypical childhood epilepsy with centrotemporal spikes (ACECTS)
Childhood epilepsy with centrotemporal spikes (CECTS)
Benign epilepsy with centrotemporal spikes (BECTS)
Benign rolandic epilepsy of childhood (BREC)
Benign focal epilepsy of childhood (BFEC)
ILAE = International League Against Epilepsy
See
• Epileptic acquired aphasia
• Continuous spike-wave during slow-wave sleep (CSWS)
• Electrical status epilepticus in sleep (ESES)
• Epilepsy aphasia spectrum disorders
• Atypical childhood epilepsy with centrotemporal spikes (ACECTS)
• Childhood epilepsy with centrotemporal spikes (CECTS)
• Benign epilepsy with centrotemporal spikes (BECTS)
• Benign rolandic epilepsy of childhood (BREC)
• Benign focal epilepsy of childhood (BFEC)
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Note: While
While no other monogenic causes are known for self-limited epilepsy with centrotemporal spikes (SeLECTS) and Landau-Kleffner syndrome (LKS), pathogenic variants in the genes
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Evaluate for early intervention & need for special education.
Assess for developmental regression across all areas.
EEG
Careful clinical history to identify seizures
In infancy & childhood, sleep-deprived or sleep EEG w/monitoring to capture sleep, as this is essential to identify DEE-SWAS
Gross motor & fine motor skills;
Mobility, ADL, & need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Screening for behavior concerns incl sleep disturbances, ADHD, &/or ASD
In persons w/null variants, consider eval for psychiatric disorders (e.g., anxiety, mood, psychotic disorders).
Eval of aspiration risk & nutritional status
Consider need for gastrostomy tube in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; DEE-SWAS = developmental and epileptic encephalopathy with spike-wave activation in sleep; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Mediates coagonistic effects on NMDAR in neurons via its enantiomer, D-serine
NMDAR coagonists are specifically effective in persons w/
Orally available non-essential amino acid
Has been demonstrated to cause improvements in behavior, development, EEG pattern, & sometimes also seizure frequency. After description of 1st treated case in 2019,
NMDAR = N-methyl-D-aspartate receptor
In individuals with
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for severe, persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
AAC = augmentative and alternative communication; ASM = anti-seizure medication; DEE = developmental and/or epileptic encephalopathy; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Consultation with a pediatric psychiatrist may be helpful in evaluation and treatment of psychiatric disorders.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Assess for new manifestations such as seizures, changes in tone, movement disorders, & regression
Assess for more subtle seizure types that many not have been recognized.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
In individuals with
In individuals with
It is appropriate to clarify the genetic status of apparently asymptomatic relatives of an affected individual by molecular genetic testing for the
See
Several treatments are now under investigation in individuals with
A clinical trial on the evaluation of radiprodil in children with
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Evaluate for early intervention & need for special education.
• Assess for developmental regression across all areas.
• EEG
• Careful clinical history to identify seizures
• In infancy & childhood, sleep-deprived or sleep EEG w/monitoring to capture sleep, as this is essential to identify DEE-SWAS
• Gross motor & fine motor skills;
• Mobility, ADL, & need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• Screening for behavior concerns incl sleep disturbances, ADHD, &/or ASD
• In persons w/null variants, consider eval for psychiatric disorders (e.g., anxiety, mood, psychotic disorders).
• Eval of aspiration risk & nutritional status
• Consider need for gastrostomy tube in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Mediates coagonistic effects on NMDAR in neurons via its enantiomer, D-serine
• NMDAR coagonists are specifically effective in persons w/
• Orally available non-essential amino acid
• Has been demonstrated to cause improvements in behavior, development, EEG pattern, & sometimes also seizure frequency. After description of 1st treated case in 2019,
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for severe, persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Assess for new manifestations such as seizures, changes in tone, movement disorders, & regression
• Assess for more subtle seizure types that many not have been recognized.
• A clinical trial on the evaluation of radiprodil in children with
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Evaluate for early intervention & need for special education.
Assess for developmental regression across all areas.
EEG
Careful clinical history to identify seizures
In infancy & childhood, sleep-deprived or sleep EEG w/monitoring to capture sleep, as this is essential to identify DEE-SWAS
Gross motor & fine motor skills;
Mobility, ADL, & need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Screening for behavior concerns incl sleep disturbances, ADHD, &/or ASD
In persons w/null variants, consider eval for psychiatric disorders (e.g., anxiety, mood, psychotic disorders).
Eval of aspiration risk & nutritional status
Consider need for gastrostomy tube in persons w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; DEE-SWAS = developmental and epileptic encephalopathy with spike-wave activation in sleep; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech-language eval
• Evaluate for early intervention & need for special education.
• Assess for developmental regression across all areas.
• EEG
• Careful clinical history to identify seizures
• In infancy & childhood, sleep-deprived or sleep EEG w/monitoring to capture sleep, as this is essential to identify DEE-SWAS
• Gross motor & fine motor skills;
• Mobility, ADL, & need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• Screening for behavior concerns incl sleep disturbances, ADHD, &/or ASD
• In persons w/null variants, consider eval for psychiatric disorders (e.g., anxiety, mood, psychotic disorders).
• Eval of aspiration risk & nutritional status
• Consider need for gastrostomy tube in persons w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for
Mediates coagonistic effects on NMDAR in neurons via its enantiomer, D-serine
NMDAR coagonists are specifically effective in persons w/
Orally available non-essential amino acid
Has been demonstrated to cause improvements in behavior, development, EEG pattern, & sometimes also seizure frequency. After description of 1st treated case in 2019,
NMDAR = N-methyl-D-aspartate receptor
In individuals with
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for severe, persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
AAC = augmentative and alternative communication; ASM = anti-seizure medication; DEE = developmental and/or epileptic encephalopathy; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Consultation with a pediatric psychiatrist may be helpful in evaluation and treatment of psychiatric disorders.
• Mediates coagonistic effects on NMDAR in neurons via its enantiomer, D-serine
• NMDAR coagonists are specifically effective in persons w/
• Orally available non-essential amino acid
• Has been demonstrated to cause improvements in behavior, development, EEG pattern, & sometimes also seizure frequency. After description of 1st treated case in 2019,
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for severe, persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Targeted Therapy
Mediates coagonistic effects on NMDAR in neurons via its enantiomer, D-serine
NMDAR coagonists are specifically effective in persons w/
Orally available non-essential amino acid
Has been demonstrated to cause improvements in behavior, development, EEG pattern, & sometimes also seizure frequency. After description of 1st treated case in 2019,
NMDAR = N-methyl-D-aspartate receptor
In individuals with
• Mediates coagonistic effects on NMDAR in neurons via its enantiomer, D-serine
• NMDAR coagonists are specifically effective in persons w/
• Orally available non-essential amino acid
• Has been demonstrated to cause improvements in behavior, development, EEG pattern, & sometimes also seizure frequency. After description of 1st treated case in 2019,
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for severe, persistent feeding issues.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
AAC = augmentative and alternative communication; ASM = anti-seizure medication; DEE = developmental and/or epileptic encephalopathy; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Consultation with a pediatric psychiatrist may be helpful in evaluation and treatment of psychiatric disorders.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for severe, persistent feeding issues.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
##
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
##
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Consultation with a pediatric psychiatrist may be helpful in evaluation and treatment of psychiatric disorders.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Assess for new manifestations such as seizures, changes in tone, movement disorders, & regression
Assess for more subtle seizure types that many not have been recognized.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
• Assess for new manifestations such as seizures, changes in tone, movement disorders, & regression
• Assess for more subtle seizure types that many not have been recognized.
## Agents/Circumstances to Avoid
In individuals with
In individuals with
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic relatives of an affected individual by molecular genetic testing for the
See
## Therapies Under Investigation
Several treatments are now under investigation in individuals with
A clinical trial on the evaluation of radiprodil in children with
Search
• A clinical trial on the evaluation of radiprodil in children with
## Genetic Counseling
Note: Compound heterozygous
Some individuals diagnosed with a
Approximately 50% of individuals diagnosed with a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
The family history of some individuals diagnosed with a
If a parent of the proband is affected and/or is known to have the
If the
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most heath care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Some individuals diagnosed with a
• Approximately 50% of individuals diagnosed with a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• The family history of some individuals diagnosed with a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• If a parent of the proband is affected and/or is known to have the
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Note: Compound heterozygous
## Risk to Family Members
Some individuals diagnosed with a
Approximately 50% of individuals diagnosed with a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
The family history of some individuals diagnosed with a
If a parent of the proband is affected and/or is known to have the
If the
If the parents have not been tested for the
• Some individuals diagnosed with a
• Approximately 50% of individuals diagnosed with a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• The family history of some individuals diagnosed with a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• If a parent of the proband is affected and/or is known to have the
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most heath care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Spain
Italy
United Kingdom
•
• Spain
•
•
• Italy
•
•
•
•
•
•
•
•
• United Kingdom
•
•
•
•
•
•
•
•
•
## Molecular Genetics
GRIN2A-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GRIN2A-Related Disorders (
The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-activated ion channel permeable to sodium, calcium, and potassium ions that is highly expressed throughout the brain and plays important roles in mediating excitatory neurotransmission critical for development, learning, memory, and other higher cognitive functions. The NMDAR is a heterotetrametric molecule composed of two NMDA receptor 1 subunits (GluN1) and two different NMDA receptor 2 subunits (GluN2A and GluN2B). The GluN2A subunit is encoded by
In vitro tests on
Loss of function (usually associated with milder phenotypes, such as speech abnormalities and/or seizures with mild intellectual disability or normal intellect)
Gain of function (usually associated with more severe phenotypes, such as severe developmental and epileptic encephalopathies)
• Loss of function (usually associated with milder phenotypes, such as speech abnormalities and/or seizures with mild intellectual disability or normal intellect)
• Gain of function (usually associated with more severe phenotypes, such as severe developmental and epileptic encephalopathies)
## Molecular Pathogenesis
The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-activated ion channel permeable to sodium, calcium, and potassium ions that is highly expressed throughout the brain and plays important roles in mediating excitatory neurotransmission critical for development, learning, memory, and other higher cognitive functions. The NMDAR is a heterotetrametric molecule composed of two NMDA receptor 1 subunits (GluN1) and two different NMDA receptor 2 subunits (GluN2A and GluN2B). The GluN2A subunit is encoded by
In vitro tests on
Loss of function (usually associated with milder phenotypes, such as speech abnormalities and/or seizures with mild intellectual disability or normal intellect)
Gain of function (usually associated with more severe phenotypes, such as severe developmental and epileptic encephalopathies)
• Loss of function (usually associated with milder phenotypes, such as speech abnormalities and/or seizures with mild intellectual disability or normal intellect)
• Gain of function (usually associated with more severe phenotypes, such as severe developmental and epileptic encephalopathies)
## Chapter Notes
Dr Vincent Strehlow (
Professor Ingrid Scheffer and Dr Ken Myers are happy to assist with enquiries related to patient management. Professor Angela Morgan is happy to assist with enquiries related to speech and language management.
Contact Dr Vincent Strehlow and Dr Johannes R Lemke to inquire about review of
The authors thank all the families and individuals who have contributed to
Most of the pathophysiologic findings and understanding of mechanisms have been through the comprehensive functional investigations at the Center for Functional Evaluation of Rare Variants at Emory University, Atlanta, United States, lead by Dr Stephen Traynelis.
4 July 2024 (gm) Comprehensive update posted live
29 September 2016 (bp) Review posted live
12 October 2015 (kam) Original submission
• 4 July 2024 (gm) Comprehensive update posted live
• 29 September 2016 (bp) Review posted live
• 12 October 2015 (kam) Original submission
## Author Notes
Dr Vincent Strehlow (
Professor Ingrid Scheffer and Dr Ken Myers are happy to assist with enquiries related to patient management. Professor Angela Morgan is happy to assist with enquiries related to speech and language management.
Contact Dr Vincent Strehlow and Dr Johannes R Lemke to inquire about review of
## Acknowledgments
The authors thank all the families and individuals who have contributed to
Most of the pathophysiologic findings and understanding of mechanisms have been through the comprehensive functional investigations at the Center for Functional Evaluation of Rare Variants at Emory University, Atlanta, United States, lead by Dr Stephen Traynelis.
## Revision History
4 July 2024 (gm) Comprehensive update posted live
29 September 2016 (bp) Review posted live
12 October 2015 (kam) Original submission
• 4 July 2024 (gm) Comprehensive update posted live
• 29 September 2016 (bp) Review posted live
• 12 October 2015 (kam) Original submission
## Key Sections in This
## References
## Literature Cited
|
[] |
29/9/2016
|
4/7/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
grin2b
|
grin2b
|
[
"GRIN2B Encephalopathy",
"GRIN2B Encephalopathy",
"Glutamate receptor ionotropic, NMDA 2B",
"GRIN2B",
"GRIN2B-Related Neurodevelopmental Disorder"
] |
Konrad Platzer, Johannes R Lemke
|
Summary The diagnosis of a
|
## Diagnosis
Formal diagnostic criteria for
Mild-to-profound developmental delay (DD) or intellectual disability (ID); AND
Any of the following features presenting in infancy or childhood:
Epilepsy
Autism spectrum disorder / behavioral issues
Microcephaly
Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
Dystonic, dyskinetic, or choreiform movement disorder
Cortical visual impairment
The diagnosis of a
Note: (1) Larger contiguous-gene deletions including but not limited to
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of many disorders with intellectual disability overlap, most children with
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
For references, see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Mild-to-profound developmental delay (DD) or intellectual disability (ID); AND
• Any of the following features presenting in infancy or childhood:
• Epilepsy
• Autism spectrum disorder / behavioral issues
• Microcephaly
• Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Cortical visual impairment
• Epilepsy
• Autism spectrum disorder / behavioral issues
• Microcephaly
• Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Cortical visual impairment
• Epilepsy
• Autism spectrum disorder / behavioral issues
• Microcephaly
• Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Cortical visual impairment
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Mild-to-profound developmental delay (DD) or intellectual disability (ID); AND
Any of the following features presenting in infancy or childhood:
Epilepsy
Autism spectrum disorder / behavioral issues
Microcephaly
Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
Dystonic, dyskinetic, or choreiform movement disorder
Cortical visual impairment
• Mild-to-profound developmental delay (DD) or intellectual disability (ID); AND
• Any of the following features presenting in infancy or childhood:
• Epilepsy
• Autism spectrum disorder / behavioral issues
• Microcephaly
• Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Cortical visual impairment
• Epilepsy
• Autism spectrum disorder / behavioral issues
• Microcephaly
• Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Cortical visual impairment
• Epilepsy
• Autism spectrum disorder / behavioral issues
• Microcephaly
• Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Cortical visual impairment
## Establishing the Diagnosis
The diagnosis of a
Note: (1) Larger contiguous-gene deletions including but not limited to
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of many disorders with intellectual disability overlap, most children with
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
For references, see
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Unless otherwise noted, the information in this section is based on extended data of
The degree of DD/ID can be severe or profound (61%, 33/54), moderate (24%, 13/54), or mild (15%, 8/54) using standard assessments of psychomotor development or IQ testing.
Signs of developmental regression have been noted in four children (7%, 4/61), one of whom had transient regression of language skills at age six years with improvement beginning at age eight years and another who had recurrent periods of global regression starting at age three years. No detailed information is available for the other two children.
Hypotonia has been reported in more than half the affected individuals (56%, 34/61). Five (15% of those with muscular hypotonia) required tube feeding. All five of these individuals had severe ID.
Spasticity was seen in 14 (23%) of 61 individuals, all with severe ID.
Epilepsy is present in 31 (51%) of 61 of individuals and characterized by the following.
Onset is from birth to age nine years.
Seizure frequency ranges from multiple episodes per day to a few seizures per year.
Seizures are refractory to anti-seizure medication in approximately half of individuals treated.
Seizures may be generalized (58%, 18/31) and/or focal (48%, 15/31) and/or epileptic spasms (35%, 11/31) with some individuals displaying multiple seizure types over time.
EEG patterns comprise generalized, focal, and multifocal epileptiform activity and/or hypsarrhythmia.
Autistic features were seen in 16 (26%) of 61 individuals. In addition, in one study of the behavioral phenotype of five individuals with
Microcephaly occurred in 11 (18%) of 61 individuals; all 11 had severe ID. Three of these also had an MCD.
Movement disorders (10%, 6/61) included involuntary dystonic, dyskinetic, and/or choreiform movements.
Cortical visual impairment (CVI) (8%, 5/61) has been reported in four affected individuals: three also had an MCD, and the fourth, who had a normal brain MRI, was identified in a cohort of individuals with ID and CVI [
Note: A report of an individual with approximately 50% mosaicism for a
A malformation of cortical development (MCD) has been seen in six (13%) of 47 individuals; the diffuse cortical dysplasia was consistent with that of polymicrogyria. Cortical findings included a mixture of large and small gyri separated by shallow sulci (
Other findings included the following:
Hypoplastic corpus callosum of varying degrees
Enlarged and mildly dysplastic basal ganglia
Hippocampal dysplasia with thick leaves and open hilus
Enlarged tecta
Absent septum pellucidum
The malformation of cortical development is also consistent with that of tubulinopathies (see
Generalized cerebral volume loss indicating cerebral atrophy was seen in four other individuals (9%, 4/47).
Variant class and intellectual outcome show a significant correlation: heterozygotes for a
Missense variants in
Penetrance of
The prevalence of
The prevalence of
• Onset is from birth to age nine years.
• Seizure frequency ranges from multiple episodes per day to a few seizures per year.
• Seizures are refractory to anti-seizure medication in approximately half of individuals treated.
• Seizures may be generalized (58%, 18/31) and/or focal (48%, 15/31) and/or epileptic spasms (35%, 11/31) with some individuals displaying multiple seizure types over time.
• EEG patterns comprise generalized, focal, and multifocal epileptiform activity and/or hypsarrhythmia.
• Hypoplastic corpus callosum of varying degrees
• Enlarged and mildly dysplastic basal ganglia
• Hippocampal dysplasia with thick leaves and open hilus
• Enlarged tecta
• Absent septum pellucidum
## Clinical Description
Unless otherwise noted, the information in this section is based on extended data of
The degree of DD/ID can be severe or profound (61%, 33/54), moderate (24%, 13/54), or mild (15%, 8/54) using standard assessments of psychomotor development or IQ testing.
Signs of developmental regression have been noted in four children (7%, 4/61), one of whom had transient regression of language skills at age six years with improvement beginning at age eight years and another who had recurrent periods of global regression starting at age three years. No detailed information is available for the other two children.
Hypotonia has been reported in more than half the affected individuals (56%, 34/61). Five (15% of those with muscular hypotonia) required tube feeding. All five of these individuals had severe ID.
Spasticity was seen in 14 (23%) of 61 individuals, all with severe ID.
Epilepsy is present in 31 (51%) of 61 of individuals and characterized by the following.
Onset is from birth to age nine years.
Seizure frequency ranges from multiple episodes per day to a few seizures per year.
Seizures are refractory to anti-seizure medication in approximately half of individuals treated.
Seizures may be generalized (58%, 18/31) and/or focal (48%, 15/31) and/or epileptic spasms (35%, 11/31) with some individuals displaying multiple seizure types over time.
EEG patterns comprise generalized, focal, and multifocal epileptiform activity and/or hypsarrhythmia.
Autistic features were seen in 16 (26%) of 61 individuals. In addition, in one study of the behavioral phenotype of five individuals with
Microcephaly occurred in 11 (18%) of 61 individuals; all 11 had severe ID. Three of these also had an MCD.
Movement disorders (10%, 6/61) included involuntary dystonic, dyskinetic, and/or choreiform movements.
Cortical visual impairment (CVI) (8%, 5/61) has been reported in four affected individuals: three also had an MCD, and the fourth, who had a normal brain MRI, was identified in a cohort of individuals with ID and CVI [
Note: A report of an individual with approximately 50% mosaicism for a
A malformation of cortical development (MCD) has been seen in six (13%) of 47 individuals; the diffuse cortical dysplasia was consistent with that of polymicrogyria. Cortical findings included a mixture of large and small gyri separated by shallow sulci (
Other findings included the following:
Hypoplastic corpus callosum of varying degrees
Enlarged and mildly dysplastic basal ganglia
Hippocampal dysplasia with thick leaves and open hilus
Enlarged tecta
Absent septum pellucidum
The malformation of cortical development is also consistent with that of tubulinopathies (see
Generalized cerebral volume loss indicating cerebral atrophy was seen in four other individuals (9%, 4/47).
• Onset is from birth to age nine years.
• Seizure frequency ranges from multiple episodes per day to a few seizures per year.
• Seizures are refractory to anti-seizure medication in approximately half of individuals treated.
• Seizures may be generalized (58%, 18/31) and/or focal (48%, 15/31) and/or epileptic spasms (35%, 11/31) with some individuals displaying multiple seizure types over time.
• EEG patterns comprise generalized, focal, and multifocal epileptiform activity and/or hypsarrhythmia.
• Hypoplastic corpus callosum of varying degrees
• Enlarged and mildly dysplastic basal ganglia
• Hippocampal dysplasia with thick leaves and open hilus
• Enlarged tecta
• Absent septum pellucidum
## DD/ID
The degree of DD/ID can be severe or profound (61%, 33/54), moderate (24%, 13/54), or mild (15%, 8/54) using standard assessments of psychomotor development or IQ testing.
Signs of developmental regression have been noted in four children (7%, 4/61), one of whom had transient regression of language skills at age six years with improvement beginning at age eight years and another who had recurrent periods of global regression starting at age three years. No detailed information is available for the other two children.
## Muscle Tone Abnormalities
Hypotonia has been reported in more than half the affected individuals (56%, 34/61). Five (15% of those with muscular hypotonia) required tube feeding. All five of these individuals had severe ID.
Spasticity was seen in 14 (23%) of 61 individuals, all with severe ID.
## Epilepsy
Epilepsy is present in 31 (51%) of 61 of individuals and characterized by the following.
Onset is from birth to age nine years.
Seizure frequency ranges from multiple episodes per day to a few seizures per year.
Seizures are refractory to anti-seizure medication in approximately half of individuals treated.
Seizures may be generalized (58%, 18/31) and/or focal (48%, 15/31) and/or epileptic spasms (35%, 11/31) with some individuals displaying multiple seizure types over time.
EEG patterns comprise generalized, focal, and multifocal epileptiform activity and/or hypsarrhythmia.
• Onset is from birth to age nine years.
• Seizure frequency ranges from multiple episodes per day to a few seizures per year.
• Seizures are refractory to anti-seizure medication in approximately half of individuals treated.
• Seizures may be generalized (58%, 18/31) and/or focal (48%, 15/31) and/or epileptic spasms (35%, 11/31) with some individuals displaying multiple seizure types over time.
• EEG patterns comprise generalized, focal, and multifocal epileptiform activity and/or hypsarrhythmia.
## ASD
Autistic features were seen in 16 (26%) of 61 individuals. In addition, in one study of the behavioral phenotype of five individuals with
## Other
Microcephaly occurred in 11 (18%) of 61 individuals; all 11 had severe ID. Three of these also had an MCD.
Movement disorders (10%, 6/61) included involuntary dystonic, dyskinetic, and/or choreiform movements.
Cortical visual impairment (CVI) (8%, 5/61) has been reported in four affected individuals: three also had an MCD, and the fourth, who had a normal brain MRI, was identified in a cohort of individuals with ID and CVI [
Note: A report of an individual with approximately 50% mosaicism for a
## Brain Imaging
A malformation of cortical development (MCD) has been seen in six (13%) of 47 individuals; the diffuse cortical dysplasia was consistent with that of polymicrogyria. Cortical findings included a mixture of large and small gyri separated by shallow sulci (
Other findings included the following:
Hypoplastic corpus callosum of varying degrees
Enlarged and mildly dysplastic basal ganglia
Hippocampal dysplasia with thick leaves and open hilus
Enlarged tecta
Absent septum pellucidum
The malformation of cortical development is also consistent with that of tubulinopathies (see
Generalized cerebral volume loss indicating cerebral atrophy was seen in four other individuals (9%, 4/47).
• Hypoplastic corpus callosum of varying degrees
• Enlarged and mildly dysplastic basal ganglia
• Hippocampal dysplasia with thick leaves and open hilus
• Enlarged tecta
• Absent septum pellucidum
## Genotype-Phenotype Correlations
Variant class and intellectual outcome show a significant correlation: heterozygotes for a
Missense variants in
## Penetrance
Penetrance of
## Prevalence
The prevalence of
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Phenotypic features associated with heterozygous
All genes known to be associated with ID, early-onset epileptic encephalopathy, and malformations of cortical development (especially diffuse polymicrogyria and tubulinopathies) should be included in the differential diagnosis of
Genes to Consider in the Differential Diagnosis of
See linked
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Treatment of Manifestations in Individuals with
ASM = anti-seizure medication
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., medication used to treat attention-deficit/hyperactivity disorder) when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
See
In vitro studies on oocytes of
Search
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
ASM = anti-seizure medication
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., medication used to treat attention-deficit/hyperactivity disorder) when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
• Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., medication used to treat attention-deficit/hyperactivity disorder) when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
In vitro studies on oocytes of
Search
## Genetic Counseling
To date all probands with a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred
Theoretically, if the parent is the individual in whom the
The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the proband represents a simplex case (i.e., the only affected family member) and the
In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was 10% [
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Risk to future pregnancies is presumed to be low, as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• To date all probands with a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred
• Theoretically, if the parent is the individual in whom the
• The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the proband represents a simplex case (i.e., the only affected family member) and the
• In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was 10% [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
To date all probands with a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred
Theoretically, if the parent is the individual in whom the
The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the proband represents a simplex case (i.e., the only affected family member) and the
In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was 10% [
• To date all probands with a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred
• Theoretically, if the parent is the individual in whom the
• The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the proband represents a simplex case (i.e., the only affected family member) and the
• In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was 10% [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Risk to future pregnancies is presumed to be low, as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
Canada
•
•
•
•
•
•
•
• Canada
•
•
• Canada
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
GRIN2B-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GRIN2B-Related Neurodevelopmental Disorder (
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels expressed throughout the brain mediating excitatory neurotransmission. Signaling via NMDAR plays an important role in brain development, learning, memory, and other higher cognitive functions. NMDAR are diheterotetramers or triheterotetramers composed of two glycine-binding GluN1subunits (encoded by
Compared with the ubiquitously expressed GluN1 subunits, the GluN2 subunits show specific spatiotemporal expression profiles throughout the central nervous system [
Of note, discussion of the phenotypes associated with large rearrangements at 12p13.1 that involve
## Molecular Pathogenesis
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels expressed throughout the brain mediating excitatory neurotransmission. Signaling via NMDAR plays an important role in brain development, learning, memory, and other higher cognitive functions. NMDAR are diheterotetramers or triheterotetramers composed of two glycine-binding GluN1subunits (encoded by
Compared with the ubiquitously expressed GluN1 subunits, the GluN2 subunits show specific spatiotemporal expression profiles throughout the central nervous system [
Of note, discussion of the phenotypes associated with large rearrangements at 12p13.1 that involve
## Chapter Notes
Konrad Platzer, MDInstitute of Human GeneticsUniversity of Leipzig Hospitals and ClinicsPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
Johannes R Lemke, MDInstitute of Human GeneticsUniversity of Leipzig Hospitals and ClinicsPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
25 March 2021 (aa) Revision: incorporated parental mosaicism data from
31 May 2018 (bp) Review posted live
30 October 2017 (jrl) Original submission
• 25 March 2021 (aa) Revision: incorporated parental mosaicism data from
• 31 May 2018 (bp) Review posted live
• 30 October 2017 (jrl) Original submission
## Author Notes
Konrad Platzer, MDInstitute of Human GeneticsUniversity of Leipzig Hospitals and ClinicsPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
Johannes R Lemke, MDInstitute of Human GeneticsUniversity of Leipzig Hospitals and ClinicsPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
## Revision History
25 March 2021 (aa) Revision: incorporated parental mosaicism data from
31 May 2018 (bp) Review posted live
30 October 2017 (jrl) Original submission
• 25 March 2021 (aa) Revision: incorporated parental mosaicism data from
• 31 May 2018 (bp) Review posted live
• 30 October 2017 (jrl) Original submission
## References
## Literature Cited
MRI of individuals with malformation of cortical development
A-D: patient 1; E-H: patient 2; I-L: patient 3; M-P: patient 4; Q-T: patient 5; U-X: patient 6; AA-DD: normal control
Column 1. T
Column 2. T
Column 3. T
Column 4. T
Reproduced with permission from
|
[] |
31/5/2018
|
25/3/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
grin2d-dee
|
grin2d-dee
|
[
"Glutamate receptor ionotropic, NMDA 2D",
"GRIN2D",
"GRIN2D-Related Developmental and Epileptic Encephalopathy"
] |
Konrad Platzer, Ilona Krey, Johannes R Lemke
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Mild-to-profound developmental delay (DD) or intellectual disability (ID); AND
Any of the following presenting in infancy or childhood:
Epilepsy
Muscular tone abnormalities such as hypotonia and spasticity
Dystonic, dyskinetic, or choreiform movement disorder
Autism spectrum disorder
Cortical visual impairment
The diagnosis of
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
To date, all reported
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date,
• Mild-to-profound developmental delay (DD) or intellectual disability (ID); AND
• Any of the following presenting in infancy or childhood:
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Cortical visual impairment
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Cortical visual impairment
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Cortical visual impairment
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Suggestive Findings
Mild-to-profound developmental delay (DD) or intellectual disability (ID); AND
Any of the following presenting in infancy or childhood:
Epilepsy
Muscular tone abnormalities such as hypotonia and spasticity
Dystonic, dyskinetic, or choreiform movement disorder
Autism spectrum disorder
Cortical visual impairment
• Mild-to-profound developmental delay (DD) or intellectual disability (ID); AND
• Any of the following presenting in infancy or childhood:
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Cortical visual impairment
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Cortical visual impairment
• Epilepsy
• Muscular tone abnormalities such as hypotonia and spasticity
• Dystonic, dyskinetic, or choreiform movement disorder
• Autism spectrum disorder
• Cortical visual impairment
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous
Because the phenotype of
Note: Single-gene testing (sequence analysis of
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
To date, all reported
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
To date,
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Clinical Characteristics
To date, a pathogenic missense variant in
In 36% (8/22), no speech was noted, while 2/22 were able to speak single words.
Of the 22 individuals reported, five (all of whom also had epilepsy) were noted to regress, consistent with an encephalopathic course. In 10% (2/22), the regression was further specified to primarily affect motor skills.
When known, seizure type differed at onset and included the following:
Febrile seizures (1/18)
Focal seizures (4/18)
Absence seizures (3/18)
Generalized seizures (5/18)
Epileptic spasms (5/18)
Eleven of the 19 individuals with seizures had multiple seizure types after the initial onset of seizures.
Use of anti-seizure medication varied considerably, with differing levels of success. No particularly successful treatment regimen was evident.
EEG findings include hypsarrhythmia, focal and multifocal as well as generalized epileptic discharges; different EEG patterns varied over time.
Muscular hypotonia: 54% (in 12/22)
Movement disorder with athetoid movements, jerky movements, ballism, mild dyskinesia, and choreiform movements: 36% (8/22)
Cortical visual impairment: 32% (7/22)
Spasticity (primarily of the lower limbs): 18% (4/22)
Ataxic gait: 3% (3/22)
Autism spectrum disorder: 18% (4/22)
Recurrent sleeping disorder 27% (6/22)
Feeding difficulties in 27% (6/22), including one individual who required tube feeding [
Recurrent vomiting and constipation
No genotype-phenotype correlations have been identified.
Penetrance of
The prevalence of
Use of an empiric incidence estimation algorithm [
A genetic contribution to neurodevelopmental disorders can be estimated at 0.006% based on the presence of two
• Febrile seizures (1/18)
• Focal seizures (4/18)
• Absence seizures (3/18)
• Generalized seizures (5/18)
• Epileptic spasms (5/18)
• Muscular hypotonia: 54% (in 12/22)
• Movement disorder with athetoid movements, jerky movements, ballism, mild dyskinesia, and choreiform movements: 36% (8/22)
• Cortical visual impairment: 32% (7/22)
• Spasticity (primarily of the lower limbs): 18% (4/22)
• Ataxic gait: 3% (3/22)
• Autism spectrum disorder: 18% (4/22)
• Recurrent sleeping disorder 27% (6/22)
• Feeding difficulties in 27% (6/22), including one individual who required tube feeding [
• Recurrent vomiting and constipation
## Clinical Description
To date, a pathogenic missense variant in
In 36% (8/22), no speech was noted, while 2/22 were able to speak single words.
Of the 22 individuals reported, five (all of whom also had epilepsy) were noted to regress, consistent with an encephalopathic course. In 10% (2/22), the regression was further specified to primarily affect motor skills.
When known, seizure type differed at onset and included the following:
Febrile seizures (1/18)
Focal seizures (4/18)
Absence seizures (3/18)
Generalized seizures (5/18)
Epileptic spasms (5/18)
Eleven of the 19 individuals with seizures had multiple seizure types after the initial onset of seizures.
Use of anti-seizure medication varied considerably, with differing levels of success. No particularly successful treatment regimen was evident.
EEG findings include hypsarrhythmia, focal and multifocal as well as generalized epileptic discharges; different EEG patterns varied over time.
Muscular hypotonia: 54% (in 12/22)
Movement disorder with athetoid movements, jerky movements, ballism, mild dyskinesia, and choreiform movements: 36% (8/22)
Cortical visual impairment: 32% (7/22)
Spasticity (primarily of the lower limbs): 18% (4/22)
Ataxic gait: 3% (3/22)
Autism spectrum disorder: 18% (4/22)
Recurrent sleeping disorder 27% (6/22)
Feeding difficulties in 27% (6/22), including one individual who required tube feeding [
Recurrent vomiting and constipation
• Febrile seizures (1/18)
• Focal seizures (4/18)
• Absence seizures (3/18)
• Generalized seizures (5/18)
• Epileptic spasms (5/18)
• Muscular hypotonia: 54% (in 12/22)
• Movement disorder with athetoid movements, jerky movements, ballism, mild dyskinesia, and choreiform movements: 36% (8/22)
• Cortical visual impairment: 32% (7/22)
• Spasticity (primarily of the lower limbs): 18% (4/22)
• Ataxic gait: 3% (3/22)
• Autism spectrum disorder: 18% (4/22)
• Recurrent sleeping disorder 27% (6/22)
• Feeding difficulties in 27% (6/22), including one individual who required tube feeding [
• Recurrent vomiting and constipation
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Penetrance of
## Prevalence
The prevalence of
Use of an empiric incidence estimation algorithm [
A genetic contribution to neurodevelopmental disorders can be estimated at 0.006% based on the presence of two
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because the phenotypic features associated with
Intellectual disability without other distinctive findings: see OMIM
Developmental and epileptic encephalopathy: see OMIM
Of note, malformation of cortical development – described in some individuals with
• Intellectual disability without other distinctive findings: see OMIM
• Developmental and epileptic encephalopathy: see OMIM
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl eval of aspiration risk & nutritional status, weight gain, constipation & GERD
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive & speech/language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric neurology, pediatric ophthalmology, developmental pediatrics, feeding, orthopedics, physical medicine and rehabilitation, physical therapy, occupational therapy, and ethics.
Treatment of Manifestations in Individuals with
Many ASMs may be effective; no ASM has been demonstrated effective specifically for this disorder.
Education of parents / care givers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
Monitor those w/seizures.
Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
OT = occupational therapy; PT = physical therapy
See
Given the understanding of the drug memantine on
Search
• To incl eval of aspiration risk & nutritional status, weight gain, constipation & GERD
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive & speech/language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; no ASM has been demonstrated effective specifically for this disorder.
• Education of parents / care givers
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Monitor those w/seizures.
• Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl eval of aspiration risk & nutritional status, weight gain, constipation & GERD
Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl motor, adaptive, cognitive & speech/language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl eval of aspiration risk & nutritional status, weight gain, constipation & GERD
• Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl motor, adaptive, cognitive & speech/language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric neurology, pediatric ophthalmology, developmental pediatrics, feeding, orthopedics, physical medicine and rehabilitation, physical therapy, occupational therapy, and ethics.
Treatment of Manifestations in Individuals with
Many ASMs may be effective; no ASM has been demonstrated effective specifically for this disorder.
Education of parents / care givers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; no ASM has been demonstrated effective specifically for this disorder.
• Education of parents / care givers
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Educational Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Individualized education plan (IEP) services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Individualized education plan (IEP) services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Social/Behavioral Difficulties
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
Monitor those w/seizures.
Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures.
• Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Given the understanding of the drug memantine on
Search
## Genetic Counseling
All probands reported to date with
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If the proband represents a simplex case (i.e., the only affected family member) and the
In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was found to be 10% [
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Risk to future pregnancies is presumed to be low, as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• All probands reported to date with
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If the proband represents a simplex case (i.e., the only affected family member) and the
• In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was found to be 10% [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
All probands reported to date with
Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If the proband represents a simplex case (i.e., the only affected family member) and the
In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was found to be 10% [
• All probands reported to date with
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If the proband represents a simplex case (i.e., the only affected family member) and the
• In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was found to be 10% [
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Risk to future pregnancies is presumed to be low, as the proband most likely has a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
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## Molecular Genetics
GRIN2D-Related Developmental and Epileptic Encephalopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for GRIN2D-Related Developmental and Epileptic Encephalopathy (
N-methyl D-aspartate receptors (NMDARs) are ligand-gated subunit receptors that mediate excitatory synaptic transmission in the central nervous system. NMDARs, tetrameric assemblies of two GluN1 and two GluN2 subunits, play important roles in brain development, synaptic plasticity, learning, and memory.
The NMDARs encoded by the GRIN gene family include
All GluN subunits have a similar structure: an amino terminal domain (ATD), an agonist-binding domain (ABD; S1 and S2), a transmembrane domain (M1, M2, M3, and M4), and a C-terminal domain (CTD) [
## Molecular Pathogenesis
N-methyl D-aspartate receptors (NMDARs) are ligand-gated subunit receptors that mediate excitatory synaptic transmission in the central nervous system. NMDARs, tetrameric assemblies of two GluN1 and two GluN2 subunits, play important roles in brain development, synaptic plasticity, learning, and memory.
The NMDARs encoded by the GRIN gene family include
All GluN subunits have a similar structure: an amino terminal domain (ATD), an agonist-binding domain (ABD; S1 and S2), a transmembrane domain (M1, M2, M3, and M4), and a C-terminal domain (CTD) [
## Chapter Notes
Konrad Platzer, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
Ilona Krey, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
Johannes R Lemke, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
The authors (Konrad Platzer, Ilona Krey, and Johannes Lemke) are available to help clinicians evaluate variants of uncertain significance in
The authors are actively involved in clinical research regarding individuals with GRIN disorders (
The authors are also interested in hearing from clinicians treating families affected by developmental and epileptic encephalopathy in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
28 July 2022 (bp) Review posted live
20 May 2022 (kp) Original submission
• 28 July 2022 (bp) Review posted live
• 20 May 2022 (kp) Original submission
## Author Notes
Konrad Platzer, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
Ilona Krey, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
Johannes R Lemke, MDInstitute of Human GeneticsUniversity of Leipzig Medical CenterPhilipp-Rosenthal-Str. 5504103 Leipzig, Germany
The authors (Konrad Platzer, Ilona Krey, and Johannes Lemke) are available to help clinicians evaluate variants of uncertain significance in
The authors are actively involved in clinical research regarding individuals with GRIN disorders (
The authors are also interested in hearing from clinicians treating families affected by developmental and epileptic encephalopathy in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
## Revision History
28 July 2022 (bp) Review posted live
20 May 2022 (kp) Original submission
• 28 July 2022 (bp) Review posted live
• 20 May 2022 (kp) Original submission
## References
## Literature Cited
|
[
"AM Bertoli-Avella, C Beetz, N Ameziane, ME Rocha, P Guatibonza, C Pereira, M Calvo, N Herrera-Ordonez, M Segura-Castel, D Diego-Alvarez, M Zawada, KK Kandaswamy, M Werber, O Paknia, S Zielske, D Ugrinovski, G Warnack, K Kampe, MI Iurașcu, C Cozma, F Vogel, A Alhashem, J Hertecant, AM Al-Shamsi, AF Alswaid, W Eyaid, F Al Mutairi, A Alfares, MA Albalwi, M Alfadhel, NA Al-Sannaa, W Reardon, Y Alanay, A Rolfs, P Bauer. Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.. Eur J Hum Genet. 2021;29:141-53",
"MG Chez, Q Burton, T Dowling, M Chang, P Khanna, C Kramer. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observation of initial clinical response and maintenance tolerability.. J Child Neurol. 2007;22:574-9",
"CA Erickson, DJ Posey, KA Stigler, J Mullett, AR Katschke, CJ McDougle. A retrospective study of memantine in children and adolescents with pervasive developmental disorders.. Psychopharmacology (Berl) 2007;191:141-7",
"M Ghasemi, SC Schachter. The NMDA receptor complex as a therapeutic target in epilepsy: a review.. Epilepsy Behav. 2011;22:617-40",
"J Jiao, L Li, M Sun, J Fang, L Meng, Y Zhang, C Jia, L Ma. Identification of a novel GRIN2D variant in a neonate with intractable epileptic encephalopathy-a case report.. BMC Pediatr. 2021;21:5",
"J Kaplanis, KE Samocha, L Wiel, Z Zhang, KJ Arvai, RY Eberhardt, G Gallone, SH Lelieveld, HC Martin, JF McRae, PJ Short, RI Torene, E de Boer, P Danecek, EJ Gardner, N Huang, J Lord, I Martincorena, R Pfundt, MRF Reijnders, A Yeung, HG Yntema. Deciphering Developmental Disorders Study, Vissers LELM, Juusola J, Wright CF, Brunner HG, Firth HV, FitzPatrick DR, Barrett JC, Hurles ME, Gilissen C, Retterer K. Evidence for 28 genetic disorders discovered by combining healthcare and research data.. Nature. 2020;586:757-62",
"SE Kotermanski, JW Johnson. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine.. J Neurosci. 2009;29:2774-9",
"JR Lemke. Predicting incidences of neurodevelopmental disorders.. Brain. 2020;143:1046-8",
"D Li, H Yuan, XR Ortiz-Gonzalez, ED Marsh, L Tian, EM McCormick, GJ Kosobucki, W Chen, AJ Schulien, R Chiavacci, A Tankovic, C Naase, F Brueckner, C von Stülpnagel-Steinbeis, C Hu, H Kusumoto, UB Hedrich, G Elsen, K Hörtnagel, E Aizenman, JR Lemke, H Hakonarson, SF Traynelis, MJ Falk. GRIN2D Recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers.. Am J Hum Genet. 2016;99:802-16",
"JA López-Rivera, V Smuk, C Leu, G Nasr, D Vegh, A Stefanski, E Pérez-Palma, R Busch, L Jehi, I Najm, I Blümcke, D Lal. Incidence and prevalence of major epilepsy-associated brain lesions.. Epilepsy Behav Rep. 2022;18",
"CT Myers, G Hollingsworth, AM Muir, AL Schneider, Z Thuesmunn, A Knupp, C King, A Lacroix, MG Mehaffey, SF Berkovic, GL Carvill, LG Sadleir, IE Scheffer, HC Mefford. Parental mosaicism in \"de novo\" epileptic encephalopathies.. N Engl J Med. 2018;378:1646-8",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"SF Traynelis, LP Wollmuth, CJ McBain, FS Menniti, KM Vance, KK Ogden, KB Hansen, H Yuan, SJ Myers, R Dingledine. Glutamate receptor ion channels: structure, regulation, and function.. Pharmacol Rev. 2010;62:405-96",
"N Tsuchida, K Hamada, M Shiina, M Kato, Y Kobayashi, J Tohyama, K Kimura, K Hoshino, V Ganesan, KW Teik, M Nakashima, S Mitsuhashi, T Mizuguchi, A Takata, N Miyake, H Saitsu, K Ogata, S Miyatake, N Matsumoto. GRIN2D variants in three cases of developmental and epileptic encephalopathy.. Clin Genet. 2018;94:538-47",
"W Xiang-Wei, V Kannan, Y Xu, GJ Kosobucki, AJ Schulien, H Kusumoto, C Moufawad El Achkar, S Bhattacharya, G Lesca, S Nguyen, KL Helbig, JM Cuisset, CD Fenger, D Marjanovic, E Schuler, Y Wu, X Bao, Y Zhang, N Dirkx, AS Schoonjans, S Syrbe, SJ Myers, A Poduri, E Aizenman, SF Traynelis, JR Lemke, H Yuan, Y Jiang. Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy.. Brain. 2019;142:3009-27"
] |
28/7/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
gr_22q11deletion
|
gr_22q11deletion
|
[
"22q11.2DS",
"22q11.2DS",
"Velocardiofacial Syndrome",
"Autosomal Dominant Opitz G/BBB Syndrome",
"Cayler Cardiofacial Syndrome",
"DiGeorge Syndrome",
"Conotruncal Anomaly Face Syndrome",
"Sedlackova Syndrome",
"Not applicable",
"T-box transcription factor TBX1",
"Not applicable",
"TBX1",
"22q11.2 Deletion Syndrome"
] |
22q11.2 Deletion Syndrome
|
Donna M McDonald-McGinn, Heather S Hain, Beverly S Emanuel, Elaine H Zackai
|
Summary Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS. The diagnosis of 22q11.2DS is established by identification of a heterozygous deletion at chromosome 22q11.2 on chromosomal microarray analysis or other genomic analyses. 22q11.2DS is an autosomal dominant contiguous gene deletion syndrome. In 22q11.2DS caused by a 3.0 (2.54)-Mb deletion, the deletion is
|
DiGeorge syndrome
Velocardiofacial syndrome
Conotruncal anomaly face syndrome
Autosomal dominant Opitz G/BBB syndrome
Sedlackova syndrome
Cayler cardiofacial syndrome
For synonyms and outdated names see
• DiGeorge syndrome
• Velocardiofacial syndrome
• Conotruncal anomaly face syndrome
• Autosomal dominant Opitz G/BBB syndrome
• Sedlackova syndrome
• Cayler cardiofacial syndrome
## Diagnosis
22q11.2 deletion syndrome (22q11.2DS)
Congenital heart disease (in 64% of individuals), particularly conotruncal defects (e.g., ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, truncus arteriosus)
Palatal abnormalities (in 67%) including velopharyngeal insufficiency, submucosal cleft palate, bifid uvula, cleft palate, and hypernasal speech, dysphagia
Laryngotracheoesophageal abnormalities including vascular ring, laryngeal web, laryngotracheomalacia, and subglottic stenosis
Gastrointestinal anomalies including constipation with or without structural gastrointestinal anomalies (e.g., anteriorly placed/imperforate anus, esophageal atresia, jejunal atresia, intestinal malrotation, Hirschsprung disease), accessory spleens, diaphragmatic hernia, umbilical hernia, and inguinal hernia
Immune deficiency (in 77%) (e.g., frequent infections, thymic hypoplasia)
Autoimmune disorders (e.g., juvenile rheumatoid arthritis, Graves disease, vitiligo)
Ophthalmologic findings including tortuous retinal vessels, ptosis, posterior embryotoxon, sclerocornea, coloboma, cataract, anophthalmia, and strabismus
Other craniofacial features (e.g., hooded eyelids, ear anomalies, prominent nasal bridge, bulbous nose, micrognathia, asymmetric crying facies, craniosynostosis)
Hearing loss (sensorineural and/or conductive)
CNS abnormalities including hypotonia in infancy, microcephaly, polymicrogyria, and seizures (idiopathic or associated with hypocalcemia)
Developmental delay and/or learning difficulties (in 70%-90%), especially a nonverbal learning disability
Psychiatric illness including autism spectrum disorder (20% of children), schizophrenia (25% of adults), attention deficit disorder, anxiety, perseveration, and difficulty with social interactions
Early-onset Parkinson disease
Skeletal anomalies including occipital-cervical anomaly, scoliosis, rib and vertebral anomalies, clubfoot, and polydactyly
Genitourinary tract anomalies including renal anomalies (in 16%) (e.g., hydronephrosis, renal agenesis, multicystic/dysplastic kidney), cryptorchidism, and hypospadias
NOTE: See the National Human Genome Research Institute (NHGRI)
Hypoparathyroidism and hypocalcemia (in 50%)
Growth hormone deficiency
Hypothyroidism
Cytopenias (hemolytic anemia, neutropenia, thrombocytopenia)
The diagnosis of 22q11.2DS is established in a proband by identification of a heterozygous deletion at chromosome 22q11.2 (see
Note: Approximately 5% of individuals with 22q11.2DS have a heterozygous 1.5-Mb deletion extending from LCRs A-B; about 2% have a deletion extending from LCRs A-C; Approximately 5% have a smaller heterozygous deletion extending from LCRs B-D or C-D.
ISCN nomenclature for this deletion:
Note: (1) Since these deletions are recurrent and mediated by segmental duplications, the unique genetic sequence that is deleted is the same in all individuals with each deletion; however, the reported size of the deletion may: (a) may be larger if adjacent segmental duplications are included in the size; and (b) may vary based on the design of the microarray used to detect it (see
Note: (1) Most individuals with a 22q11.2 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2004 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. The early arrays used to detect the 22q11.2 deletion were BAC CGH arrays with approximately 25 kb or less for resolution [
Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 22q11.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is possible to size the deletion routinely by use of targeted methods; in particular, MLPA can be used to detect the different deletion sizes by LCR.
Genomic Testing Used in 22q11.2 Deletion Syndrome
ISCN: seq[GRCh37] del(22)(q11.2) chr22:18,912,231-21,465,672del
ClinGen ID:
See
Standardized ISCN annotation and interpretation for genomic variants from the
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 22q11.2 region.
Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods.
The commercially available fluorescence in situ hybridization (FISH) probes, N25 and TUPLE, along with
Targeted FISH, MLPA, or other quantitative method analysis may be used to test at-risk relatives of a proband who is known to have the 22q11.2 recurrent deletion.
• Congenital heart disease (in 64% of individuals), particularly conotruncal defects (e.g., ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, truncus arteriosus)
• Palatal abnormalities (in 67%) including velopharyngeal insufficiency, submucosal cleft palate, bifid uvula, cleft palate, and hypernasal speech, dysphagia
• Laryngotracheoesophageal abnormalities including vascular ring, laryngeal web, laryngotracheomalacia, and subglottic stenosis
• Gastrointestinal anomalies including constipation with or without structural gastrointestinal anomalies (e.g., anteriorly placed/imperforate anus, esophageal atresia, jejunal atresia, intestinal malrotation, Hirschsprung disease), accessory spleens, diaphragmatic hernia, umbilical hernia, and inguinal hernia
• Immune deficiency (in 77%) (e.g., frequent infections, thymic hypoplasia)
• Autoimmune disorders (e.g., juvenile rheumatoid arthritis, Graves disease, vitiligo)
• Ophthalmologic findings including tortuous retinal vessels, ptosis, posterior embryotoxon, sclerocornea, coloboma, cataract, anophthalmia, and strabismus
• Other craniofacial features (e.g., hooded eyelids, ear anomalies, prominent nasal bridge, bulbous nose, micrognathia, asymmetric crying facies, craniosynostosis)
• Hearing loss (sensorineural and/or conductive)
• CNS abnormalities including hypotonia in infancy, microcephaly, polymicrogyria, and seizures (idiopathic or associated with hypocalcemia)
• Developmental delay and/or learning difficulties (in 70%-90%), especially a nonverbal learning disability
• Psychiatric illness including autism spectrum disorder (20% of children), schizophrenia (25% of adults), attention deficit disorder, anxiety, perseveration, and difficulty with social interactions
• Early-onset Parkinson disease
• Skeletal anomalies including occipital-cervical anomaly, scoliosis, rib and vertebral anomalies, clubfoot, and polydactyly
• Genitourinary tract anomalies including renal anomalies (in 16%) (e.g., hydronephrosis, renal agenesis, multicystic/dysplastic kidney), cryptorchidism, and hypospadias
• Hypoparathyroidism and hypocalcemia (in 50%)
• Growth hormone deficiency
• Hypothyroidism
• Cytopenias (hemolytic anemia, neutropenia, thrombocytopenia)
• Note: (1) Most individuals with a 22q11.2 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2004 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. The early arrays used to detect the 22q11.2 deletion were BAC CGH arrays with approximately 25 kb or less for resolution [
• Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 22q11.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is possible to size the deletion routinely by use of targeted methods; in particular, MLPA can be used to detect the different deletion sizes by LCR.
• ISCN: seq[GRCh37] del(22)(q11.2) chr22:18,912,231-21,465,672del
• ClinGen ID:
## Suggestive Findings
22q11.2 deletion syndrome (22q11.2DS)
Congenital heart disease (in 64% of individuals), particularly conotruncal defects (e.g., ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, truncus arteriosus)
Palatal abnormalities (in 67%) including velopharyngeal insufficiency, submucosal cleft palate, bifid uvula, cleft palate, and hypernasal speech, dysphagia
Laryngotracheoesophageal abnormalities including vascular ring, laryngeal web, laryngotracheomalacia, and subglottic stenosis
Gastrointestinal anomalies including constipation with or without structural gastrointestinal anomalies (e.g., anteriorly placed/imperforate anus, esophageal atresia, jejunal atresia, intestinal malrotation, Hirschsprung disease), accessory spleens, diaphragmatic hernia, umbilical hernia, and inguinal hernia
Immune deficiency (in 77%) (e.g., frequent infections, thymic hypoplasia)
Autoimmune disorders (e.g., juvenile rheumatoid arthritis, Graves disease, vitiligo)
Ophthalmologic findings including tortuous retinal vessels, ptosis, posterior embryotoxon, sclerocornea, coloboma, cataract, anophthalmia, and strabismus
Other craniofacial features (e.g., hooded eyelids, ear anomalies, prominent nasal bridge, bulbous nose, micrognathia, asymmetric crying facies, craniosynostosis)
Hearing loss (sensorineural and/or conductive)
CNS abnormalities including hypotonia in infancy, microcephaly, polymicrogyria, and seizures (idiopathic or associated with hypocalcemia)
Developmental delay and/or learning difficulties (in 70%-90%), especially a nonverbal learning disability
Psychiatric illness including autism spectrum disorder (20% of children), schizophrenia (25% of adults), attention deficit disorder, anxiety, perseveration, and difficulty with social interactions
Early-onset Parkinson disease
Skeletal anomalies including occipital-cervical anomaly, scoliosis, rib and vertebral anomalies, clubfoot, and polydactyly
Genitourinary tract anomalies including renal anomalies (in 16%) (e.g., hydronephrosis, renal agenesis, multicystic/dysplastic kidney), cryptorchidism, and hypospadias
NOTE: See the National Human Genome Research Institute (NHGRI)
Hypoparathyroidism and hypocalcemia (in 50%)
Growth hormone deficiency
Hypothyroidism
Cytopenias (hemolytic anemia, neutropenia, thrombocytopenia)
• Congenital heart disease (in 64% of individuals), particularly conotruncal defects (e.g., ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, truncus arteriosus)
• Palatal abnormalities (in 67%) including velopharyngeal insufficiency, submucosal cleft palate, bifid uvula, cleft palate, and hypernasal speech, dysphagia
• Laryngotracheoesophageal abnormalities including vascular ring, laryngeal web, laryngotracheomalacia, and subglottic stenosis
• Gastrointestinal anomalies including constipation with or without structural gastrointestinal anomalies (e.g., anteriorly placed/imperforate anus, esophageal atresia, jejunal atresia, intestinal malrotation, Hirschsprung disease), accessory spleens, diaphragmatic hernia, umbilical hernia, and inguinal hernia
• Immune deficiency (in 77%) (e.g., frequent infections, thymic hypoplasia)
• Autoimmune disorders (e.g., juvenile rheumatoid arthritis, Graves disease, vitiligo)
• Ophthalmologic findings including tortuous retinal vessels, ptosis, posterior embryotoxon, sclerocornea, coloboma, cataract, anophthalmia, and strabismus
• Other craniofacial features (e.g., hooded eyelids, ear anomalies, prominent nasal bridge, bulbous nose, micrognathia, asymmetric crying facies, craniosynostosis)
• Hearing loss (sensorineural and/or conductive)
• CNS abnormalities including hypotonia in infancy, microcephaly, polymicrogyria, and seizures (idiopathic or associated with hypocalcemia)
• Developmental delay and/or learning difficulties (in 70%-90%), especially a nonverbal learning disability
• Psychiatric illness including autism spectrum disorder (20% of children), schizophrenia (25% of adults), attention deficit disorder, anxiety, perseveration, and difficulty with social interactions
• Early-onset Parkinson disease
• Skeletal anomalies including occipital-cervical anomaly, scoliosis, rib and vertebral anomalies, clubfoot, and polydactyly
• Genitourinary tract anomalies including renal anomalies (in 16%) (e.g., hydronephrosis, renal agenesis, multicystic/dysplastic kidney), cryptorchidism, and hypospadias
• Hypoparathyroidism and hypocalcemia (in 50%)
• Growth hormone deficiency
• Hypothyroidism
• Cytopenias (hemolytic anemia, neutropenia, thrombocytopenia)
## Establishing the Diagnosis
The diagnosis of 22q11.2DS is established in a proband by identification of a heterozygous deletion at chromosome 22q11.2 (see
Note: Approximately 5% of individuals with 22q11.2DS have a heterozygous 1.5-Mb deletion extending from LCRs A-B; about 2% have a deletion extending from LCRs A-C; Approximately 5% have a smaller heterozygous deletion extending from LCRs B-D or C-D.
ISCN nomenclature for this deletion:
Note: (1) Since these deletions are recurrent and mediated by segmental duplications, the unique genetic sequence that is deleted is the same in all individuals with each deletion; however, the reported size of the deletion may: (a) may be larger if adjacent segmental duplications are included in the size; and (b) may vary based on the design of the microarray used to detect it (see
Note: (1) Most individuals with a 22q11.2 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2004 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. The early arrays used to detect the 22q11.2 deletion were BAC CGH arrays with approximately 25 kb or less for resolution [
Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 22q11.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is possible to size the deletion routinely by use of targeted methods; in particular, MLPA can be used to detect the different deletion sizes by LCR.
Genomic Testing Used in 22q11.2 Deletion Syndrome
ISCN: seq[GRCh37] del(22)(q11.2) chr22:18,912,231-21,465,672del
ClinGen ID:
See
Standardized ISCN annotation and interpretation for genomic variants from the
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 22q11.2 region.
Targeted deletion analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods.
The commercially available fluorescence in situ hybridization (FISH) probes, N25 and TUPLE, along with
Targeted FISH, MLPA, or other quantitative method analysis may be used to test at-risk relatives of a proband who is known to have the 22q11.2 recurrent deletion.
• Note: (1) Most individuals with a 22q11.2 recurrent deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) Prior to 2004 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. The early arrays used to detect the 22q11.2 deletion were BAC CGH arrays with approximately 25 kb or less for resolution [
• Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 22q11.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is possible to size the deletion routinely by use of targeted methods; in particular, MLPA can be used to detect the different deletion sizes by LCR.
• ISCN: seq[GRCh37] del(22)(q11.2) chr22:18,912,231-21,465,672del
• ClinGen ID:
## Clinical Characteristics
This section summarizes findings based on publications of individuals with 22q11.2 deletion syndrome (22q11.2DS).
Cardiac Findings in Individuals with 22q11.2 Deletion Syndrome
Includes with and without pulmonary atresia
Includes right aortic arch, vascular ring, double aortic arch, and left aortic arch with aberrant right subclavian artery
Palatal Findings with 22q11.2 Deletion Syndrome
Cleft lip and palate (CLP)
Overt cleft palate
Submucosal cleft palate (SMCP)
CP + VPI
SMCP + VPI
VPI w/out CP
From
Either unilateral or bilateral
Includes classic (5.1%), occult (2.4%), and bifid uvula (13.6%)
No overt abnormality, but children too young to provide an adequate speech sample or poor cooperation
Constipation is a chronic feature in the majority of individuals. In addition, structural anomalies such as imperforate anus, intestinal malrotation, intestinal non-rotation, congenital diaphragmatic hernia, esophageal atresia, tracheoesophageal fistula, Hirschsprung disease, and feeding difficulties secondary to a vascular ring have all been reported and can contribute to significant feeding and swallowing problems and in some instances to constipation [
CD4+ lymphopenia is associated with
Abnormalities of humoral immunity were observed in 17% of individuals [
Palatal dysfunction, gastroesophageal reflux, and aspiration pneumonia can all contribute to recurrent infection, especially in persons with congenital heart disease. Furthermore, dysphagia can lead to poor nutrition, which further impairs cellular immunity. Thus, older children and adults continue to have infections, including 25%-33% with recurrent sinusitis or otitis media and 4%-7% with recurrent lower respiratory infections [
A study of 24 individuals with 22q11.2DS and MRI/ MRA showed more than half (13/24) had significant radiographic findings, including persistent
In 55 toddlers assessed with Bayley Scales, mental development was average in 22%, mildly delayed in 20%, and significantly delayed in 58%. The mean mental developmental index was 67±15, which falls in the significantly delayed range, and the mean psychomotor developmental index was 61±13. Speech and language delays were present in all children assessed. In the same study, in a group of 24 preschoolers assessed using the WPPSI-R, the full-scale IQ was 78±12, the mean performance IQ was 78±12, and the mean verbal IQ was 81±13. In total language, 20% were average, 46% were mildly delayed, and 34% were significantly delayed with receptive language scores higher than expressive [
In a group of 80 school-aged children assessed with the age-appropriate Weschler IQ test, the mean IQ score was 76.8±13.0; 39% attained full-scale IQ scores in the average range, 31% in the low-average range, and 31% in the borderline range [
Older individuals with 22q11.2DS generally have an atypical neuropsychologic profile across multiple domains, the most striking aspect of which is a significantly higher verbal IQ score than performance IQ score.
It has been suggested that 60% of adults have a psychiatric disorder. Most notably, schizophrenia is identified in approximately 25% of individuals; however, anxiety and depressive disorders are also quite common [
The most common extremity manifestation is
Abnormal lung lobation [
Dental carries
Malignancies including hepatoblastoma, renal cell carcinoma, thyroid carcinoma, melanoma, leukemia, Wilms tumor, and neuroblastoma [
Autosomal recessive disorders (reported in individuals with 22q11.2DS and a pathogenic variant of the second allele) including Bernard-Soulier syndrome (caused by a pathogenic variant in
A correlation between CD4+ lymphopenia and deletion breakpoints has been reported. CD3 and CD4 counts were significantly lower in individuals with 22q11.2 proximal deletions (A-B, A-C, A-D) compared to those with nested and distal deletions (B-D, C-D, D-E, D-F) [
Penetrance is complete in the majority of individuals with 22q11.2DS; variability is marked. Nested deletions are often familial and have reduced penetrance and/or a milder expression.
It is now recognized that 22q11.2DS encompasses the phenotypes previously described as DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAF), some cases of autosomal dominant Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (asymmetric crying facies) [
The term DiGeorge syndrome is now reserved for individuals who have clinical features of 22q11.2DS but do not have an identified 22q11.2 deletion.
Autosomal dominant Opitz G/BBB syndrome may also be referred to as hypertelorism with esophageal abnormality and hypospadias.
22q11.2DS is the most frequent chromosome microdeletion syndrome. In a population-based study in Sweden, the mean annual incidence was 14.1:100,000 live births [
• Cleft lip and palate (CLP)
• Overt cleft palate
• Submucosal cleft palate (SMCP)
• CP + VPI
• SMCP + VPI
• VPI w/out CP
• Abnormal lung lobation [
• Dental carries
• Malignancies including hepatoblastoma, renal cell carcinoma, thyroid carcinoma, melanoma, leukemia, Wilms tumor, and neuroblastoma [
• Autosomal recessive disorders (reported in individuals with 22q11.2DS and a pathogenic variant of the second allele) including Bernard-Soulier syndrome (caused by a pathogenic variant in
## Clinical Description
This section summarizes findings based on publications of individuals with 22q11.2 deletion syndrome (22q11.2DS).
Cardiac Findings in Individuals with 22q11.2 Deletion Syndrome
Includes with and without pulmonary atresia
Includes right aortic arch, vascular ring, double aortic arch, and left aortic arch with aberrant right subclavian artery
Palatal Findings with 22q11.2 Deletion Syndrome
Cleft lip and palate (CLP)
Overt cleft palate
Submucosal cleft palate (SMCP)
CP + VPI
SMCP + VPI
VPI w/out CP
From
Either unilateral or bilateral
Includes classic (5.1%), occult (2.4%), and bifid uvula (13.6%)
No overt abnormality, but children too young to provide an adequate speech sample or poor cooperation
Constipation is a chronic feature in the majority of individuals. In addition, structural anomalies such as imperforate anus, intestinal malrotation, intestinal non-rotation, congenital diaphragmatic hernia, esophageal atresia, tracheoesophageal fistula, Hirschsprung disease, and feeding difficulties secondary to a vascular ring have all been reported and can contribute to significant feeding and swallowing problems and in some instances to constipation [
CD4+ lymphopenia is associated with
Abnormalities of humoral immunity were observed in 17% of individuals [
Palatal dysfunction, gastroesophageal reflux, and aspiration pneumonia can all contribute to recurrent infection, especially in persons with congenital heart disease. Furthermore, dysphagia can lead to poor nutrition, which further impairs cellular immunity. Thus, older children and adults continue to have infections, including 25%-33% with recurrent sinusitis or otitis media and 4%-7% with recurrent lower respiratory infections [
A study of 24 individuals with 22q11.2DS and MRI/ MRA showed more than half (13/24) had significant radiographic findings, including persistent
In 55 toddlers assessed with Bayley Scales, mental development was average in 22%, mildly delayed in 20%, and significantly delayed in 58%. The mean mental developmental index was 67±15, which falls in the significantly delayed range, and the mean psychomotor developmental index was 61±13. Speech and language delays were present in all children assessed. In the same study, in a group of 24 preschoolers assessed using the WPPSI-R, the full-scale IQ was 78±12, the mean performance IQ was 78±12, and the mean verbal IQ was 81±13. In total language, 20% were average, 46% were mildly delayed, and 34% were significantly delayed with receptive language scores higher than expressive [
In a group of 80 school-aged children assessed with the age-appropriate Weschler IQ test, the mean IQ score was 76.8±13.0; 39% attained full-scale IQ scores in the average range, 31% in the low-average range, and 31% in the borderline range [
Older individuals with 22q11.2DS generally have an atypical neuropsychologic profile across multiple domains, the most striking aspect of which is a significantly higher verbal IQ score than performance IQ score.
It has been suggested that 60% of adults have a psychiatric disorder. Most notably, schizophrenia is identified in approximately 25% of individuals; however, anxiety and depressive disorders are also quite common [
The most common extremity manifestation is
Abnormal lung lobation [
Dental carries
Malignancies including hepatoblastoma, renal cell carcinoma, thyroid carcinoma, melanoma, leukemia, Wilms tumor, and neuroblastoma [
Autosomal recessive disorders (reported in individuals with 22q11.2DS and a pathogenic variant of the second allele) including Bernard-Soulier syndrome (caused by a pathogenic variant in
• Cleft lip and palate (CLP)
• Overt cleft palate
• Submucosal cleft palate (SMCP)
• CP + VPI
• SMCP + VPI
• VPI w/out CP
• Abnormal lung lobation [
• Dental carries
• Malignancies including hepatoblastoma, renal cell carcinoma, thyroid carcinoma, melanoma, leukemia, Wilms tumor, and neuroblastoma [
• Autosomal recessive disorders (reported in individuals with 22q11.2DS and a pathogenic variant of the second allele) including Bernard-Soulier syndrome (caused by a pathogenic variant in
## Genotype-Phenotype Correlations
A correlation between CD4+ lymphopenia and deletion breakpoints has been reported. CD3 and CD4 counts were significantly lower in individuals with 22q11.2 proximal deletions (A-B, A-C, A-D) compared to those with nested and distal deletions (B-D, C-D, D-E, D-F) [
## Penetrance
Penetrance is complete in the majority of individuals with 22q11.2DS; variability is marked. Nested deletions are often familial and have reduced penetrance and/or a milder expression.
## Nomenclature
It is now recognized that 22q11.2DS encompasses the phenotypes previously described as DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CTAF), some cases of autosomal dominant Opitz G/BBB syndrome, and Cayler cardiofacial syndrome (asymmetric crying facies) [
The term DiGeorge syndrome is now reserved for individuals who have clinical features of 22q11.2DS but do not have an identified 22q11.2 deletion.
Autosomal dominant Opitz G/BBB syndrome may also be referred to as hypertelorism with esophageal abnormality and hypospadias.
## Prevalence
22q11.2DS is the most frequent chromosome microdeletion syndrome. In a population-based study in Sweden, the mean annual incidence was 14.1:100,000 live births [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
A small percentage (<1%) of individuals with clinical findings of 22q11.2DS have chromosome rearrangements involving 22q11.2, such as a translocation between chromosome 22 and another autosome.
## Differential Diagnosis
All of the clinical findings associated with 22q11.2 deletion syndrome (22q11.2DS) can also occur as an isolated anomaly in an otherwise healthy individual. Genetic disorders and teratogenic exposures that may cause a clinical phenotype similar to 22q11.2DS are discussed in this section.
Genes of Interest in the Differential Diagnosis of 22q11.2 Deletion Syndrome
AD = autosomal dominant; AR = autosomal recessive; CHARGE =
Pathogenic variants in
VACTERL association (when congenital heart disease, vertebral, renal, and limb anomalies are present). VATER association is a diagnosis of exclusion without an established etiology to date (OMIM
Oculoauriculovertebral (Goldenhar) syndrome (OAVS) (when ear anomalies, vertebral defects, heart disease, renal anomalies are present) (OMIM
• VACTERL association (when congenital heart disease, vertebral, renal, and limb anomalies are present). VATER association is a diagnosis of exclusion without an established etiology to date (OMIM
• Oculoauriculovertebral (Goldenhar) syndrome (OAVS) (when ear anomalies, vertebral defects, heart disease, renal anomalies are present) (OMIM
## Single-Gene Disorders
Genes of Interest in the Differential Diagnosis of 22q11.2 Deletion Syndrome
AD = autosomal dominant; AR = autosomal recessive; CHARGE =
Pathogenic variants in
## Chromosome Disorders
## Other
VACTERL association (when congenital heart disease, vertebral, renal, and limb anomalies are present). VATER association is a diagnosis of exclusion without an established etiology to date (OMIM
Oculoauriculovertebral (Goldenhar) syndrome (OAVS) (when ear anomalies, vertebral defects, heart disease, renal anomalies are present) (OMIM
• VACTERL association (when congenital heart disease, vertebral, renal, and limb anomalies are present). VATER association is a diagnosis of exclusion without an established etiology to date (OMIM
• Oculoauriculovertebral (Goldenhar) syndrome (OAVS) (when ear anomalies, vertebral defects, heart disease, renal anomalies are present) (OMIM
## Management
Clinical practice guidelines for the evaluation and treatment of individuals with 22q11.2 deletion syndrome (22q11.2DS) have been published. See
To establish the extent of disease and needs of an individual diagnosed with 22q11.2DS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with 22q11.2 Deletion Syndrome
Clinical eval of the palate
Consider assessment of carotid arteries prior to surgical procedures involving the pharynx.
Consider effects on speech prior to adenoidectomy.
To screen for palatal anomalies that may affect feeding & speech development
Consider pre- & postoperative sleep studies when performing pharyngeal procedures.
A ↓ absolute lymphocyte count necessitates eval of T- & B-cell subsets & referral to immunologist.
Immunologic eval; may incl flow cytometry, immunoglobulins, & T-cell function
Serum ionized calcium
Intact parathyroid hormone
To assess for hypoparathyroidism
Endocrinology eval if abnormal
By age 1 yr
Referral to early intervention
In those w/anxiety, mood disorder, behavioral differences, or frank psychosis
In teens & adults: incl assessment for at-risk behaviors.
Treatment of Manifestations in Individuals with 22q11.2 Deletion Syndrome
Modification of spoon placement when eating
Standard treatment for gastroesophageal reflux w/acid blockade
Prokinetic agents
Postural therapy
Standard treatment for gastrointestinal dysmotility & to facilitate bowel evacuation
OT, PT, & speech therapy
Introduction of sign language by age 1 yr
Educational & behavioral therapy
OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with 22q11.2 Deletion Syndrome
Every 3-6 mos in infancy, every 5 yrs through childhood, then every 1-2 yrs
Preoperatively & postoperatively
Regularly during pregnancy
VPI = velopharyngeal incompetence
Infants with lymphocyte abnormalities should not be immunized with live vaccines (e.g., oral polio, MMR).
Carbonated drinks and alcohol consumption may exacerbate hypocalcemia.
Caffeine intake may contribute to or worsen anxiety.
It is appropriate to clarify the genetic status of apparently asymptomatic sibs and parents of an affected individual in order to identify as early as possible those family members who would benefit from cardiac and immunologic evaluation and evaluations and surveillance for other complications of 22q11.2DS.
See
Pregnant women must be monitored medically, taking into account any preexisting conditions including congenital heart disease, scoliosis, and reactive airway disease. Additional surveillance should include calcium, thyroid, and platelet levels. In addition, individuals with changes in mental status/behavior should be referred for immediate evaluation by a mental health care provider.
A fetus at high risk of having 22q11.2DS should undergo a level II ultrasound with fetal echocardiogram to evaluate for the following anomalies: congenital heart disease; airway, palate, swallowing, and gastrointestinal differences possibly leading to polyhydramnios (congenital diaphragmatic hernia, tracheoesophageal fistula, subglottic stenosis, vascular ring, laryngeal web, cleft palate, and cleft and lip/palate); renal anomalies; skeletal differences such as club foot and craniosynostosis; and umbilical and inguinal hernia.
Search
• Clinical eval of the palate
• Consider assessment of carotid arteries prior to surgical procedures involving the pharynx.
• Consider effects on speech prior to adenoidectomy.
• To screen for palatal anomalies that may affect feeding & speech development
• Consider pre- & postoperative sleep studies when performing pharyngeal procedures.
• A ↓ absolute lymphocyte count necessitates eval of T- & B-cell subsets & referral to immunologist.
• Immunologic eval; may incl flow cytometry, immunoglobulins, & T-cell function
• Serum ionized calcium
• Intact parathyroid hormone
• To assess for hypoparathyroidism
• Endocrinology eval if abnormal
• By age 1 yr
• Referral to early intervention
• In those w/anxiety, mood disorder, behavioral differences, or frank psychosis
• In teens & adults: incl assessment for at-risk behaviors.
• Modification of spoon placement when eating
• Standard treatment for gastroesophageal reflux w/acid blockade
• Prokinetic agents
• Postural therapy
• Standard treatment for gastrointestinal dysmotility & to facilitate bowel evacuation
• OT, PT, & speech therapy
• Introduction of sign language by age 1 yr
• Educational & behavioral therapy
• Every 3-6 mos in infancy, every 5 yrs through childhood, then every 1-2 yrs
• Preoperatively & postoperatively
• Regularly during pregnancy
## Evaluations Following Initial Diagnosis
Clinical practice guidelines for the evaluation and treatment of individuals with 22q11.2 deletion syndrome (22q11.2DS) have been published. See
To establish the extent of disease and needs of an individual diagnosed with 22q11.2DS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with 22q11.2 Deletion Syndrome
Clinical eval of the palate
Consider assessment of carotid arteries prior to surgical procedures involving the pharynx.
Consider effects on speech prior to adenoidectomy.
To screen for palatal anomalies that may affect feeding & speech development
Consider pre- & postoperative sleep studies when performing pharyngeal procedures.
A ↓ absolute lymphocyte count necessitates eval of T- & B-cell subsets & referral to immunologist.
Immunologic eval; may incl flow cytometry, immunoglobulins, & T-cell function
Serum ionized calcium
Intact parathyroid hormone
To assess for hypoparathyroidism
Endocrinology eval if abnormal
By age 1 yr
Referral to early intervention
In those w/anxiety, mood disorder, behavioral differences, or frank psychosis
In teens & adults: incl assessment for at-risk behaviors.
• Clinical eval of the palate
• Consider assessment of carotid arteries prior to surgical procedures involving the pharynx.
• Consider effects on speech prior to adenoidectomy.
• To screen for palatal anomalies that may affect feeding & speech development
• Consider pre- & postoperative sleep studies when performing pharyngeal procedures.
• A ↓ absolute lymphocyte count necessitates eval of T- & B-cell subsets & referral to immunologist.
• Immunologic eval; may incl flow cytometry, immunoglobulins, & T-cell function
• Serum ionized calcium
• Intact parathyroid hormone
• To assess for hypoparathyroidism
• Endocrinology eval if abnormal
• By age 1 yr
• Referral to early intervention
• In those w/anxiety, mood disorder, behavioral differences, or frank psychosis
• In teens & adults: incl assessment for at-risk behaviors.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with 22q11.2 Deletion Syndrome
Modification of spoon placement when eating
Standard treatment for gastroesophageal reflux w/acid blockade
Prokinetic agents
Postural therapy
Standard treatment for gastrointestinal dysmotility & to facilitate bowel evacuation
OT, PT, & speech therapy
Introduction of sign language by age 1 yr
Educational & behavioral therapy
OT = occupational therapy; PT = physical therapy
• Modification of spoon placement when eating
• Standard treatment for gastroesophageal reflux w/acid blockade
• Prokinetic agents
• Postural therapy
• Standard treatment for gastrointestinal dysmotility & to facilitate bowel evacuation
• OT, PT, & speech therapy
• Introduction of sign language by age 1 yr
• Educational & behavioral therapy
## Surveillance
Recommended Surveillance for Individuals with 22q11.2 Deletion Syndrome
Every 3-6 mos in infancy, every 5 yrs through childhood, then every 1-2 yrs
Preoperatively & postoperatively
Regularly during pregnancy
VPI = velopharyngeal incompetence
• Every 3-6 mos in infancy, every 5 yrs through childhood, then every 1-2 yrs
• Preoperatively & postoperatively
• Regularly during pregnancy
## Agents/Circumstances to Avoid
Infants with lymphocyte abnormalities should not be immunized with live vaccines (e.g., oral polio, MMR).
Carbonated drinks and alcohol consumption may exacerbate hypocalcemia.
Caffeine intake may contribute to or worsen anxiety.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic sibs and parents of an affected individual in order to identify as early as possible those family members who would benefit from cardiac and immunologic evaluation and evaluations and surveillance for other complications of 22q11.2DS.
See
## Pregnancy Management
Pregnant women must be monitored medically, taking into account any preexisting conditions including congenital heart disease, scoliosis, and reactive airway disease. Additional surveillance should include calcium, thyroid, and platelet levels. In addition, individuals with changes in mental status/behavior should be referred for immediate evaluation by a mental health care provider.
A fetus at high risk of having 22q11.2DS should undergo a level II ultrasound with fetal echocardiogram to evaluate for the following anomalies: congenital heart disease; airway, palate, swallowing, and gastrointestinal differences possibly leading to polyhydramnios (congenital diaphragmatic hernia, tracheoesophageal fistula, subglottic stenosis, vascular ring, laryngeal web, cleft palate, and cleft and lip/palate); renal anomalies; skeletal differences such as club foot and craniosynostosis; and umbilical and inguinal hernia.
## Therapies Under Investigation
Search
## Genetic Counseling
22q11.2 deletion syndrome (22q11.2DS) is a contiguous gene deletion syndrome inherited in an autosomal dominant manner.
In 22q11.2DS caused by a 3.0 (2.54)-Mb deletion, the deletion is
The proportion of individuals with a nested deletion (i.e., a recurrent, atypical shorter deleted segment [LCR22B-D] nested within the large typically deleted region) inherited from an affected parent is higher (60%).
Genomic testing capable of identifying the deletion identified in the proband is recommended for the parents of a proband in order to reliably determine recurrence risk.
If the 22q11.2 deletion cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with 22q11.2DS may appear to be negative because of failure to recognize the disorder in family members because of clinical variability and/or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless the parents have been tested for the 22q11.2 deletion identified in the proband.
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. Apparently asymptomatic adults with somatic mosaicism have been identified [
If a parent is affected and/or is known to have a 22q11.2 deletion, the risk to the sibs is 50%. The phenotype in a sib who inherits the deletion cannot be predicted because 22q11.2DS is associated with significant intrafamilial clinical variability.
If the 22q11.2 deletion identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
If the parents have not been tested for the 22q11.2 deletion but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for 22q11.2DS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
In the (unlikely) event that a parent has a balanced structural chromosome rearrangement involving the 22q11.2 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• In 22q11.2DS caused by a 3.0 (2.54)-Mb deletion, the deletion is
• The proportion of individuals with a nested deletion (i.e., a recurrent, atypical shorter deleted segment [LCR22B-D] nested within the large typically deleted region) inherited from an affected parent is higher (60%).
• Genomic testing capable of identifying the deletion identified in the proband is recommended for the parents of a proband in order to reliably determine recurrence risk.
• If the 22q11.2 deletion cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with 22q11.2DS may appear to be negative because of failure to recognize the disorder in family members because of clinical variability and/or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless the parents have been tested for the 22q11.2 deletion identified in the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. Apparently asymptomatic adults with somatic mosaicism have been identified [
• If a parent is affected and/or is known to have a 22q11.2 deletion, the risk to the sibs is 50%. The phenotype in a sib who inherits the deletion cannot be predicted because 22q11.2DS is associated with significant intrafamilial clinical variability.
• If the 22q11.2 deletion identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• If the parents have not been tested for the 22q11.2 deletion but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for 22q11.2DS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
• In the (unlikely) event that a parent has a balanced structural chromosome rearrangement involving the 22q11.2 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
22q11.2 deletion syndrome (22q11.2DS) is a contiguous gene deletion syndrome inherited in an autosomal dominant manner.
## Risk to Family Members
In 22q11.2DS caused by a 3.0 (2.54)-Mb deletion, the deletion is
The proportion of individuals with a nested deletion (i.e., a recurrent, atypical shorter deleted segment [LCR22B-D] nested within the large typically deleted region) inherited from an affected parent is higher (60%).
Genomic testing capable of identifying the deletion identified in the proband is recommended for the parents of a proband in order to reliably determine recurrence risk.
If the 22q11.2 deletion cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with 22q11.2DS may appear to be negative because of failure to recognize the disorder in family members because of clinical variability and/or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless the parents have been tested for the 22q11.2 deletion identified in the proband.
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. Apparently asymptomatic adults with somatic mosaicism have been identified [
If a parent is affected and/or is known to have a 22q11.2 deletion, the risk to the sibs is 50%. The phenotype in a sib who inherits the deletion cannot be predicted because 22q11.2DS is associated with significant intrafamilial clinical variability.
If the 22q11.2 deletion identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
If the parents have not been tested for the 22q11.2 deletion but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for 22q11.2DS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
In the (unlikely) event that a parent has a balanced structural chromosome rearrangement involving the 22q11.2 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• In 22q11.2DS caused by a 3.0 (2.54)-Mb deletion, the deletion is
• The proportion of individuals with a nested deletion (i.e., a recurrent, atypical shorter deleted segment [LCR22B-D] nested within the large typically deleted region) inherited from an affected parent is higher (60%).
• Genomic testing capable of identifying the deletion identified in the proband is recommended for the parents of a proband in order to reliably determine recurrence risk.
• If the 22q11.2 deletion cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with 22q11.2DS may appear to be negative because of failure to recognize the disorder in family members because of clinical variability and/or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless the parents have been tested for the 22q11.2 deletion identified in the proband.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. Apparently asymptomatic adults with somatic mosaicism have been identified [
• If a parent is affected and/or is known to have a 22q11.2 deletion, the risk to the sibs is 50%. The phenotype in a sib who inherits the deletion cannot be predicted because 22q11.2DS is associated with significant intrafamilial clinical variability.
• If the 22q11.2 deletion identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
• If the parents have not been tested for the 22q11.2 deletion but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for 22q11.2DS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.
• In the (unlikely) event that a parent has a balanced structural chromosome rearrangement involving the 22q11.2 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
## Resources
P.O. Box 2269
Cinnaminson NJ 08077
15 Meridian Avenue
Stourbridge West Midlands DY8 1049
United Kingdom
•
• P.O. Box 2269
• Cinnaminson NJ 08077
•
•
• 15 Meridian Avenue
• Stourbridge West Midlands DY8 1049
• United Kingdom
•
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
22q11.2 Deletion Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for 22q11.2 Deletion Syndrome (
The 3.0-Mb deletion at chromosome 22q11.2 (referred to in CMA nomenclature as a 2.54-Mb deletion with coordinates ~18912231-21465672, genome build
More than 85% of individuals with a 22q11.2 deletion have deletions in the same ~3.0-Mb (2.54-Mb by CMA) region; the remainder have either variant deletion endpoints or recurrent, atypical shorter deleted segments nested within the large typically deleted region (TDR) (see
3.0 (2.54)-Mb del:
2-Mb atypical del: ISCN: NA
1.5-Mb del:
Distal deletion:
A small 20-kb deletion within the TDR was reported in an individual with a classic VCFS/DGS phenotype [
A small number of individuals have the deletion as the result of unbalanced translocations that delete the 22pter → q11 region. (For more information, see
• 3.0 (2.54)-Mb del:
• 2-Mb atypical del: ISCN: NA
• 1.5-Mb del:
• Distal deletion:
## Molecular Pathogenesis
The 3.0-Mb deletion at chromosome 22q11.2 (referred to in CMA nomenclature as a 2.54-Mb deletion with coordinates ~18912231-21465672, genome build
More than 85% of individuals with a 22q11.2 deletion have deletions in the same ~3.0-Mb (2.54-Mb by CMA) region; the remainder have either variant deletion endpoints or recurrent, atypical shorter deleted segments nested within the large typically deleted region (TDR) (see
3.0 (2.54)-Mb del:
2-Mb atypical del: ISCN: NA
1.5-Mb del:
Distal deletion:
A small 20-kb deletion within the TDR was reported in an individual with a classic VCFS/DGS phenotype [
A small number of individuals have the deletion as the result of unbalanced translocations that delete the 22pter → q11 region. (For more information, see
• 3.0 (2.54)-Mb del:
• 2-Mb atypical del: ISCN: NA
• 1.5-Mb del:
• Distal deletion:
## Chapter Notes
8 May 2025 (aa) Revision:
9 May 2024 (ma) Revision: thymus tissue implantation
27 February 2020 (sw) Comprehensive update posted live
28 February 2013 (me) Comprehensive update posted live
16 December 2005 (me) Comprehensive update posted live
23 July 2003 (me) Comprehensive update posted live
23 September 1999 (me) Review posted live
7 August 1998 (dmm) Original submission
• 8 May 2025 (aa) Revision:
• 9 May 2024 (ma) Revision: thymus tissue implantation
• 27 February 2020 (sw) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 16 December 2005 (me) Comprehensive update posted live
• 23 July 2003 (me) Comprehensive update posted live
• 23 September 1999 (me) Review posted live
• 7 August 1998 (dmm) Original submission
## Revision History
8 May 2025 (aa) Revision:
9 May 2024 (ma) Revision: thymus tissue implantation
27 February 2020 (sw) Comprehensive update posted live
28 February 2013 (me) Comprehensive update posted live
16 December 2005 (me) Comprehensive update posted live
23 July 2003 (me) Comprehensive update posted live
23 September 1999 (me) Review posted live
7 August 1998 (dmm) Original submission
• 8 May 2025 (aa) Revision:
• 9 May 2024 (ma) Revision: thymus tissue implantation
• 27 February 2020 (sw) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 16 December 2005 (me) Comprehensive update posted live
• 23 July 2003 (me) Comprehensive update posted live
• 23 September 1999 (me) Review posted live
• 7 August 1998 (dmm) Original submission
## References
## Literature Cited
The majority of affected individuals (85%) have a 2.54-Mb deletion encompassing approximately 40 genes; a subset of individuals have a smaller atypical or "nested" deletion.
Adapted from
|
[] |
23/9/1999
|
27/2/2020
|
8/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
gr_22q13_3
|
gr_22q13_3
|
[
"22q13.3 Deletion Syndrome",
"22q13.3 Deletion Syndrome",
"SH3 and multiple ankyrin repeat domains protein 3",
"SHANK3",
"Phelan-McDermid Syndrome-SHANK3 Related"
] |
Phelan-McDermid Syndrome-
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Katy Phelan, R Curtis Rogers, Luigi Boccuto
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Summary Phelan-McDermid syndrome- The diagnosis of PMS- PMS- Once a 22q13.3 deletion involving
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## Diagnosis
No clinical diagnostic criteria have been established for Phelan-McDermid syndrome-
PMS-
Moderate-to-profound developmental delay (DD) or intellectual disability (ID) with absent to severely delayed speech
AND
Any of the following features presenting in infancy or childhood:
Minor dysmorphic facial features (see
Generalized hypotonia
Decreased perspiration and/or tendency to overheat
Normal stature and head circumference for age and sex
Neurobehavioral/psychiatric manifestations including mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like features
Regression / loss of skills
Epilepsy
Sleep disturbances, including difficulty falling asleep and staying asleep, hypersomnia, and parasomnias
The diagnosis of PMS-
A 9-Mb heterozygous deletion at chromosome 22q13.3 with involvement of at least part of
A heterozygous pathogenic (or likely pathogenic) variant in
A chromosomal rearrangement with breakpoints disrupting
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: It is imperative that the identification of terminal deletions by CMA be followed by
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Karyotype screening for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by CMA.
If the phenotype is consistent with PMS-
Molecular Genetic Testing Used in Phelan-McDermid Syndrome-
See
See
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 22q13.3 region.
According to the Phelan-McDermid Syndrome DataHub (last updated in 2021), of 537 individuals with microarray and/or sequencing results, 464 (86.4%) have terminal or interstitial deletions and 73 (13.6%) have
Disruption of
Although some 22q13 deletions may be visible by karyotype, CMA is recommended to detect submicroscopic deletions. Karyotype may be necessary to characterize complex rearrangements (e.g., recombinant chromosomes resulting from a parental inversion). Follow-up karyotype of deletions detected by CMA is essential because of the risk for
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Intragenic
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
• Moderate-to-profound developmental delay (DD) or intellectual disability (ID) with absent to severely delayed speech
• Any of the following features presenting in infancy or childhood:
• Minor dysmorphic facial features (see
• Generalized hypotonia
• Decreased perspiration and/or tendency to overheat
• Normal stature and head circumference for age and sex
• Neurobehavioral/psychiatric manifestations including mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like features
• Regression / loss of skills
• Epilepsy
• Sleep disturbances, including difficulty falling asleep and staying asleep, hypersomnia, and parasomnias
• Minor dysmorphic facial features (see
• Generalized hypotonia
• Decreased perspiration and/or tendency to overheat
• Normal stature and head circumference for age and sex
• Neurobehavioral/psychiatric manifestations including mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like features
• Regression / loss of skills
• Epilepsy
• Sleep disturbances, including difficulty falling asleep and staying asleep, hypersomnia, and parasomnias
• Minor dysmorphic facial features (see
• Generalized hypotonia
• Decreased perspiration and/or tendency to overheat
• Normal stature and head circumference for age and sex
• Neurobehavioral/psychiatric manifestations including mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like features
• Regression / loss of skills
• Epilepsy
• Sleep disturbances, including difficulty falling asleep and staying asleep, hypersomnia, and parasomnias
• A 9-Mb heterozygous deletion at chromosome 22q13.3 with involvement of at least part of
• A heterozygous pathogenic (or likely pathogenic) variant in
• A chromosomal rearrangement with breakpoints disrupting
## Suggestive Findings
PMS-
Moderate-to-profound developmental delay (DD) or intellectual disability (ID) with absent to severely delayed speech
AND
Any of the following features presenting in infancy or childhood:
Minor dysmorphic facial features (see
Generalized hypotonia
Decreased perspiration and/or tendency to overheat
Normal stature and head circumference for age and sex
Neurobehavioral/psychiatric manifestations including mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like features
Regression / loss of skills
Epilepsy
Sleep disturbances, including difficulty falling asleep and staying asleep, hypersomnia, and parasomnias
• Moderate-to-profound developmental delay (DD) or intellectual disability (ID) with absent to severely delayed speech
• Any of the following features presenting in infancy or childhood:
• Minor dysmorphic facial features (see
• Generalized hypotonia
• Decreased perspiration and/or tendency to overheat
• Normal stature and head circumference for age and sex
• Neurobehavioral/psychiatric manifestations including mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like features
• Regression / loss of skills
• Epilepsy
• Sleep disturbances, including difficulty falling asleep and staying asleep, hypersomnia, and parasomnias
• Minor dysmorphic facial features (see
• Generalized hypotonia
• Decreased perspiration and/or tendency to overheat
• Normal stature and head circumference for age and sex
• Neurobehavioral/psychiatric manifestations including mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like features
• Regression / loss of skills
• Epilepsy
• Sleep disturbances, including difficulty falling asleep and staying asleep, hypersomnia, and parasomnias
• Minor dysmorphic facial features (see
• Generalized hypotonia
• Decreased perspiration and/or tendency to overheat
• Normal stature and head circumference for age and sex
• Neurobehavioral/psychiatric manifestations including mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like features
• Regression / loss of skills
• Epilepsy
• Sleep disturbances, including difficulty falling asleep and staying asleep, hypersomnia, and parasomnias
## Establishing the Diagnosis
The diagnosis of PMS-
A 9-Mb heterozygous deletion at chromosome 22q13.3 with involvement of at least part of
A heterozygous pathogenic (or likely pathogenic) variant in
A chromosomal rearrangement with breakpoints disrupting
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Note: It is imperative that the identification of terminal deletions by CMA be followed by
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Karyotype screening for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by CMA.
If the phenotype is consistent with PMS-
Molecular Genetic Testing Used in Phelan-McDermid Syndrome-
See
See
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 22q13.3 region.
According to the Phelan-McDermid Syndrome DataHub (last updated in 2021), of 537 individuals with microarray and/or sequencing results, 464 (86.4%) have terminal or interstitial deletions and 73 (13.6%) have
Disruption of
Although some 22q13 deletions may be visible by karyotype, CMA is recommended to detect submicroscopic deletions. Karyotype may be necessary to characterize complex rearrangements (e.g., recombinant chromosomes resulting from a parental inversion). Follow-up karyotype of deletions detected by CMA is essential because of the risk for
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Intragenic
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
• A 9-Mb heterozygous deletion at chromosome 22q13.3 with involvement of at least part of
• A heterozygous pathogenic (or likely pathogenic) variant in
• A chromosomal rearrangement with breakpoints disrupting
## Option 1
Note: It is imperative that the identification of terminal deletions by CMA be followed by
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
## Karyotype
Karyotype screening for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by CMA.
If the phenotype is consistent with PMS-
Molecular Genetic Testing Used in Phelan-McDermid Syndrome-
See
See
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 22q13.3 region.
According to the Phelan-McDermid Syndrome DataHub (last updated in 2021), of 537 individuals with microarray and/or sequencing results, 464 (86.4%) have terminal or interstitial deletions and 73 (13.6%) have
Disruption of
Although some 22q13 deletions may be visible by karyotype, CMA is recommended to detect submicroscopic deletions. Karyotype may be necessary to characterize complex rearrangements (e.g., recombinant chromosomes resulting from a parental inversion). Follow-up karyotype of deletions detected by CMA is essential because of the risk for
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Intragenic
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
## Clinical Characteristics
More than 600 individuals have been identified with pathogenic genetic alterations involving
Phelan-McDermid Syndrome-
Unless otherwise specified, data is derived from
Rolling over: eight months
Crawling: approximately 16 months
Walking: approximately three years
Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking.
Gait is typically broad based and unsteady.
Individuals may walk on their toes to achieve balance.
In a study of 21 individuals with PMS-
Receptive communication skills are more advanced than expressive language skills, as evidenced by the ability of affected children to follow simple commands, demonstrate humor, and express emotions.
Developmental assessment using the Developmental Profile II (DPII) and the Scales of Independent Behavior-Revised – Full Scale (SIB-R) demonstrated that while all participants had moderate-to-profound intellectual disability, compared to most children with this level of impairment, those with PMS-
Developmental delay with a maximum developmental age equivalent of three to 4.5 years and more pronounced delays in older individuals than in younger children as measured by the Bayley-II-NL scale of infant development (a trend referred to as "growing into deficit") was reported by one group [
Toilet training is difficult to achieve and requires extreme vigilance by parents and caregivers. Children may stay dry at night but become wet or soiled during the day because they are unable to communicate their needs.
Language in 33% at a mean age of three years;
Motor skills in 50% at a mean age of four years;
Self-help skills in 50% at a mean age of four years;
Social engagement/responsiveness in 33% at a mean age of five years;
Purposeful hand movement in 28% at a mean age of seven years;
Constructive/imaginative play in 22% at a mean age of seven years.
No apparent cause for the regression has been found in a majority of individuals, although infection, changes in hormone status, and stressful life events may be possible triggers [
Autoimmune dysfunction has been proposed as a trigger for regression, with
Additionally, an affected female in her mid-twenties presented with regression and dystonic spastic hemiparesis; she was subsequently diagnosed with concomitant multiple sclerosis that responded to steroid treatment [
Habitual chewing or mouthing
Tooth grinding
Agitation in unfamiliar, noisy, or crowded surroundings
Aggressive behavior, including biting, hair pulling, or pinching, which is seen in approximately 25% of affected individuals
The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately.
The behavior is not self-injurious but is often directed at the parent or caregiver.
Catatonia, which may present after neurologic regression, psychosis, and loss of skills [
Schizophrenia and/or bipolar disorder [
Bipolar disorder is reported more commonly in individuals with small deletions and
Prevalence of schizophrenia or schizoaffective disorder has been estimated at around 5%.
Volumetric MRI in 11 affected children demonstrated decreased volumes of the striatum and left pallidum and reduced volume of the cerebellar vermis, which was associated with increased repetitive behavior severity [
Volumetric investigations have also shown global atrophy of the white matter correlated with structural connectivity losses suggestive of accelerated central nervous system aging [
In individuals with a ring chromosome 22, MRI studies may show
The prevalence of sleep disturbances increases with age, with a rate of 53% in toddlers to 90% in adults [
The primary sleep disturbances include difficulty falling asleep, frequent nighttime awakenings, difficulty returning to sleep after a nighttime awakening event, and hypersomnia and parasomnias, including enuresis, night terrors, sleepwalking, and sleep apnea.
Sleep disturbances are more prevalent in individuals with a
Distinct metabolic profiles indicated a minor disruption of the major metabolic pathways involved in energy production in those with sleep disturbances [
Cortical visual impairment, characterized by extensive use of peripheral vision. Blindness and optic nerve hypoplasia have been associated with cortical visual impairment [
Difficulty in processing cluttered images
Problems with depth perception
A tendency to look away from objects before reaching for them
Cystic kidneys
Renal agenesis or dysplastic kidneys
Hydronephrosis or pyelectasis
Vesicoureteral reflux
Horseshoe kidney
Precautions must be taken to avoid dehydration and nutritional deficits, including zinc deficiency.
Regression and severe psychiatric disorders may accompany worsening gastrointestinal issues [
Two individuals with PMS-
Two affected males with abnormal liver function developed hepatic steatosis [
Weight is not increased, giving some of the children a tall, thin appearance.
Whereas children may have increased height for age, adults tend to fall within the normal range for height.
Most adults are also within the normal range for weight, although inactivity and overeating (possibly a manifestation of compulsive mouthing) result in increased weight gain in approximately 10% of affected individuals.
The majority of cases are found in individuals with 22q13 deletions, occurring in only about 1% of individuals with intragenic
Progressive lymphedema leading to pleural effusions has been reported in a female with PMS-
The characteristics may change over time, particularly if the individual is on anticonvulsants that tend to coarsen the features.
Adults have a more prominent, square jaw and less bulbous-appearing nose.
Other less common features include dolichocephaly, strabismus, and abnormal toenails that may be dysplastic, thin, and flaky in the neonate and toddler but may harden and become ingrown as the individual ages.
Fingernails are usually normal but occasionally may be thin and dysplastic.
In older individuals, behavioral problems tend to subside, developmental abilities improve, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints are reported as less frequent [
Children with a ring chromosome 22 should be monitored for NF2 in the same manner as if they had an affected parent. This includes baseline and annual ocular, dermal, and neurologic examinations between ages two and ten years with annual audiology screening and brain MRI every two years after age ten years [
Mosaicism is particularly common in 22q13 deletion associated with ring chromosomes because of the instability of the ring structure during cell division. Low-level mosaicism for monosomy 22 or dicentric ring chromosome 22 should be interpreted with caution, as either abnormality might represent an in vitro artifact. Despite this, one adult with characteristic features of PMS-
Common features of individuals who have pathogenic variants involving solely
When compared to individuals with larger deletions involving adjacent genes, those with solely
In general, there is a statistically significant correlation between larger deletion sizes and a more significant degree of developmental delay and hypotonia [
Larger deletions are also associated with an increased likelihood of dysmorphic features and medical comorbidities. Individuals with larger deletions are more likely to have renal/urinary tract anomalies and lymphedema compared to those with smaller deletions or pathogenic variants involving
Although there is a tendency for larger deletions to be correlated with more severe intellectual and physical phenotypes than smaller deletions, the correlation is not 100%; individuals with the same size deletion may vary significantly in their presentation [
Although it was previously thought that features of PMS-
Previously referred to as 22q13.3 deletion syndrome to reflect the chromosomal basis of this deletion, the condition was subsequently referred to as Phelan-McDermid syndrome (PMS).
Although the majority of individuals with PMS have a genetic alternation that involves
The prevalence of PMS-
• Rolling over: eight months
• Crawling: approximately 16 months
• Walking: approximately three years
• Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking.
• Gait is typically broad based and unsteady.
• Individuals may walk on their toes to achieve balance.
• Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking.
• Gait is typically broad based and unsteady.
• Individuals may walk on their toes to achieve balance.
• Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking.
• Gait is typically broad based and unsteady.
• Individuals may walk on their toes to achieve balance.
• In a study of 21 individuals with PMS-
• Receptive communication skills are more advanced than expressive language skills, as evidenced by the ability of affected children to follow simple commands, demonstrate humor, and express emotions.
• Developmental assessment using the Developmental Profile II (DPII) and the Scales of Independent Behavior-Revised – Full Scale (SIB-R) demonstrated that while all participants had moderate-to-profound intellectual disability, compared to most children with this level of impairment, those with PMS-
• Developmental delay with a maximum developmental age equivalent of three to 4.5 years and more pronounced delays in older individuals than in younger children as measured by the Bayley-II-NL scale of infant development (a trend referred to as "growing into deficit") was reported by one group [
• Toilet training is difficult to achieve and requires extreme vigilance by parents and caregivers. Children may stay dry at night but become wet or soiled during the day because they are unable to communicate their needs.
• Language in 33% at a mean age of three years;
• Motor skills in 50% at a mean age of four years;
• Self-help skills in 50% at a mean age of four years;
• Social engagement/responsiveness in 33% at a mean age of five years;
• Purposeful hand movement in 28% at a mean age of seven years;
• Constructive/imaginative play in 22% at a mean age of seven years.
• Autoimmune dysfunction has been proposed as a trigger for regression, with
• Additionally, an affected female in her mid-twenties presented with regression and dystonic spastic hemiparesis; she was subsequently diagnosed with concomitant multiple sclerosis that responded to steroid treatment [
• Habitual chewing or mouthing
• Tooth grinding
• Agitation in unfamiliar, noisy, or crowded surroundings
• Aggressive behavior, including biting, hair pulling, or pinching, which is seen in approximately 25% of affected individuals
• The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately.
• The behavior is not self-injurious but is often directed at the parent or caregiver.
• The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately.
• The behavior is not self-injurious but is often directed at the parent or caregiver.
• Catatonia, which may present after neurologic regression, psychosis, and loss of skills [
• Schizophrenia and/or bipolar disorder [
• Bipolar disorder is reported more commonly in individuals with small deletions and
• Prevalence of schizophrenia or schizoaffective disorder has been estimated at around 5%.
• Bipolar disorder is reported more commonly in individuals with small deletions and
• Prevalence of schizophrenia or schizoaffective disorder has been estimated at around 5%.
• The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately.
• The behavior is not self-injurious but is often directed at the parent or caregiver.
• Bipolar disorder is reported more commonly in individuals with small deletions and
• Prevalence of schizophrenia or schizoaffective disorder has been estimated at around 5%.
• Volumetric MRI in 11 affected children demonstrated decreased volumes of the striatum and left pallidum and reduced volume of the cerebellar vermis, which was associated with increased repetitive behavior severity [
• Volumetric investigations have also shown global atrophy of the white matter correlated with structural connectivity losses suggestive of accelerated central nervous system aging [
• In individuals with a ring chromosome 22, MRI studies may show
• The prevalence of sleep disturbances increases with age, with a rate of 53% in toddlers to 90% in adults [
• The primary sleep disturbances include difficulty falling asleep, frequent nighttime awakenings, difficulty returning to sleep after a nighttime awakening event, and hypersomnia and parasomnias, including enuresis, night terrors, sleepwalking, and sleep apnea.
• Sleep disturbances are more prevalent in individuals with a
• Distinct metabolic profiles indicated a minor disruption of the major metabolic pathways involved in energy production in those with sleep disturbances [
• Cortical visual impairment, characterized by extensive use of peripheral vision. Blindness and optic nerve hypoplasia have been associated with cortical visual impairment [
• Difficulty in processing cluttered images
• Problems with depth perception
• A tendency to look away from objects before reaching for them
• Cystic kidneys
• Renal agenesis or dysplastic kidneys
• Hydronephrosis or pyelectasis
• Vesicoureteral reflux
• Horseshoe kidney
• Precautions must be taken to avoid dehydration and nutritional deficits, including zinc deficiency.
• Regression and severe psychiatric disorders may accompany worsening gastrointestinal issues [
• Two individuals with PMS-
• Two affected males with abnormal liver function developed hepatic steatosis [
• Weight is not increased, giving some of the children a tall, thin appearance.
• Whereas children may have increased height for age, adults tend to fall within the normal range for height.
• Most adults are also within the normal range for weight, although inactivity and overeating (possibly a manifestation of compulsive mouthing) result in increased weight gain in approximately 10% of affected individuals.
• The majority of cases are found in individuals with 22q13 deletions, occurring in only about 1% of individuals with intragenic
• Progressive lymphedema leading to pleural effusions has been reported in a female with PMS-
• The characteristics may change over time, particularly if the individual is on anticonvulsants that tend to coarsen the features.
• Adults have a more prominent, square jaw and less bulbous-appearing nose.
• Other less common features include dolichocephaly, strabismus, and abnormal toenails that may be dysplastic, thin, and flaky in the neonate and toddler but may harden and become ingrown as the individual ages.
• Fingernails are usually normal but occasionally may be thin and dysplastic.
• Common features of individuals who have pathogenic variants involving solely
• When compared to individuals with larger deletions involving adjacent genes, those with solely
• In general, there is a statistically significant correlation between larger deletion sizes and a more significant degree of developmental delay and hypotonia [
• Larger deletions are also associated with an increased likelihood of dysmorphic features and medical comorbidities. Individuals with larger deletions are more likely to have renal/urinary tract anomalies and lymphedema compared to those with smaller deletions or pathogenic variants involving
• Although there is a tendency for larger deletions to be correlated with more severe intellectual and physical phenotypes than smaller deletions, the correlation is not 100%; individuals with the same size deletion may vary significantly in their presentation [
## Clinical Description
More than 600 individuals have been identified with pathogenic genetic alterations involving
Phelan-McDermid Syndrome-
Unless otherwise specified, data is derived from
Rolling over: eight months
Crawling: approximately 16 months
Walking: approximately three years
Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking.
Gait is typically broad based and unsteady.
Individuals may walk on their toes to achieve balance.
In a study of 21 individuals with PMS-
Receptive communication skills are more advanced than expressive language skills, as evidenced by the ability of affected children to follow simple commands, demonstrate humor, and express emotions.
Developmental assessment using the Developmental Profile II (DPII) and the Scales of Independent Behavior-Revised – Full Scale (SIB-R) demonstrated that while all participants had moderate-to-profound intellectual disability, compared to most children with this level of impairment, those with PMS-
Developmental delay with a maximum developmental age equivalent of three to 4.5 years and more pronounced delays in older individuals than in younger children as measured by the Bayley-II-NL scale of infant development (a trend referred to as "growing into deficit") was reported by one group [
Toilet training is difficult to achieve and requires extreme vigilance by parents and caregivers. Children may stay dry at night but become wet or soiled during the day because they are unable to communicate their needs.
Language in 33% at a mean age of three years;
Motor skills in 50% at a mean age of four years;
Self-help skills in 50% at a mean age of four years;
Social engagement/responsiveness in 33% at a mean age of five years;
Purposeful hand movement in 28% at a mean age of seven years;
Constructive/imaginative play in 22% at a mean age of seven years.
No apparent cause for the regression has been found in a majority of individuals, although infection, changes in hormone status, and stressful life events may be possible triggers [
Autoimmune dysfunction has been proposed as a trigger for regression, with
Additionally, an affected female in her mid-twenties presented with regression and dystonic spastic hemiparesis; she was subsequently diagnosed with concomitant multiple sclerosis that responded to steroid treatment [
Habitual chewing or mouthing
Tooth grinding
Agitation in unfamiliar, noisy, or crowded surroundings
Aggressive behavior, including biting, hair pulling, or pinching, which is seen in approximately 25% of affected individuals
The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately.
The behavior is not self-injurious but is often directed at the parent or caregiver.
Catatonia, which may present after neurologic regression, psychosis, and loss of skills [
Schizophrenia and/or bipolar disorder [
Bipolar disorder is reported more commonly in individuals with small deletions and
Prevalence of schizophrenia or schizoaffective disorder has been estimated at around 5%.
Volumetric MRI in 11 affected children demonstrated decreased volumes of the striatum and left pallidum and reduced volume of the cerebellar vermis, which was associated with increased repetitive behavior severity [
Volumetric investigations have also shown global atrophy of the white matter correlated with structural connectivity losses suggestive of accelerated central nervous system aging [
In individuals with a ring chromosome 22, MRI studies may show
The prevalence of sleep disturbances increases with age, with a rate of 53% in toddlers to 90% in adults [
The primary sleep disturbances include difficulty falling asleep, frequent nighttime awakenings, difficulty returning to sleep after a nighttime awakening event, and hypersomnia and parasomnias, including enuresis, night terrors, sleepwalking, and sleep apnea.
Sleep disturbances are more prevalent in individuals with a
Distinct metabolic profiles indicated a minor disruption of the major metabolic pathways involved in energy production in those with sleep disturbances [
Cortical visual impairment, characterized by extensive use of peripheral vision. Blindness and optic nerve hypoplasia have been associated with cortical visual impairment [
Difficulty in processing cluttered images
Problems with depth perception
A tendency to look away from objects before reaching for them
Cystic kidneys
Renal agenesis or dysplastic kidneys
Hydronephrosis or pyelectasis
Vesicoureteral reflux
Horseshoe kidney
Precautions must be taken to avoid dehydration and nutritional deficits, including zinc deficiency.
Regression and severe psychiatric disorders may accompany worsening gastrointestinal issues [
Two individuals with PMS-
Two affected males with abnormal liver function developed hepatic steatosis [
Weight is not increased, giving some of the children a tall, thin appearance.
Whereas children may have increased height for age, adults tend to fall within the normal range for height.
Most adults are also within the normal range for weight, although inactivity and overeating (possibly a manifestation of compulsive mouthing) result in increased weight gain in approximately 10% of affected individuals.
The majority of cases are found in individuals with 22q13 deletions, occurring in only about 1% of individuals with intragenic
Progressive lymphedema leading to pleural effusions has been reported in a female with PMS-
The characteristics may change over time, particularly if the individual is on anticonvulsants that tend to coarsen the features.
Adults have a more prominent, square jaw and less bulbous-appearing nose.
Other less common features include dolichocephaly, strabismus, and abnormal toenails that may be dysplastic, thin, and flaky in the neonate and toddler but may harden and become ingrown as the individual ages.
Fingernails are usually normal but occasionally may be thin and dysplastic.
In older individuals, behavioral problems tend to subside, developmental abilities improve, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints are reported as less frequent [
Children with a ring chromosome 22 should be monitored for NF2 in the same manner as if they had an affected parent. This includes baseline and annual ocular, dermal, and neurologic examinations between ages two and ten years with annual audiology screening and brain MRI every two years after age ten years [
Mosaicism is particularly common in 22q13 deletion associated with ring chromosomes because of the instability of the ring structure during cell division. Low-level mosaicism for monosomy 22 or dicentric ring chromosome 22 should be interpreted with caution, as either abnormality might represent an in vitro artifact. Despite this, one adult with characteristic features of PMS-
• Rolling over: eight months
• Crawling: approximately 16 months
• Walking: approximately three years
• Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking.
• Gait is typically broad based and unsteady.
• Individuals may walk on their toes to achieve balance.
• Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking.
• Gait is typically broad based and unsteady.
• Individuals may walk on their toes to achieve balance.
• Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking.
• Gait is typically broad based and unsteady.
• Individuals may walk on their toes to achieve balance.
• In a study of 21 individuals with PMS-
• Receptive communication skills are more advanced than expressive language skills, as evidenced by the ability of affected children to follow simple commands, demonstrate humor, and express emotions.
• Developmental assessment using the Developmental Profile II (DPII) and the Scales of Independent Behavior-Revised – Full Scale (SIB-R) demonstrated that while all participants had moderate-to-profound intellectual disability, compared to most children with this level of impairment, those with PMS-
• Developmental delay with a maximum developmental age equivalent of three to 4.5 years and more pronounced delays in older individuals than in younger children as measured by the Bayley-II-NL scale of infant development (a trend referred to as "growing into deficit") was reported by one group [
• Toilet training is difficult to achieve and requires extreme vigilance by parents and caregivers. Children may stay dry at night but become wet or soiled during the day because they are unable to communicate their needs.
• Language in 33% at a mean age of three years;
• Motor skills in 50% at a mean age of four years;
• Self-help skills in 50% at a mean age of four years;
• Social engagement/responsiveness in 33% at a mean age of five years;
• Purposeful hand movement in 28% at a mean age of seven years;
• Constructive/imaginative play in 22% at a mean age of seven years.
• Autoimmune dysfunction has been proposed as a trigger for regression, with
• Additionally, an affected female in her mid-twenties presented with regression and dystonic spastic hemiparesis; she was subsequently diagnosed with concomitant multiple sclerosis that responded to steroid treatment [
• Habitual chewing or mouthing
• Tooth grinding
• Agitation in unfamiliar, noisy, or crowded surroundings
• Aggressive behavior, including biting, hair pulling, or pinching, which is seen in approximately 25% of affected individuals
• The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately.
• The behavior is not self-injurious but is often directed at the parent or caregiver.
• The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately.
• The behavior is not self-injurious but is often directed at the parent or caregiver.
• Catatonia, which may present after neurologic regression, psychosis, and loss of skills [
• Schizophrenia and/or bipolar disorder [
• Bipolar disorder is reported more commonly in individuals with small deletions and
• Prevalence of schizophrenia or schizoaffective disorder has been estimated at around 5%.
• Bipolar disorder is reported more commonly in individuals with small deletions and
• Prevalence of schizophrenia or schizoaffective disorder has been estimated at around 5%.
• The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately.
• The behavior is not self-injurious but is often directed at the parent or caregiver.
• Bipolar disorder is reported more commonly in individuals with small deletions and
• Prevalence of schizophrenia or schizoaffective disorder has been estimated at around 5%.
• Volumetric MRI in 11 affected children demonstrated decreased volumes of the striatum and left pallidum and reduced volume of the cerebellar vermis, which was associated with increased repetitive behavior severity [
• Volumetric investigations have also shown global atrophy of the white matter correlated with structural connectivity losses suggestive of accelerated central nervous system aging [
• In individuals with a ring chromosome 22, MRI studies may show
• The prevalence of sleep disturbances increases with age, with a rate of 53% in toddlers to 90% in adults [
• The primary sleep disturbances include difficulty falling asleep, frequent nighttime awakenings, difficulty returning to sleep after a nighttime awakening event, and hypersomnia and parasomnias, including enuresis, night terrors, sleepwalking, and sleep apnea.
• Sleep disturbances are more prevalent in individuals with a
• Distinct metabolic profiles indicated a minor disruption of the major metabolic pathways involved in energy production in those with sleep disturbances [
• Cortical visual impairment, characterized by extensive use of peripheral vision. Blindness and optic nerve hypoplasia have been associated with cortical visual impairment [
• Difficulty in processing cluttered images
• Problems with depth perception
• A tendency to look away from objects before reaching for them
• Cystic kidneys
• Renal agenesis or dysplastic kidneys
• Hydronephrosis or pyelectasis
• Vesicoureteral reflux
• Horseshoe kidney
• Precautions must be taken to avoid dehydration and nutritional deficits, including zinc deficiency.
• Regression and severe psychiatric disorders may accompany worsening gastrointestinal issues [
• Two individuals with PMS-
• Two affected males with abnormal liver function developed hepatic steatosis [
• Weight is not increased, giving some of the children a tall, thin appearance.
• Whereas children may have increased height for age, adults tend to fall within the normal range for height.
• Most adults are also within the normal range for weight, although inactivity and overeating (possibly a manifestation of compulsive mouthing) result in increased weight gain in approximately 10% of affected individuals.
• The majority of cases are found in individuals with 22q13 deletions, occurring in only about 1% of individuals with intragenic
• Progressive lymphedema leading to pleural effusions has been reported in a female with PMS-
• The characteristics may change over time, particularly if the individual is on anticonvulsants that tend to coarsen the features.
• Adults have a more prominent, square jaw and less bulbous-appearing nose.
• Other less common features include dolichocephaly, strabismus, and abnormal toenails that may be dysplastic, thin, and flaky in the neonate and toddler but may harden and become ingrown as the individual ages.
• Fingernails are usually normal but occasionally may be thin and dysplastic.
## Genotype-Phenotype Correlations
Common features of individuals who have pathogenic variants involving solely
When compared to individuals with larger deletions involving adjacent genes, those with solely
In general, there is a statistically significant correlation between larger deletion sizes and a more significant degree of developmental delay and hypotonia [
Larger deletions are also associated with an increased likelihood of dysmorphic features and medical comorbidities. Individuals with larger deletions are more likely to have renal/urinary tract anomalies and lymphedema compared to those with smaller deletions or pathogenic variants involving
Although there is a tendency for larger deletions to be correlated with more severe intellectual and physical phenotypes than smaller deletions, the correlation is not 100%; individuals with the same size deletion may vary significantly in their presentation [
• Common features of individuals who have pathogenic variants involving solely
• When compared to individuals with larger deletions involving adjacent genes, those with solely
• In general, there is a statistically significant correlation between larger deletion sizes and a more significant degree of developmental delay and hypotonia [
• Larger deletions are also associated with an increased likelihood of dysmorphic features and medical comorbidities. Individuals with larger deletions are more likely to have renal/urinary tract anomalies and lymphedema compared to those with smaller deletions or pathogenic variants involving
• Although there is a tendency for larger deletions to be correlated with more severe intellectual and physical phenotypes than smaller deletions, the correlation is not 100%; individuals with the same size deletion may vary significantly in their presentation [
## Penetrance
Although it was previously thought that features of PMS-
## Nomenclature
Previously referred to as 22q13.3 deletion syndrome to reflect the chromosomal basis of this deletion, the condition was subsequently referred to as Phelan-McDermid syndrome (PMS).
Although the majority of individuals with PMS have a genetic alternation that involves
## Prevalence
The prevalence of PMS-
## Genetically Related (Allelic) Disorders
Intellectual disability and/or neurobehavioral/psychiatric manifestations that may be observed in individuals with Phelan-McDermid syndrome (PMS)-
## Differential Diagnosis
Other Disorders to Consider in the Differential Diagnosis of Phelan-McDermid Syndrome-
Hypotonia
Developmental delay
Speech delay
Autism/autistic traits
Minor dysmorphic features
Hypotonia
Epicanthal folds
Narrow palpebral fissures
Broad nasal root
Speech delay
Renal abnormalities
Developmental delay
Cardiac defects
Palatal defects
Immune deficiency
Hypocalcemia
Neonatal hypotonia
Feeding difficulty
Intellectual deficit
Strabismus
↑ appetite w/significant weight gain
Dolichocephaly, narrow bitemporal diameter
Almond-shaped eyes
Small-appearing mouth w/thin upper lip & down-turned corners
Small hands & feet
Hypernasal speech, weak or squeaky cry in infancy
Hypogonadism
Infantile hypotonia
Developmental delay
Absent speech
Unsteady gait
Minor dysmorphic features
Microcephaly w/flat occiput
Ataxia
Paroxysmal laughter, easily excitable
Hypotonia
Speech delay
Autistic-like behavior
Developmental delay
Large head, long face, prominent forehead & chin, protruding ears
Connective tissue findings (joint laxity)
Large testes (post-pubertal)
Hypotonia
Intellectual disability
Delayed speech
Autistic-like behavior
Gastroesophageal reflux
Intestinal/anal atresia
Chronic constipation
Short stature
Vertebral malformations
Simple, low-set ears
Characteristic personality traits: outgoing, talkative, & impulsive behavior
Neonatal hypotonia & difficulty feeding
Intellectual disability
Delays in motor development
Dysmorphic features incl dolichocephaly, pointed chin, large hands
Autistic-like behavior
Receptive language skills more advanced than expressive language skills
Attention-deficit disorder &/or aggressiveness
Hypotonia
Speech delay
Psychomotor retardation
Flat midface
↓ sensitivity to pain
Inattention & hyperactivity
Distinctive facial features
Behavioral abnormalities
Intellectual disability
Thick hands and feet
Absence of hypotonia
Obesity
Macroorchidism
AD = autosomal dominant; MOI = mode of inheritance; PMS = Phelan-McDermid syndrome; PWCR = Prader-Willi critical region; XL = X-linked
Behavioral abnormalities in SMS: significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors
• Hypotonia
• Developmental delay
• Speech delay
• Autism/autistic traits
• Minor dysmorphic features
• Hypotonia
• Epicanthal folds
• Narrow palpebral fissures
• Broad nasal root
• Speech delay
• Renal abnormalities
• Developmental delay
• Cardiac defects
• Palatal defects
• Immune deficiency
• Hypocalcemia
• Neonatal hypotonia
• Feeding difficulty
• Intellectual deficit
• Strabismus
• ↑ appetite w/significant weight gain
• Dolichocephaly, narrow bitemporal diameter
• Almond-shaped eyes
• Small-appearing mouth w/thin upper lip & down-turned corners
• Small hands & feet
• Hypernasal speech, weak or squeaky cry in infancy
• Hypogonadism
• Infantile hypotonia
• Developmental delay
• Absent speech
• Unsteady gait
• Minor dysmorphic features
• Microcephaly w/flat occiput
• Ataxia
• Paroxysmal laughter, easily excitable
• Hypotonia
• Speech delay
• Autistic-like behavior
• Developmental delay
• Large head, long face, prominent forehead & chin, protruding ears
• Connective tissue findings (joint laxity)
• Large testes (post-pubertal)
• Hypotonia
• Intellectual disability
• Delayed speech
• Autistic-like behavior
• Gastroesophageal reflux
• Intestinal/anal atresia
• Chronic constipation
• Short stature
• Vertebral malformations
• Simple, low-set ears
• Characteristic personality traits: outgoing, talkative, & impulsive behavior
• Neonatal hypotonia & difficulty feeding
• Intellectual disability
• Delays in motor development
• Dysmorphic features incl dolichocephaly, pointed chin, large hands
• Autistic-like behavior
• Receptive language skills more advanced than expressive language skills
• Attention-deficit disorder &/or aggressiveness
• Hypotonia
• Speech delay
• Psychomotor retardation
• Flat midface
• ↓ sensitivity to pain
• Inattention & hyperactivity
• Distinctive facial features
• Behavioral abnormalities
• Intellectual disability
• Thick hands and feet
• Absence of hypotonia
• Obesity
• Macroorchidism
## Management
Various updated consensus clinical management guidelines for Phelan-McDermid syndrome-
To establish the extent of disease and needs in an individual diagnosed with PMS-
Phelan-McDermid Syndrome-
To incl brain MRI in those w/microcephaly, seizures, developmental regression, focal neurologic findings on exam, or symptoms of ↑ intracranial pressure
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To assess for hearing loss
Esp important in those w/a ring chromosome 22, who are at risk for NF2
To incl eval of aspiration risk & nutritional status
Assess for sucking & swallowing difficulties & need for feeding therapy in infancy.
Assess for signs & symptoms of GERD.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Renal ultrasound
Voiding cystourethrogram, if clinically indicated
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; NF2 =
Liver function tests may include serum albumin, total protein, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, total bilirubin, and conjugated bilirubin levels.
Clinical geneticist, certified genetic counselor, certified advanced genetic nurse.
It is not intuitive that individuals with a deletion of chromosome 22q13 might be at risk for
Phelan-McDermid Syndrome-
NF2 =
There is no cure for PMS-
Phelan-McDermid Syndrome-
Many ASMs may be effective; none have been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Parents may keep sleep diary to document sleep habits.
Investigation of co-occurring conditions & possible mental health issues may be necessary.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; VUR = vesicoureteral reflux
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities, including hypertonia or dystonia, consider involving appropriate specialists to aid in managing baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in the treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Phelan-McDermid Syndrome-
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & developmental regression.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease
Educate caregivers about a heightened awareness of potential injuries or infections due to decreased perception of pain.
Phelan-McDermid Syndrome-
BAER = brain stem auditory evoked response; NF2 =
Annual brain MRI can start at an older age in individuals from families in which the onset of tumors is known to be later [
It is not clear if earlier surveillance (e.g., brain MRI before age 10 years) is beneficial, and it is not known at what age surveillance by brain MRI can be safely stopped.
BAER may be useful in detecting changes in auditory nerve function before changes can be visualized by brain MRI.
Exposure to high temperatures and extended periods in the sun should be avoided because individuals with PMS-
Considering that individuals with PMS-
In affected individuals with a ring chromosome 22, radiotherapy for NF2-associated tumors should be avoided in children when malignancy risks are likely to be substantially higher [
See
Insulin-like growth factor 1 (IGF-1) was investigated in a placebo-controlled, double-blind crossover study involving nine children with PMS-
Several studies have investigated the effects of growth hormone (GH), which induces the expression of IGF-1, activates similar target pathways, and is significantly less expensive. Preliminary results revealed improvement in social withdrawal, hyperactivity, and sensory symptoms and led to a clinical trial (
Search
• To incl brain MRI in those w/microcephaly, seizures, developmental regression, focal neurologic findings on exam, or symptoms of ↑ intracranial pressure
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To assess for hearing loss
• Esp important in those w/a ring chromosome 22, who are at risk for NF2
• To incl eval of aspiration risk & nutritional status
• Assess for sucking & swallowing difficulties & need for feeding therapy in infancy.
• Assess for signs & symptoms of GERD.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Renal ultrasound
• Voiding cystourethrogram, if clinically indicated
• Community or
• Social work involvement for parental support
• Home nursing referral
• Many ASMs may be effective; none have been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Parents may keep sleep diary to document sleep habits.
• Investigation of co-occurring conditions & possible mental health issues may be necessary.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities, including hypertonia or dystonia, consider involving appropriate specialists to aid in managing baclofen, tizanidine, Botox
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & developmental regression.
• Insulin-like growth factor 1 (IGF-1) was investigated in a placebo-controlled, double-blind crossover study involving nine children with PMS-
• Several studies have investigated the effects of growth hormone (GH), which induces the expression of IGF-1, activates similar target pathways, and is significantly less expensive. Preliminary results revealed improvement in social withdrawal, hyperactivity, and sensory symptoms and led to a clinical trial (
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PMS-
Phelan-McDermid Syndrome-
To incl brain MRI in those w/microcephaly, seizures, developmental regression, focal neurologic findings on exam, or symptoms of ↑ intracranial pressure
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To assess for hearing loss
Esp important in those w/a ring chromosome 22, who are at risk for NF2
To incl eval of aspiration risk & nutritional status
Assess for sucking & swallowing difficulties & need for feeding therapy in infancy.
Assess for signs & symptoms of GERD.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Renal ultrasound
Voiding cystourethrogram, if clinically indicated
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; NF2 =
Liver function tests may include serum albumin, total protein, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, total bilirubin, and conjugated bilirubin levels.
Clinical geneticist, certified genetic counselor, certified advanced genetic nurse.
It is not intuitive that individuals with a deletion of chromosome 22q13 might be at risk for
Phelan-McDermid Syndrome-
NF2 =
• To incl brain MRI in those w/microcephaly, seizures, developmental regression, focal neurologic findings on exam, or symptoms of ↑ intracranial pressure
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To assess for hearing loss
• Esp important in those w/a ring chromosome 22, who are at risk for NF2
• To incl eval of aspiration risk & nutritional status
• Assess for sucking & swallowing difficulties & need for feeding therapy in infancy.
• Assess for signs & symptoms of GERD.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Renal ultrasound
• Voiding cystourethrogram, if clinically indicated
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for PMS-
Phelan-McDermid Syndrome-
Many ASMs may be effective; none have been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Parents may keep sleep diary to document sleep habits.
Investigation of co-occurring conditions & possible mental health issues may be necessary.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; OT = occupational therapy; VUR = vesicoureteral reflux
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities, including hypertonia or dystonia, consider involving appropriate specialists to aid in managing baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in the treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Many ASMs may be effective; none have been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Parents may keep sleep diary to document sleep habits.
• Investigation of co-occurring conditions & possible mental health issues may be necessary.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities, including hypertonia or dystonia, consider involving appropriate specialists to aid in managing baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding the type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities, including hypertonia or dystonia, consider involving appropriate specialists to aid in managing baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities, including hypertonia or dystonia, consider involving appropriate specialists to aid in managing baclofen, tizanidine, Botox
## Neurobehavioral/Psychiatric Concerns
Children may qualify for and benefit from interventions used in the treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Phelan-McDermid Syndrome-
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & developmental regression.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease
Educate caregivers about a heightened awareness of potential injuries or infections due to decreased perception of pain.
Phelan-McDermid Syndrome-
BAER = brain stem auditory evoked response; NF2 =
Annual brain MRI can start at an older age in individuals from families in which the onset of tumors is known to be later [
It is not clear if earlier surveillance (e.g., brain MRI before age 10 years) is beneficial, and it is not known at what age surveillance by brain MRI can be safely stopped.
BAER may be useful in detecting changes in auditory nerve function before changes can be visualized by brain MRI.
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & developmental regression.
## Agents/Circumstances to Avoid
Exposure to high temperatures and extended periods in the sun should be avoided because individuals with PMS-
Considering that individuals with PMS-
In affected individuals with a ring chromosome 22, radiotherapy for NF2-associated tumors should be avoided in children when malignancy risks are likely to be substantially higher [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Insulin-like growth factor 1 (IGF-1) was investigated in a placebo-controlled, double-blind crossover study involving nine children with PMS-
Several studies have investigated the effects of growth hormone (GH), which induces the expression of IGF-1, activates similar target pathways, and is significantly less expensive. Preliminary results revealed improvement in social withdrawal, hyperactivity, and sensory symptoms and led to a clinical trial (
Search
• Insulin-like growth factor 1 (IGF-1) was investigated in a placebo-controlled, double-blind crossover study involving nine children with PMS-
• Several studies have investigated the effects of growth hormone (GH), which induces the expression of IGF-1, activates similar target pathways, and is significantly less expensive. Preliminary results revealed improvement in social withdrawal, hyperactivity, and sensory symptoms and led to a clinical trial (
## Genetic Counseling
Phelan-McDermid syndrome-
Recurrence risk in family members depends on the genetic mechanism underlying PMS-
Most probands with PMS-
Some probands with a 22q13 deletion have the deletion as the result of:
An unbalanced structural rearrangement that includes 22q13 (e.g., a reciprocal translocation, insertional translocation, or inversion). About half of these individuals have a parent who is a carrier of a balanced translocation [
Ring chromosome 22.
Note: Karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by chromosomal microarray analysis (CMA). Individuals with PMS-
Rarely, a proband with a 22q13.3 deletion inherited a genetic alteration from a heterozygous or mosaic parent.
Mild expression of PMS-
Maternal mosaicism has been described in several families:
Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
Evaluation of the parents by genomic testing that will detect the 22q13.3 deletion identified in the proband is recommended. In addition, karyotype of the parents is recommended to determine if a parent has a predisposing chromosomal anomaly.
If the 22q13 deletion identified in the proband is not identified in either parent, a chromosome anomaly is not detected in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism [
* Although the probability of parental mosaicism for 22q13.3 deletion is low, it is important that parental mosaicism be considered when parental studies are performed (see
The family history of some individuals diagnosed with PMS-
If a parent has a non-mosaic 22q13.3 deletion, the risk to each sib of inheriting the deletion is 50% [
If a parent has a balanced chromosomal rearrangement, a ring chromosome 22, or other complex chromosomal rearrangement, the risk to sibs is increased and depends on the specific chromosomal rearrangement and the possibility of other variables.
It is not possible to reliably predict the phenotype in a sib who inherits a familial genetic alteration (see
If the proband represents a simplex case (i.e., the only affected family member) and neither parent has a detected 22q13.3 deletion or a chromosomal rearrangement, the recurrence risk to sibs of PMS-
Most probands with PMS-
Rarely, a proband with an intragenic
Transmission of an intragenic
The frequency of parental mosaicism for a
Molecular genetic testing is recommended for the parents of the proband to assess their genetic status and inform recurrence risk counseling.
If the
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with PMS-
If a parent of the proband is affected and/or known to have an intragenic
If the
If the parents have not been tested for the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with PMS-
Once a 22q13.3 deletion involving
Prenatal testing to detect the genetic alteration identified in the proband may be offered in the following instances:
The parents do not have a
A parent has a balanced chromosomal rearrangement that resulted in a previous child with a 22q13.3 deletion. Note: Most unbalanced chromosomal rearrangements can be detected by CMA. Conventional cytogenetic analysis can be considered to exclude rare chromosomal rearrangements (such as translocations) that involve
Note: Prenatal test results cannot reliably predict the phenotype.
Differences in perspective regarding the use of prenatal testing may exist among medical professionals and within families. While most centers would consider the use of prenatal testing to be a personal decision, a discussion of these issues may be helpful.
• Most probands with PMS-
• Some probands with a 22q13 deletion have the deletion as the result of:
• An unbalanced structural rearrangement that includes 22q13 (e.g., a reciprocal translocation, insertional translocation, or inversion). About half of these individuals have a parent who is a carrier of a balanced translocation [
• Ring chromosome 22.
• Note: Karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by chromosomal microarray analysis (CMA). Individuals with PMS-
• An unbalanced structural rearrangement that includes 22q13 (e.g., a reciprocal translocation, insertional translocation, or inversion). About half of these individuals have a parent who is a carrier of a balanced translocation [
• Ring chromosome 22.
• Note: Karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by chromosomal microarray analysis (CMA). Individuals with PMS-
• Rarely, a proband with a 22q13.3 deletion inherited a genetic alteration from a heterozygous or mosaic parent.
• Mild expression of PMS-
• Maternal mosaicism has been described in several families:
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Mild expression of PMS-
• Maternal mosaicism has been described in several families:
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Evaluation of the parents by genomic testing that will detect the 22q13.3 deletion identified in the proband is recommended. In addition, karyotype of the parents is recommended to determine if a parent has a predisposing chromosomal anomaly.
• If the 22q13 deletion identified in the proband is not identified in either parent, a chromosome anomaly is not detected in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism [
• * Although the probability of parental mosaicism for 22q13.3 deletion is low, it is important that parental mosaicism be considered when parental studies are performed (see
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism [
• * Although the probability of parental mosaicism for 22q13.3 deletion is low, it is important that parental mosaicism be considered when parental studies are performed (see
• The family history of some individuals diagnosed with PMS-
• An unbalanced structural rearrangement that includes 22q13 (e.g., a reciprocal translocation, insertional translocation, or inversion). About half of these individuals have a parent who is a carrier of a balanced translocation [
• Ring chromosome 22.
• Note: Karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by chromosomal microarray analysis (CMA). Individuals with PMS-
• Mild expression of PMS-
• Maternal mosaicism has been described in several families:
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism [
• * Although the probability of parental mosaicism for 22q13.3 deletion is low, it is important that parental mosaicism be considered when parental studies are performed (see
• If a parent has a non-mosaic 22q13.3 deletion, the risk to each sib of inheriting the deletion is 50% [
• If a parent has a balanced chromosomal rearrangement, a ring chromosome 22, or other complex chromosomal rearrangement, the risk to sibs is increased and depends on the specific chromosomal rearrangement and the possibility of other variables.
• It is not possible to reliably predict the phenotype in a sib who inherits a familial genetic alteration (see
• If the proband represents a simplex case (i.e., the only affected family member) and neither parent has a detected 22q13.3 deletion or a chromosomal rearrangement, the recurrence risk to sibs of PMS-
• Most probands with PMS-
• Rarely, a proband with an intragenic
• Transmission of an intragenic
• The frequency of parental mosaicism for a
• Transmission of an intragenic
• The frequency of parental mosaicism for a
• Molecular genetic testing is recommended for the parents of the proband to assess their genetic status and inform recurrence risk counseling.
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with PMS-
• Transmission of an intragenic
• The frequency of parental mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or known to have an intragenic
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with PMS-
• The parents do not have a
• A parent has a balanced chromosomal rearrangement that resulted in a previous child with a 22q13.3 deletion. Note: Most unbalanced chromosomal rearrangements can be detected by CMA. Conventional cytogenetic analysis can be considered to exclude rare chromosomal rearrangements (such as translocations) that involve
## Mode of Inheritance
Phelan-McDermid syndrome-
Recurrence risk in family members depends on the genetic mechanism underlying PMS-
## 22q13.3 Deletion – Risk to Family Members
Most probands with PMS-
Some probands with a 22q13 deletion have the deletion as the result of:
An unbalanced structural rearrangement that includes 22q13 (e.g., a reciprocal translocation, insertional translocation, or inversion). About half of these individuals have a parent who is a carrier of a balanced translocation [
Ring chromosome 22.
Note: Karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by chromosomal microarray analysis (CMA). Individuals with PMS-
Rarely, a proband with a 22q13.3 deletion inherited a genetic alteration from a heterozygous or mosaic parent.
Mild expression of PMS-
Maternal mosaicism has been described in several families:
Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
Evaluation of the parents by genomic testing that will detect the 22q13.3 deletion identified in the proband is recommended. In addition, karyotype of the parents is recommended to determine if a parent has a predisposing chromosomal anomaly.
If the 22q13 deletion identified in the proband is not identified in either parent, a chromosome anomaly is not detected in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism [
* Although the probability of parental mosaicism for 22q13.3 deletion is low, it is important that parental mosaicism be considered when parental studies are performed (see
The family history of some individuals diagnosed with PMS-
If a parent has a non-mosaic 22q13.3 deletion, the risk to each sib of inheriting the deletion is 50% [
If a parent has a balanced chromosomal rearrangement, a ring chromosome 22, or other complex chromosomal rearrangement, the risk to sibs is increased and depends on the specific chromosomal rearrangement and the possibility of other variables.
It is not possible to reliably predict the phenotype in a sib who inherits a familial genetic alteration (see
If the proband represents a simplex case (i.e., the only affected family member) and neither parent has a detected 22q13.3 deletion or a chromosomal rearrangement, the recurrence risk to sibs of PMS-
• Most probands with PMS-
• Some probands with a 22q13 deletion have the deletion as the result of:
• An unbalanced structural rearrangement that includes 22q13 (e.g., a reciprocal translocation, insertional translocation, or inversion). About half of these individuals have a parent who is a carrier of a balanced translocation [
• Ring chromosome 22.
• Note: Karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by chromosomal microarray analysis (CMA). Individuals with PMS-
• An unbalanced structural rearrangement that includes 22q13 (e.g., a reciprocal translocation, insertional translocation, or inversion). About half of these individuals have a parent who is a carrier of a balanced translocation [
• Ring chromosome 22.
• Note: Karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by chromosomal microarray analysis (CMA). Individuals with PMS-
• Rarely, a proband with a 22q13.3 deletion inherited a genetic alteration from a heterozygous or mosaic parent.
• Mild expression of PMS-
• Maternal mosaicism has been described in several families:
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Mild expression of PMS-
• Maternal mosaicism has been described in several families:
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Evaluation of the parents by genomic testing that will detect the 22q13.3 deletion identified in the proband is recommended. In addition, karyotype of the parents is recommended to determine if a parent has a predisposing chromosomal anomaly.
• If the 22q13 deletion identified in the proband is not identified in either parent, a chromosome anomaly is not detected in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism [
• * Although the probability of parental mosaicism for 22q13.3 deletion is low, it is important that parental mosaicism be considered when parental studies are performed (see
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism [
• * Although the probability of parental mosaicism for 22q13.3 deletion is low, it is important that parental mosaicism be considered when parental studies are performed (see
• The family history of some individuals diagnosed with PMS-
• An unbalanced structural rearrangement that includes 22q13 (e.g., a reciprocal translocation, insertional translocation, or inversion). About half of these individuals have a parent who is a carrier of a balanced translocation [
• Ring chromosome 22.
• Note: Karyotype screening of the proband for a ring chromosome 22 must be done if a terminal 22q13.3 deletion is detected by chromosomal microarray analysis (CMA). Individuals with PMS-
• Mild expression of PMS-
• Maternal mosaicism has been described in several families:
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• Recurrence in two affected brothers of a 3.5-Mb deletion of maternal origin (testing of parental peripheral blood did not detect a balanced chromosomal rearrangement or low-level mosaicism, leading to the suspicion of maternal germline mosaicism) [
• An asymptomatic mosaic mother with a 22q13 deletion resulting from a structural chromosomal anomaly transmitted the deletion to two affected children (the derivative chromosome 22 was observed in 6% of maternal peripheral blood cells) [K Phelan, unpublished data].
• An asymptomatic mother with mosaicism for a ring chromosome 22 (in fewer than 2% of peripheral blood cells) transmitted the ring chromosome 22 to her affected child [K Phelan, unpublished data].
• The proband has a
• The proband inherited a deletion from a parent with germline (or somatic and germline) mosaicism [
• * Although the probability of parental mosaicism for 22q13.3 deletion is low, it is important that parental mosaicism be considered when parental studies are performed (see
• If a parent has a non-mosaic 22q13.3 deletion, the risk to each sib of inheriting the deletion is 50% [
• If a parent has a balanced chromosomal rearrangement, a ring chromosome 22, or other complex chromosomal rearrangement, the risk to sibs is increased and depends on the specific chromosomal rearrangement and the possibility of other variables.
• It is not possible to reliably predict the phenotype in a sib who inherits a familial genetic alteration (see
• If the proband represents a simplex case (i.e., the only affected family member) and neither parent has a detected 22q13.3 deletion or a chromosomal rearrangement, the recurrence risk to sibs of PMS-
## Intragenic
Most probands with PMS-
Rarely, a proband with an intragenic
Transmission of an intragenic
The frequency of parental mosaicism for a
Molecular genetic testing is recommended for the parents of the proband to assess their genetic status and inform recurrence risk counseling.
If the
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with PMS-
If a parent of the proband is affected and/or known to have an intragenic
If the
If the parents have not been tested for the
• Most probands with PMS-
• Rarely, a proband with an intragenic
• Transmission of an intragenic
• The frequency of parental mosaicism for a
• Transmission of an intragenic
• The frequency of parental mosaicism for a
• Molecular genetic testing is recommended for the parents of the proband to assess their genetic status and inform recurrence risk counseling.
• If the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with PMS-
• Transmission of an intragenic
• The frequency of parental mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or known to have an intragenic
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with PMS-
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with PMS-
## Prenatal Testing and Preimplantation Genetic Testing
Once a 22q13.3 deletion involving
Prenatal testing to detect the genetic alteration identified in the proband may be offered in the following instances:
The parents do not have a
A parent has a balanced chromosomal rearrangement that resulted in a previous child with a 22q13.3 deletion. Note: Most unbalanced chromosomal rearrangements can be detected by CMA. Conventional cytogenetic analysis can be considered to exclude rare chromosomal rearrangements (such as translocations) that involve
Note: Prenatal test results cannot reliably predict the phenotype.
Differences in perspective regarding the use of prenatal testing may exist among medical professionals and within families. While most centers would consider the use of prenatal testing to be a personal decision, a discussion of these issues may be helpful.
• The parents do not have a
• A parent has a balanced chromosomal rearrangement that resulted in a previous child with a 22q13.3 deletion. Note: Most unbalanced chromosomal rearrangements can be detected by CMA. Conventional cytogenetic analysis can be considered to exclude rare chromosomal rearrangements (such as translocations) that involve
## Resources
United Kingdom
•
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Phelan-McDermid Syndrome-SHANK3 Related: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Phelan-McDermid Syndrome-SHANK3 Related (
The size of the 22q13.3 deletion in Phelan-McDermid syndrome-
The product of the main mRNA isoform of
In addition to deletion/disruption of
## Molecular Pathogenesis
The size of the 22q13.3 deletion in Phelan-McDermid syndrome-
The product of the main mRNA isoform of
In addition to deletion/disruption of
## Chapter Notes
The authors gratefully acknowledge the members of the Phelan-McDermid Syndrome Foundation for their participation in research and for their generous sharing of information.
6 June 2024 (ma) Comprehensive update posted live
7 June 2018 (ha) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
25 October 2007 (me) Comprehensive update posted live
11 May 2005 (me) Review posted live
22 November 2004 (kp) Original submission
• 6 June 2024 (ma) Comprehensive update posted live
• 7 June 2018 (ha) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 25 October 2007 (me) Comprehensive update posted live
• 11 May 2005 (me) Review posted live
• 22 November 2004 (kp) Original submission
## Acknowledgments
The authors gratefully acknowledge the members of the Phelan-McDermid Syndrome Foundation for their participation in research and for their generous sharing of information.
## Revision History
6 June 2024 (ma) Comprehensive update posted live
7 June 2018 (ha) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
25 October 2007 (me) Comprehensive update posted live
11 May 2005 (me) Review posted live
22 November 2004 (kp) Original submission
• 6 June 2024 (ma) Comprehensive update posted live
• 7 June 2018 (ha) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 25 October 2007 (me) Comprehensive update posted live
• 11 May 2005 (me) Review posted live
• 22 November 2004 (kp) Original submission
## References
## Literature Cited
|
[] |
11/5/2005
|
6/6/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
gr_3ms
|
gr_3ms
|
[
"Three M Syndrome",
"3M Syndrome",
"Three M Syndrome",
"3M Syndrome",
"Coiled-coil domain-containing protein 8",
"Cullin-7",
"Obscurin-like protein 1",
"CCDC8",
"CUL7",
"OBSL1",
"3-M Syndrome"
] |
3-M Syndrome
|
Rhoda Akilapa, Melita Irving, Muriel Holder-Espinasse
|
Summary 3-M syndrome is characterized by severe pre- and postnatal growth deficiency (final height five standard deviations below the mean), characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum, thick vermilion of the upper and low lips, and pointed chin), and normal intelligence. Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus. Males with 3-M syndrome can have hypogonadism and occasionally hypospadias. The diagnosis of 3-M syndrome is established in a proband with prenatal-onset persistent growth deficiency and the characteristic clinical and radiographic features and/or biallelic pathogenic variants in 3-M syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for 3-M syndrome have been published.
3-M syndrome
The diagnosis of 3-M syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of 3-M syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
Note: Targeted analysis for known founder pathogenic variants in
When the diagnosis of 3-M syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in 3-M Syndrome
NA = not applicable
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Pathogenic variants in
## Suggestive Findings
3-M syndrome
## Establishing the Diagnosis
The diagnosis of 3-M syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of 3-M syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
Note: Targeted analysis for known founder pathogenic variants in
When the diagnosis of 3-M syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in 3-M Syndrome
NA = not applicable
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Pathogenic variants in
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of 3-M syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
Note: Targeted analysis for known founder pathogenic variants in
## Option 2
When the diagnosis of 3-M syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in 3-M Syndrome
NA = not applicable
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Pathogenic variants in
## Clinical Characteristics
Most children with 3-M syndrome are evaluated for growth hormone (GH) deficiency. A small proportion are found to have partial or significant GH deficiency [
The
The
Individuals with
The number of reported individuals with
The
3-M syndrome may also be referred to as Le Merrer syndrome or Yakut short stature syndrome. Individuals previously reported to have dolichospondylic dysplasia [
3-M syndrome is rare. The prevalence is not known; approximately 250 affected individuals have been reported in the literature since the first published report in 1975 [
A
A recurrent pathogenic variant in
• The
• The
## Clinical Description
Most children with 3-M syndrome are evaluated for growth hormone (GH) deficiency. A small proportion are found to have partial or significant GH deficiency [
The
The
• The
• The
## Phenotype Correlations by Gene
Individuals with
The number of reported individuals with
## Genotype-Phenotype Correlations
The
## Nomenclature
3-M syndrome may also be referred to as Le Merrer syndrome or Yakut short stature syndrome. Individuals previously reported to have dolichospondylic dysplasia [
## Prevalence
3-M syndrome is rare. The prevalence is not known; approximately 250 affected individuals have been reported in the literature since the first published report in 1975 [
A
A recurrent pathogenic variant in
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Intrauterine growth restriction is a nonspecific finding that occurs in approximately 0.17% of all live-born children. 3-M syndrome must be distinguished from other genetic (see
Disorders of Known Genetic Cause to Consider in the Differential Diagnosis of 3-M Syndrome
SRS often shows limb length asymmetry.
Characteristic radiologic features of 3-M syndrome are absent.
IUGR is often less severe than in infants w/3-M syndrome.
Characteristic facial features incl high forehead & pseudohydrocephalic skull configuration.
AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance
Hypomethylation of the imprinting control region 1 at 11p15.5 causes SRS in 35%-67% of individuals, and maternal uniparental disomy of chromosome 7 causes SRS in 7%-10% of individuals. See Silver-Russell syndrome,
In most families, a proband with SRS represents a simplex case and has a
• SRS often shows limb length asymmetry.
• Characteristic radiologic features of 3-M syndrome are absent.
• IUGR is often less severe than in infants w/3-M syndrome.
• Characteristic facial features incl high forehead & pseudohydrocephalic skull configuration.
## Management
No clinical practice guidelines for 3-M syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
To establish the extent of disease in an individual diagnosed with 3-M syndrome, the evaluations summarized in
3-M Syndrome: Recommended Evaluations Following Initial Diagnosis
Hip US in infancy or hip radiographs in older children may be helpful.
Refer to orthopedist if hip dysplasia/dislocation or scoliosis is identified.
Gonadal function in pubertal males by physical exam & serum concentrations of FSH, LH, & testosterone;
GH deficiency &/or GH insensitivity.
FSH = follicle-stimulating hormone; GH = growth hormone; LH = luteinizing hormone; MOI = mode of inheritance; US = ultrasound
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
3-M Syndrome: Treatment of Manifestations
Refer to pediatric endocrinologist for consideration of GH treatment.
A trial of GH, particularly in prepubertal children, w/close monitoring of growth velocity & measurement of IGF-1 is recommended.
GH should be discontinued if there is reduction in growth velocity.
GH treatment should be carried out in center w/experience in managing growth disorders.
The use of GH for short stature in 3-M syndrome has been used w/varying effects; GH has yielded poor results in many w/3-M syndrome. However, there are reports of children responding well to GH, w/↑ growth velocity & marked ↑ in height SD.
Adaptive aids for people w/short stature
Surgical bone lengthening may be an option for some.
Orthopedic eval & treatment for hip dysplasia/dislocation & kyphoscoliosis
Significant joint laxity should prompt orthopedic eval & measures to control development of arthritis.
GH = growth hormone; IGF-1 = insulin-like growth factor 1; OT = occupational therapy; PT = physical therapy; SD = standard deviation
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
3-M Syndrome: Recommended Surveillance
Assess for joint hypermobility.
Examine back for kyphoscoliosis.
It is appropriate to evaluate sibs of a proband for short stature and, if present, 3-M syndrome to ensure a correct diagnosis is made in affected sibs. Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known;
Physical examination and skeletal survey for the characteristic clinical and radiographic features if the pathogenic variants in the family are not known.
See
Management of pregnancy for affected women is the same as that for women with other forms of dwarfism or small stature, which is mainly to reduce the risk of premature birth.
Search
• Hip US in infancy or hip radiographs in older children may be helpful.
• Refer to orthopedist if hip dysplasia/dislocation or scoliosis is identified.
• Gonadal function in pubertal males by physical exam & serum concentrations of FSH, LH, & testosterone;
• GH deficiency &/or GH insensitivity.
• Refer to pediatric endocrinologist for consideration of GH treatment.
• A trial of GH, particularly in prepubertal children, w/close monitoring of growth velocity & measurement of IGF-1 is recommended.
• GH should be discontinued if there is reduction in growth velocity.
• GH treatment should be carried out in center w/experience in managing growth disorders.
• The use of GH for short stature in 3-M syndrome has been used w/varying effects; GH has yielded poor results in many w/3-M syndrome. However, there are reports of children responding well to GH, w/↑ growth velocity & marked ↑ in height SD.
• Adaptive aids for people w/short stature
• Surgical bone lengthening may be an option for some.
• Orthopedic eval & treatment for hip dysplasia/dislocation & kyphoscoliosis
• Significant joint laxity should prompt orthopedic eval & measures to control development of arthritis.
• Assess for joint hypermobility.
• Examine back for kyphoscoliosis.
• Molecular genetic testing if the pathogenic variants in the family are known;
• Physical examination and skeletal survey for the characteristic clinical and radiographic features if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with 3-M syndrome, the evaluations summarized in
3-M Syndrome: Recommended Evaluations Following Initial Diagnosis
Hip US in infancy or hip radiographs in older children may be helpful.
Refer to orthopedist if hip dysplasia/dislocation or scoliosis is identified.
Gonadal function in pubertal males by physical exam & serum concentrations of FSH, LH, & testosterone;
GH deficiency &/or GH insensitivity.
FSH = follicle-stimulating hormone; GH = growth hormone; LH = luteinizing hormone; MOI = mode of inheritance; US = ultrasound
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Hip US in infancy or hip radiographs in older children may be helpful.
• Refer to orthopedist if hip dysplasia/dislocation or scoliosis is identified.
• Gonadal function in pubertal males by physical exam & serum concentrations of FSH, LH, & testosterone;
• GH deficiency &/or GH insensitivity.
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
3-M Syndrome: Treatment of Manifestations
Refer to pediatric endocrinologist for consideration of GH treatment.
A trial of GH, particularly in prepubertal children, w/close monitoring of growth velocity & measurement of IGF-1 is recommended.
GH should be discontinued if there is reduction in growth velocity.
GH treatment should be carried out in center w/experience in managing growth disorders.
The use of GH for short stature in 3-M syndrome has been used w/varying effects; GH has yielded poor results in many w/3-M syndrome. However, there are reports of children responding well to GH, w/↑ growth velocity & marked ↑ in height SD.
Adaptive aids for people w/short stature
Surgical bone lengthening may be an option for some.
Orthopedic eval & treatment for hip dysplasia/dislocation & kyphoscoliosis
Significant joint laxity should prompt orthopedic eval & measures to control development of arthritis.
GH = growth hormone; IGF-1 = insulin-like growth factor 1; OT = occupational therapy; PT = physical therapy; SD = standard deviation
• Refer to pediatric endocrinologist for consideration of GH treatment.
• A trial of GH, particularly in prepubertal children, w/close monitoring of growth velocity & measurement of IGF-1 is recommended.
• GH should be discontinued if there is reduction in growth velocity.
• GH treatment should be carried out in center w/experience in managing growth disorders.
• The use of GH for short stature in 3-M syndrome has been used w/varying effects; GH has yielded poor results in many w/3-M syndrome. However, there are reports of children responding well to GH, w/↑ growth velocity & marked ↑ in height SD.
• Adaptive aids for people w/short stature
• Surgical bone lengthening may be an option for some.
• Orthopedic eval & treatment for hip dysplasia/dislocation & kyphoscoliosis
• Significant joint laxity should prompt orthopedic eval & measures to control development of arthritis.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
3-M Syndrome: Recommended Surveillance
Assess for joint hypermobility.
Examine back for kyphoscoliosis.
• Assess for joint hypermobility.
• Examine back for kyphoscoliosis.
## Evaluation of Relatives at Risk
It is appropriate to evaluate sibs of a proband for short stature and, if present, 3-M syndrome to ensure a correct diagnosis is made in affected sibs. Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known;
Physical examination and skeletal survey for the characteristic clinical and radiographic features if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Physical examination and skeletal survey for the characteristic clinical and radiographic features if the pathogenic variants in the family are not known.
## Pregnancy Management
Management of pregnancy for affected women is the same as that for women with other forms of dwarfism or small stature, which is mainly to reduce the risk of premature birth.
## Therapies Under Investigation
Search
## Genetic Counseling
3-M syndrome is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for a 3-M syndrome-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are typically asymptomatic.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are typically asymptomatic.
Carrier testing for at-risk relatives requires prior identification of the 3-M syndrome-related pathogenic variants in the family.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals affected with 3-M syndrome and individuals known to be carriers of a
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for a 3-M syndrome-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are typically asymptomatic.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are typically asymptomatic.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals affected with 3-M syndrome and individuals known to be carriers of a
## Mode of Inheritance
3-M syndrome is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a 3-M syndrome-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are typically asymptomatic.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are typically asymptomatic.
• The parents of an affected child are presumed to be heterozygous for a 3-M syndrome-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are typically asymptomatic.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygotes (carriers) are typically asymptomatic.
## Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives requires prior identification of the 3-M syndrome-related pathogenic variants in the family.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of individuals affected with 3-M syndrome and individuals known to be carriers of a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals affected with 3-M syndrome and individuals known to be carriers of a
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
## Molecular Genetics
3-M Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for 3-M Syndrome (
A study by
Further research by
3-M Syndrome: Gene-Specific Laboratory Considerations
Genes from
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the author.
Genes from
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
A study by
Further research by
3-M Syndrome: Gene-Specific Laboratory Considerations
Genes from
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the author.
Genes from
Variant designation that does not conform to current naming conventions
## Chapter Notes
Dr Akilapa is happy to communicate with persons who have any questions regarding diagnosis of 3-M syndrome or other considerations.
Dr Irving is also interested in hearing from clinicians treating families affected by 3-M syndrome and other skeletal dysplasias in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Rhoda Akilapa, BMBS, BMedSci (2025-present)Muriel Holder-Espinasse, MD, PhD (2002-present)Melita Irving, MBBS, MD (2019-present)Robin M Winter, FRCP, F Med Sci; Institute of Child Health, London (2002-2004 *)
* Robin Winter was Professor of Clinical Genetics and Dysmorphology at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust. He contributed nearly 300 papers to medical journals on a wide breadth of topics and was an editor of the journal
27 February 2025 (sw) Comprehensive update posted live
7 February 2019 (sw) Comprehensive update posted live
26 January 2012 (me) Comprehensive update posted live
30 March 2010 (me) Comprehensive update posted live
23 June 2006 (ca) Comprehensive update posted live
11 May 2004 (me) Comprehensive update posted live
25 March 2002 (me) Review posted live
31 January 2002 (mhe) Original submission
• 27 February 2025 (sw) Comprehensive update posted live
• 7 February 2019 (sw) Comprehensive update posted live
• 26 January 2012 (me) Comprehensive update posted live
• 30 March 2010 (me) Comprehensive update posted live
• 23 June 2006 (ca) Comprehensive update posted live
• 11 May 2004 (me) Comprehensive update posted live
• 25 March 2002 (me) Review posted live
• 31 January 2002 (mhe) Original submission
## Author Notes
Dr Akilapa is happy to communicate with persons who have any questions regarding diagnosis of 3-M syndrome or other considerations.
Dr Irving is also interested in hearing from clinicians treating families affected by 3-M syndrome and other skeletal dysplasias in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
## Author History
Rhoda Akilapa, BMBS, BMedSci (2025-present)Muriel Holder-Espinasse, MD, PhD (2002-present)Melita Irving, MBBS, MD (2019-present)Robin M Winter, FRCP, F Med Sci; Institute of Child Health, London (2002-2004 *)
* Robin Winter was Professor of Clinical Genetics and Dysmorphology at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust. He contributed nearly 300 papers to medical journals on a wide breadth of topics and was an editor of the journal
## Revision History
27 February 2025 (sw) Comprehensive update posted live
7 February 2019 (sw) Comprehensive update posted live
26 January 2012 (me) Comprehensive update posted live
30 March 2010 (me) Comprehensive update posted live
23 June 2006 (ca) Comprehensive update posted live
11 May 2004 (me) Comprehensive update posted live
25 March 2002 (me) Review posted live
31 January 2002 (mhe) Original submission
• 27 February 2025 (sw) Comprehensive update posted live
• 7 February 2019 (sw) Comprehensive update posted live
• 26 January 2012 (me) Comprehensive update posted live
• 30 March 2010 (me) Comprehensive update posted live
• 23 June 2006 (ca) Comprehensive update posted live
• 11 May 2004 (me) Comprehensive update posted live
• 25 March 2002 (me) Review posted live
• 31 January 2002 (mhe) Original submission
## References
## Literature Cited
|
[] |
25/3/2002
|
27/2/2025
|
24/10/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
gsd1
|
gsd1
|
[
"GSDI",
"Glucose-6-phosphatase catalytic subunit 1",
"Glucose-6-phosphate exchanger SLC37A4",
"G6PC1",
"SLC37A4",
"Glycogen Storage Disease Type I"
] |
Glycogen Storage Disease Type I
|
Deeksha S Bali, Areeg El-Gharbawy, Stephanie Austin, Surekha Pendyal, Priya S Kishnani
|
Summary Glycogen storage disease type I (GSD I) is characterized by accumulation of glycogen and fat in the liver and kidneys resulting in hepatomegaly and nephromegaly. Severely affected infants present in the neonatal period with severe hypoglycemia due to fasting intolerance. More commonly, untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. Affected children typically have doll-like faces with full cheeks, relatively thin extremities, short stature, and a protuberant abdomen. Xanthoma and diarrhea may be present. Impaired platelet function and development of reduced or dysfunctional von Willebrand factor can lead to a bleeding tendency with frequent epistaxis and menorrhagia in females. Individuals with untreated GSD Ib are more likely to develop impaired neutrophil and monocyte function as well as chronic neutropenia resulting in recurrent bacterial infections, gingivitis, periodontitis, and genital and intestinal ulcers. Long-term complications of untreated GSD I include short stature, osteoporosis, delayed puberty, renal disease (including proximal and distal renal tubular acidosis, renal stones, and kidney failure), gout, systemic hypertension, pulmonary hypertension, hepatic adenomas with potential for malignancy, pancreatitis, and polycystic ovaries. Seizures and cognitive impairment may occur in individuals with prolonged periods of hypoglycemia. Normal growth and puberty are expected in treated children. Most affected individuals live into adulthood. The diagnosis of GSD I is established in a proband by identification of biallelic pathogenic variants in either GSD I is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GSD I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if both pathogenic variants have been identified in an affected family member.
|
## Diagnosis
The two major subtypes of glycogen storage disease type I (GSD I) are:
The lack of either G6Pase catalytic activity or glucose-6-phosphate exchanger SLC37A4 (transporter) activity in the liver leads to inadequate conversion of glucose-6-phosphate into glucose through normal glycogenolysis and gluconeogenesis pathways, resulting in severe hypoglycemia and many other signs and symptoms typical of the GSD I disorders.
Guidelines for diagnosis and management have been published by the American College of Medical Genetics and Genomics [
GSD I
Triglycerides >250 mg/dL (reference range: 150-200 mg/dL); hypertriglyceridemia causes the plasma to appear "milky."
Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)
Note: As liver biopsy is invasive, it should only be done when a diagnosis cannot be made using molecular genetic testing. Liver tissue may be obtained at the same time as another surgery (e.g., G-tube placement) as a fresh snap-frozen liver sample and diagnosis can be established using enzyme testing in those with
The diagnosis of GSD I
Biallelic pathogenic (or likely pathogenic) variants in
Deficient
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish or Amish ancestry; see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
A sample of 15-20 mg of snap-frozen liver obtained by percutaneous needle biopsy or open biopsy should be shipped on dry ice via overnight delivery to the clinical diagnostic laboratory.
In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
Note: Because of its relatively high sensitivity, molecular genetic testing is increasingly the preferred confirmatory test when weighed against the need for liver biopsy to determine the level of enzyme activity. However, liver biopsy can additionally be used to obtain histology and electronic micrographic information, which along with enzyme analysis can be used to further investigate pathology associated with variants of uncertain significance found on genetic testing.
Molecular Genetic Testing Used in Glycogen Storage Disease Type I
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
•
• Triglycerides >250 mg/dL (reference range: 150-200 mg/dL); hypertriglyceridemia causes the plasma to appear "milky."
• Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)
• Triglycerides >250 mg/dL (reference range: 150-200 mg/dL); hypertriglyceridemia causes the plasma to appear "milky."
• Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)
• Triglycerides >250 mg/dL (reference range: 150-200 mg/dL); hypertriglyceridemia causes the plasma to appear "milky."
• Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)
• Biallelic pathogenic (or likely pathogenic) variants in
• Deficient
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish or Amish ancestry; see
• For an introduction to multigene panels click
• In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
• In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
• In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
• In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
• In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
• In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
## Suggestive Findings
GSD I
Triglycerides >250 mg/dL (reference range: 150-200 mg/dL); hypertriglyceridemia causes the plasma to appear "milky."
Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)
Note: As liver biopsy is invasive, it should only be done when a diagnosis cannot be made using molecular genetic testing. Liver tissue may be obtained at the same time as another surgery (e.g., G-tube placement) as a fresh snap-frozen liver sample and diagnosis can be established using enzyme testing in those with
•
• Triglycerides >250 mg/dL (reference range: 150-200 mg/dL); hypertriglyceridemia causes the plasma to appear "milky."
• Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)
• Triglycerides >250 mg/dL (reference range: 150-200 mg/dL); hypertriglyceridemia causes the plasma to appear "milky."
• Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)
• Triglycerides >250 mg/dL (reference range: 150-200 mg/dL); hypertriglyceridemia causes the plasma to appear "milky."
• Cholesterol >200 mg/dL (reference range: 100-200 mg/dL)
## Establishing the Diagnosis
The diagnosis of GSD I
Biallelic pathogenic (or likely pathogenic) variants in
Deficient
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish or Amish ancestry; see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
A sample of 15-20 mg of snap-frozen liver obtained by percutaneous needle biopsy or open biopsy should be shipped on dry ice via overnight delivery to the clinical diagnostic laboratory.
In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
Note: Because of its relatively high sensitivity, molecular genetic testing is increasingly the preferred confirmatory test when weighed against the need for liver biopsy to determine the level of enzyme activity. However, liver biopsy can additionally be used to obtain histology and electronic micrographic information, which along with enzyme analysis can be used to further investigate pathology associated with variants of uncertain significance found on genetic testing.
Molecular Genetic Testing Used in Glycogen Storage Disease Type I
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
• Biallelic pathogenic (or likely pathogenic) variants in
• Deficient
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish or Amish ancestry; see
• For an introduction to multigene panels click
• In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
• In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
• In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
• In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
• In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
• In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
## Molecular Diagnosis
Molecular genetic testing approaches include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish or Amish ancestry; see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish or Amish ancestry; see
• For an introduction to multigene panels click
## Enzyme Activity Assay
A sample of 15-20 mg of snap-frozen liver obtained by percutaneous needle biopsy or open biopsy should be shipped on dry ice via overnight delivery to the clinical diagnostic laboratory.
In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
Note: Because of its relatively high sensitivity, molecular genetic testing is increasingly the preferred confirmatory test when weighed against the need for liver biopsy to determine the level of enzyme activity. However, liver biopsy can additionally be used to obtain histology and electronic micrographic information, which along with enzyme analysis can be used to further investigate pathology associated with variants of uncertain significance found on genetic testing.
Molecular Genetic Testing Used in Glycogen Storage Disease Type I
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
• In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
• In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
• In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
• In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
• In most individuals with GSD Ia, the G6Pase enzyme activity is <10% of normal.
• In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (between 1.0 and 2.0 µmol/min/g tissue).
## Clinical Characteristics
The clinical manifestations of glycogen storage disease type I (GSD I) are poor growth (leading to short stature) and accumulation of glycogen and fat in liver and kidneys (resulting in hepatomegaly and nephromegaly, respectively) [
Although some neonates present with severe hypoglycemia, untreated infants more commonly present at age three to four months or a little later (when the feeding interval is typically increased or when infants start sleeping through the night) with additional symptoms of hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia, and/or hypoglycemic seizures. Hypoglycemia and lactic acidosis can develop after a short fast (2-4 hours).
Untreated children typically have doll-like faces with full cheeks, relatively thin extremities, short stature, and a protuberant abdomen caused by massive hepatomegaly. The spleen may be enlarged in individuals with GSD Ib during infection, or while on treatment with G-CSF. Eruptive xanthoma may be present due to untreated hyperlipidemia and diarrhea may be present secondary to intolerance to uncooked cornstarch in some individuals, or due to inflammatory bowel-like disease. Impaired platelet function and acquired von Willebrand disease can lead to a bleeding tendency, making epistaxis and easy bruising a frequent problem in individuals with poor metabolic control.
Long-term complications of untreated GSD I include the following.
There is clinical controversy regarding the risk for cardiovascular disease in individuals with GSD I. Despite the development of hyperlipidemia in those with poor control, there is insufficient evidence indicating an increased risk of early atherosclerosis in these individuals [
Historically, prognosis was poor for untreated individuals with GSD I and many died at a young age. Early diagnosis and treatment have improved prognosis [
Better improvement of bone mineral density (BMD) is seen with optimized dietary treatment and vitamin D supplementation.
Severe anemia is often associated with hepatic adenomas, with kidney failure, persistent menorrhagia, poor nutrition, and is often multifactorial.
BMD was not associated with metabolic control or granulocyte colony-stimulating factor (G-CSF) treatment in individuals with GSD Ib, suggesting a multifactorial etiology [
Severe neutropenia and related enterocolitis and intestinal mucosal inflammation may occur in GSD Ib, leading to severe anemia. Note: Enterocolitis has been noted only in a small subset of individuals with GSD Ia.
Risk for thyroid autoimmunity and hypothyroidism is increased.
No strong genotype-phenotype correlations that can explain the clinical and biochemical features or the response to treatment have been identified for GSD I [
Individuals with GSD Ia who are homozygous for the pathogenic variant
G6Pase is a multicomponent enzyme complex often referred to as the G6Pase system. The classification of GSD I into four subtypes no longer exists. The current classification of GSD I subtypes is GSD Ia and GSD Ib.
Historically, GSD I is also referred to as von Gierke disease after Dr Edgar von Gierke, who first described the disease in 1929.
The overall incidence of GSD I is one in 100,000.
GSD Ia is the most common GSD subtype in individuals of European descent.
In Ashkenazi Jews the estimated carrier frequency of the most common pathogenic variant (
The increased frequency of some pathogenic variants in different ethnic groups (e.g.,
• Better improvement of bone mineral density (BMD) is seen with optimized dietary treatment and vitamin D supplementation.
• Severe anemia is often associated with hepatic adenomas, with kidney failure, persistent menorrhagia, poor nutrition, and is often multifactorial.
• BMD was not associated with metabolic control or granulocyte colony-stimulating factor (G-CSF) treatment in individuals with GSD Ib, suggesting a multifactorial etiology [
• Severe neutropenia and related enterocolitis and intestinal mucosal inflammation may occur in GSD Ib, leading to severe anemia. Note: Enterocolitis has been noted only in a small subset of individuals with GSD Ia.
• Risk for thyroid autoimmunity and hypothyroidism is increased.
## Clinical Description
The clinical manifestations of glycogen storage disease type I (GSD I) are poor growth (leading to short stature) and accumulation of glycogen and fat in liver and kidneys (resulting in hepatomegaly and nephromegaly, respectively) [
Although some neonates present with severe hypoglycemia, untreated infants more commonly present at age three to four months or a little later (when the feeding interval is typically increased or when infants start sleeping through the night) with additional symptoms of hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia, and/or hypoglycemic seizures. Hypoglycemia and lactic acidosis can develop after a short fast (2-4 hours).
Untreated children typically have doll-like faces with full cheeks, relatively thin extremities, short stature, and a protuberant abdomen caused by massive hepatomegaly. The spleen may be enlarged in individuals with GSD Ib during infection, or while on treatment with G-CSF. Eruptive xanthoma may be present due to untreated hyperlipidemia and diarrhea may be present secondary to intolerance to uncooked cornstarch in some individuals, or due to inflammatory bowel-like disease. Impaired platelet function and acquired von Willebrand disease can lead to a bleeding tendency, making epistaxis and easy bruising a frequent problem in individuals with poor metabolic control.
Long-term complications of untreated GSD I include the following.
There is clinical controversy regarding the risk for cardiovascular disease in individuals with GSD I. Despite the development of hyperlipidemia in those with poor control, there is insufficient evidence indicating an increased risk of early atherosclerosis in these individuals [
Historically, prognosis was poor for untreated individuals with GSD I and many died at a young age. Early diagnosis and treatment have improved prognosis [
## Prognosis
Historically, prognosis was poor for untreated individuals with GSD I and many died at a young age. Early diagnosis and treatment have improved prognosis [
## Phenotype Correlations by Gene
Better improvement of bone mineral density (BMD) is seen with optimized dietary treatment and vitamin D supplementation.
Severe anemia is often associated with hepatic adenomas, with kidney failure, persistent menorrhagia, poor nutrition, and is often multifactorial.
BMD was not associated with metabolic control or granulocyte colony-stimulating factor (G-CSF) treatment in individuals with GSD Ib, suggesting a multifactorial etiology [
Severe neutropenia and related enterocolitis and intestinal mucosal inflammation may occur in GSD Ib, leading to severe anemia. Note: Enterocolitis has been noted only in a small subset of individuals with GSD Ia.
Risk for thyroid autoimmunity and hypothyroidism is increased.
• Better improvement of bone mineral density (BMD) is seen with optimized dietary treatment and vitamin D supplementation.
• Severe anemia is often associated with hepatic adenomas, with kidney failure, persistent menorrhagia, poor nutrition, and is often multifactorial.
• BMD was not associated with metabolic control or granulocyte colony-stimulating factor (G-CSF) treatment in individuals with GSD Ib, suggesting a multifactorial etiology [
• Severe neutropenia and related enterocolitis and intestinal mucosal inflammation may occur in GSD Ib, leading to severe anemia. Note: Enterocolitis has been noted only in a small subset of individuals with GSD Ia.
• Risk for thyroid autoimmunity and hypothyroidism is increased.
## Genotype-Phenotype Correlations
No strong genotype-phenotype correlations that can explain the clinical and biochemical features or the response to treatment have been identified for GSD I [
Individuals with GSD Ia who are homozygous for the pathogenic variant
## Nomenclature
G6Pase is a multicomponent enzyme complex often referred to as the G6Pase system. The classification of GSD I into four subtypes no longer exists. The current classification of GSD I subtypes is GSD Ia and GSD Ib.
Historically, GSD I is also referred to as von Gierke disease after Dr Edgar von Gierke, who first described the disease in 1929.
## Prevalence
The overall incidence of GSD I is one in 100,000.
GSD Ia is the most common GSD subtype in individuals of European descent.
In Ashkenazi Jews the estimated carrier frequency of the most common pathogenic variant (
The increased frequency of some pathogenic variants in different ethnic groups (e.g.,
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders that can present clinically like glycogen storage disease type I (GSD I) include those summarized in
Disorders in the Differential Diagnosis of Glycogen Storage Disease Type I
Hepatomegaly
Fasting hypoglycemia
↑ AST/ALT
Hyperlipidemia
AST & ALT usually markedly ↑
Muscle involvement w/↑ CK
Normal uric acid, lactate
Hepatomegaly
Fasting hypoglycemia
↑ AST/ALT
Hepatomegaly
Growth failure
Hyperlipidemia
Pulmonary hypertension (rare)
Bone disease / osteoporosis
No fasting hypoglycemia
Significant splenomegaly
Bone infarcts, AVN of femoral head & pulmonary involvement in the form of pulmonary infiltrates
Hepatomegaly
↑ AST/ALT
Lack of hypoglycemia until end-stage liver disease
Liver cirrhosis
Fasting hypoglycemia
Ketosis
Absence of hepatomegaly
Postprandial hyperglycemia & hyperlactatemia
Hepatomegaly
Fasting ketosis
Hypoglycemia
↑ AST/ALT
↑ lipids
Male predominance
AST & ALT commonly more severely ↑
Liver fibrosis
Hepatomegaly
Fasting hypoglycemia
Fasting ketosis
↑ AST/ALT
Postprandial hyperglycemia
Chronic diarrhea
Hypophosphatemic rickets
Fanconi nephropathy
Significant short stature
Hepatomegaly
Growth failure
Hyperlipidemia
Bone & pulmonary involvement
No fasting hypoglycemia
Significant splenomegaly
Adapted from
AD = autosomal dominant; ALT = alanine aminotransferase; AR = autosomal recessive; ASMD = acid sphingomyelinase deficiency; AST = aspartate aminotransferase; AVN = avascular necrosis; CK = creatine kinase; GSD = glycogen storage disease; MOI = mode of inheritance; XL = X-linked
Fructose-1,6-bisphosphatase deficiency is one example of a disorder of gluconeogenesis; others should also be considered.
Niemann-Pick disease type B and Gaucher disease are examples of metabolic storage disorders; other metabolic storage disorders should also be considered.
• Hepatomegaly
• Fasting hypoglycemia
• ↑ AST/ALT
• Hyperlipidemia
• AST & ALT usually markedly ↑
• Muscle involvement w/↑ CK
• Normal uric acid, lactate
• Hepatomegaly
• Fasting hypoglycemia
• ↑ AST/ALT
• Hepatomegaly
• Growth failure
• Hyperlipidemia
• Pulmonary hypertension (rare)
• Bone disease / osteoporosis
• No fasting hypoglycemia
• Significant splenomegaly
• Bone infarcts, AVN of femoral head & pulmonary involvement in the form of pulmonary infiltrates
• Hepatomegaly
• ↑ AST/ALT
• Lack of hypoglycemia until end-stage liver disease
• Liver cirrhosis
• Fasting hypoglycemia
• Ketosis
• Absence of hepatomegaly
• Postprandial hyperglycemia & hyperlactatemia
• Hepatomegaly
• Fasting ketosis
• Hypoglycemia
• ↑ AST/ALT
• ↑ lipids
• Male predominance
• AST & ALT commonly more severely ↑
• Liver fibrosis
• Hepatomegaly
• Fasting hypoglycemia
• Fasting ketosis
• ↑ AST/ALT
• Postprandial hyperglycemia
• Chronic diarrhea
• Hypophosphatemic rickets
• Fanconi nephropathy
• Significant short stature
• Hepatomegaly
• Growth failure
• Hyperlipidemia
• Bone & pulmonary involvement
• No fasting hypoglycemia
• Significant splenomegaly
## Management
To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type I (GSD I), the evaluations summarized in
Recommended Evaluations at Initial Diagnosis in Individuals with Glycogen Storage Disease Type I
Serum/plasma concentration of glucose, lactic acid, uric acid, & lipids incl cholesterol & triglycerides, AST, ALT, bilirubin, albumin, PT/INR
Consultation w/metabolic specialist
Liver imaging to evaluate for hepatomegaly
Liver function tests
Measurement of length/height, weight; calculation of BMI
Eval of nutritional status
Echocardiogram to detect pulmonary hypertension when indicated
Lipid panel incl triglycerides
Developmental assessment
Assess for evidence of seizures.
Eval for anemia
Platelet aggregation studies & functional assay to evaluate platelet function
Von Willebrand factor antigen & activity
GSD Ib
GSD Ia due to homozygosity for
Assess for signs/symptoms of diarrhea, enterocolitis, &/or bowel ulcers.
Serum iron & ferritin
Community or
Social work involvement for parental support;
Home nursing referral.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Guidelines for management have been published by the American College of Medical Genetics [
Treatment includes care by a
Historical cornstarch dose recommendations based on body weight resulted in overtreatment and in poor metabolic control. Cornstarch therapy doses are now calculated based on glucose needs determined by hepatic glucose production rate [
Indications for liver transplant include large adenomas with a risk of malignant transformation, rapid increase in size and or number of adenomas, poor metabolic control, and lack of compliance leading to kidney failure (liver-kidney transplant is more beneficial in this case than kidney-only transplant). Liver-only transplant leads to normalization of the blood sugars, lactic acid, and triglycerides. This may delay the onset of kidney disease if clinically unaffected. However, it does not prevent kidney damage once renal disease has set in, warranting modification of the immunosuppressive medications and close monitoring of the kidney to prevent further progression of renal disease due to nephrotoxic effects of the medications.
Kidney transplantation can be performed for end-stage kidney disease (ESKD). Individuals who had kidney-only transplant must be monitored due to continued risk of liver metabolic disease and adenomas.
Combined liver and kidney transplantation is indicated as needed for restoration of metabolic control and treatment of kidney disease.
Perioperative care of individuals with GSD I is necessary particularly when undergoing partial hepatectomy for HCA with a risk of hemorrhage [
G-CSF should be administered subcutaneously starting at 1.0 μg/kg daily or every other day. The dose should be increased stepwise at approximately two-week intervals until the target absolute neutrophil count (ANC) of 500 to 1.0 x 10
Individuals on G-CSF should be monitored closely for changes in spleen size (particularly in the absence of infection) and signs of myelodysplasia [
Follow
Perform home
Recommended Surveillance for Individuals with Glycogen Storage Disease Type I
Every 6-12 mos beginning at age 16 yrs; earlier in those w/hepatic adenomas
Precautions against contrast-assoc kidney injury in those w/signs of kidney involvement
Measurement of length/height, weight; calculation of BMI
Eval of bone age if clinically indicated
Eval of nutritional status
Serum creatinine, uric acid
Urine microalbumin/creatinine in random (spot) urine sample
Citrate in urine for risk of stone formation
Eval by gastroenterologist
Assess w/Pediatric Crohn’s Disease Activity Index.
DD = developmental delay; TIBC = total iron binding capacity
Serum AFP and CEA levels are not reliable markers of hepatocellular carcinoma [
Avoid sucrose, galactose, fructose, high-fructose corn syrup, honey, maple syrup, molasses, agave nectar, and sorbitol.
Due to potential negative effects of sex hormones (containing estrogen) on hepatic adenomas, combined oral contraception (including high-dose estrogen) should be avoided in women with GSD I, especially those with adenomas [
Metformin and lactate-containing infusions such as Ringer’s lactate should be avoided.
Amoxicillin/clavulanic acid has been associated with an increased risk of diarrhea in individuals with GSD I (common); there is also a risk for idiopathic liver failure due to clavulanic acid (rare).
Glucagon should not be used to treat hypoglycemia because it is ineffective and may increase the risk of lactic acidosis.
Evaluation of sibs of a proband as early as possible allows for prompt diagnosis and treatment with much-improved outcome. Evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Evaluation by a metabolic physician soon after birth for symptoms pertaining to GSD I if the family-specific pathogenic variants are not known or if molecular genetic testing is not available.
See
Although successful pregnancies have been reported in women with GSD I, certain precautions should be taken:
Pre-pregnancy counseling regarding diet to avoid low blood glucose and to stress the importance of blood glucose monitoring prior to and during pregnancy
Baseline ultrasound of liver and kidneys prior to pregnancy
Consideration of referral to high-risk obstetrician
Review of medications prior to conception to weigh risks and benefits:
Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.
Metabolic control should be followed closely throughout the pregnancy. Because carbohydrate requirements may increase with pregnancy, glucose levels should be monitored closely and treated accordingly [
Abdominal ultrasound should be performed every six to 12 weeks.
Renal function should be followed closely, as this may worsen during pregnancy [
Glucose infusion during labor has been used [
Platelet count, hemoglobin, and clotting studies should be performed because of the potential for increased bleeding at delivery [
Current dietary treatment prevents hypoglycemia and greatly improves the life expectancy of individuals with GSD I. However, long-term complications – including progressive kidney failure and development of hepatic adenomas that progress to hepatocellular carcinoma – still occur. The development of new therapies for GSD I has recently evolved into new concepts involving the following:
A Phase I/II clinical trial,
Search
• Serum/plasma concentration of glucose, lactic acid, uric acid, & lipids incl cholesterol & triglycerides, AST, ALT, bilirubin, albumin, PT/INR
• Consultation w/metabolic specialist
• Liver imaging to evaluate for hepatomegaly
• Liver function tests
• Measurement of length/height, weight; calculation of BMI
• Eval of nutritional status
• Echocardiogram to detect pulmonary hypertension when indicated
• Lipid panel incl triglycerides
• Developmental assessment
• Assess for evidence of seizures.
• Eval for anemia
• Platelet aggregation studies & functional assay to evaluate platelet function
• Von Willebrand factor antigen & activity
• GSD Ib
• GSD Ia due to homozygosity for
• Assess for signs/symptoms of diarrhea, enterocolitis, &/or bowel ulcers.
• Serum iron & ferritin
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Historical cornstarch dose recommendations based on body weight resulted in overtreatment and in poor metabolic control. Cornstarch therapy doses are now calculated based on glucose needs determined by hepatic glucose production rate [
• Every 6-12 mos beginning at age 16 yrs; earlier in those w/hepatic adenomas
• Precautions against contrast-assoc kidney injury in those w/signs of kidney involvement
• Measurement of length/height, weight; calculation of BMI
• Eval of bone age if clinically indicated
• Eval of nutritional status
• Serum creatinine, uric acid
• Urine microalbumin/creatinine in random (spot) urine sample
• Citrate in urine for risk of stone formation
• Eval by gastroenterologist
• Assess w/Pediatric Crohn’s Disease Activity Index.
• Molecular genetic testing if the pathogenic variants in the family are known;
• Evaluation by a metabolic physician soon after birth for symptoms pertaining to GSD I if the family-specific pathogenic variants are not known or if molecular genetic testing is not available.
• Pre-pregnancy counseling regarding diet to avoid low blood glucose and to stress the importance of blood glucose monitoring prior to and during pregnancy
• Baseline ultrasound of liver and kidneys prior to pregnancy
• Consideration of referral to high-risk obstetrician
• Review of medications prior to conception to weigh risks and benefits:
• Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
• No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
• Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.
• Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
• No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
• Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.
• Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
• No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
• Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.
• A Phase I/II clinical trial,
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type I (GSD I), the evaluations summarized in
Recommended Evaluations at Initial Diagnosis in Individuals with Glycogen Storage Disease Type I
Serum/plasma concentration of glucose, lactic acid, uric acid, & lipids incl cholesterol & triglycerides, AST, ALT, bilirubin, albumin, PT/INR
Consultation w/metabolic specialist
Liver imaging to evaluate for hepatomegaly
Liver function tests
Measurement of length/height, weight; calculation of BMI
Eval of nutritional status
Echocardiogram to detect pulmonary hypertension when indicated
Lipid panel incl triglycerides
Developmental assessment
Assess for evidence of seizures.
Eval for anemia
Platelet aggregation studies & functional assay to evaluate platelet function
Von Willebrand factor antigen & activity
GSD Ib
GSD Ia due to homozygosity for
Assess for signs/symptoms of diarrhea, enterocolitis, &/or bowel ulcers.
Serum iron & ferritin
Community or
Social work involvement for parental support;
Home nursing referral.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Serum/plasma concentration of glucose, lactic acid, uric acid, & lipids incl cholesterol & triglycerides, AST, ALT, bilirubin, albumin, PT/INR
• Consultation w/metabolic specialist
• Liver imaging to evaluate for hepatomegaly
• Liver function tests
• Measurement of length/height, weight; calculation of BMI
• Eval of nutritional status
• Echocardiogram to detect pulmonary hypertension when indicated
• Lipid panel incl triglycerides
• Developmental assessment
• Assess for evidence of seizures.
• Eval for anemia
• Platelet aggregation studies & functional assay to evaluate platelet function
• Von Willebrand factor antigen & activity
• GSD Ib
• GSD Ia due to homozygosity for
• Assess for signs/symptoms of diarrhea, enterocolitis, &/or bowel ulcers.
• Serum iron & ferritin
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Guidelines for management have been published by the American College of Medical Genetics [
Treatment includes care by a
Historical cornstarch dose recommendations based on body weight resulted in overtreatment and in poor metabolic control. Cornstarch therapy doses are now calculated based on glucose needs determined by hepatic glucose production rate [
Indications for liver transplant include large adenomas with a risk of malignant transformation, rapid increase in size and or number of adenomas, poor metabolic control, and lack of compliance leading to kidney failure (liver-kidney transplant is more beneficial in this case than kidney-only transplant). Liver-only transplant leads to normalization of the blood sugars, lactic acid, and triglycerides. This may delay the onset of kidney disease if clinically unaffected. However, it does not prevent kidney damage once renal disease has set in, warranting modification of the immunosuppressive medications and close monitoring of the kidney to prevent further progression of renal disease due to nephrotoxic effects of the medications.
Kidney transplantation can be performed for end-stage kidney disease (ESKD). Individuals who had kidney-only transplant must be monitored due to continued risk of liver metabolic disease and adenomas.
Combined liver and kidney transplantation is indicated as needed for restoration of metabolic control and treatment of kidney disease.
Perioperative care of individuals with GSD I is necessary particularly when undergoing partial hepatectomy for HCA with a risk of hemorrhage [
G-CSF should be administered subcutaneously starting at 1.0 μg/kg daily or every other day. The dose should be increased stepwise at approximately two-week intervals until the target absolute neutrophil count (ANC) of 500 to 1.0 x 10
Individuals on G-CSF should be monitored closely for changes in spleen size (particularly in the absence of infection) and signs of myelodysplasia [
• Historical cornstarch dose recommendations based on body weight resulted in overtreatment and in poor metabolic control. Cornstarch therapy doses are now calculated based on glucose needs determined by hepatic glucose production rate [
## Surveillance
Follow
Perform home
Recommended Surveillance for Individuals with Glycogen Storage Disease Type I
Every 6-12 mos beginning at age 16 yrs; earlier in those w/hepatic adenomas
Precautions against contrast-assoc kidney injury in those w/signs of kidney involvement
Measurement of length/height, weight; calculation of BMI
Eval of bone age if clinically indicated
Eval of nutritional status
Serum creatinine, uric acid
Urine microalbumin/creatinine in random (spot) urine sample
Citrate in urine for risk of stone formation
Eval by gastroenterologist
Assess w/Pediatric Crohn’s Disease Activity Index.
DD = developmental delay; TIBC = total iron binding capacity
Serum AFP and CEA levels are not reliable markers of hepatocellular carcinoma [
• Every 6-12 mos beginning at age 16 yrs; earlier in those w/hepatic adenomas
• Precautions against contrast-assoc kidney injury in those w/signs of kidney involvement
• Measurement of length/height, weight; calculation of BMI
• Eval of bone age if clinically indicated
• Eval of nutritional status
• Serum creatinine, uric acid
• Urine microalbumin/creatinine in random (spot) urine sample
• Citrate in urine for risk of stone formation
• Eval by gastroenterologist
• Assess w/Pediatric Crohn’s Disease Activity Index.
## Agents/Circumstances to Avoid
Avoid sucrose, galactose, fructose, high-fructose corn syrup, honey, maple syrup, molasses, agave nectar, and sorbitol.
Due to potential negative effects of sex hormones (containing estrogen) on hepatic adenomas, combined oral contraception (including high-dose estrogen) should be avoided in women with GSD I, especially those with adenomas [
Metformin and lactate-containing infusions such as Ringer’s lactate should be avoided.
Amoxicillin/clavulanic acid has been associated with an increased risk of diarrhea in individuals with GSD I (common); there is also a risk for idiopathic liver failure due to clavulanic acid (rare).
Glucagon should not be used to treat hypoglycemia because it is ineffective and may increase the risk of lactic acidosis.
## Evaluation of Relatives at Risk
Evaluation of sibs of a proband as early as possible allows for prompt diagnosis and treatment with much-improved outcome. Evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Evaluation by a metabolic physician soon after birth for symptoms pertaining to GSD I if the family-specific pathogenic variants are not known or if molecular genetic testing is not available.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Evaluation by a metabolic physician soon after birth for symptoms pertaining to GSD I if the family-specific pathogenic variants are not known or if molecular genetic testing is not available.
## Pregnancy Management
Although successful pregnancies have been reported in women with GSD I, certain precautions should be taken:
Pre-pregnancy counseling regarding diet to avoid low blood glucose and to stress the importance of blood glucose monitoring prior to and during pregnancy
Baseline ultrasound of liver and kidneys prior to pregnancy
Consideration of referral to high-risk obstetrician
Review of medications prior to conception to weigh risks and benefits:
Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.
Metabolic control should be followed closely throughout the pregnancy. Because carbohydrate requirements may increase with pregnancy, glucose levels should be monitored closely and treated accordingly [
Abdominal ultrasound should be performed every six to 12 weeks.
Renal function should be followed closely, as this may worsen during pregnancy [
Glucose infusion during labor has been used [
Platelet count, hemoglobin, and clotting studies should be performed because of the potential for increased bleeding at delivery [
• Pre-pregnancy counseling regarding diet to avoid low blood glucose and to stress the importance of blood glucose monitoring prior to and during pregnancy
• Baseline ultrasound of liver and kidneys prior to pregnancy
• Consideration of referral to high-risk obstetrician
• Review of medications prior to conception to weigh risks and benefits:
• Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
• No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
• Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.
• Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
• No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
• Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.
• Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
• No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
• Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.
## Therapies Under Investigation
Current dietary treatment prevents hypoglycemia and greatly improves the life expectancy of individuals with GSD I. However, long-term complications – including progressive kidney failure and development of hepatic adenomas that progress to hepatocellular carcinoma – still occur. The development of new therapies for GSD I has recently evolved into new concepts involving the following:
A Phase I/II clinical trial,
Search
• A Phase I/II clinical trial,
## Genetic Counseling
Glycogen storage disease type I (GSD I) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GSD I-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a GSD I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GSD I-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a GSD I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Glycogen storage disease type I (GSD I) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GSD I-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a GSD I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a GSD I-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a GSD I-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
Glycogen Storage Disease Type I: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Glycogen Storage Disease Type I (
Glycogen Storage Disease Type I: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Silent amino acid change (Leu216Leu) that creates a new splice site resulting in premature termination at p.Tyr202Ter [
## Molecular Pathogenesis
Glycogen Storage Disease Type I: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Silent amino acid change (Leu216Leu) that creates a new splice site resulting in premature termination at p.Tyr202Ter [
## Chapter Notes
We acknowledge the
Jennifer Austin, MS, MA, CGC (2016-present)Deeksha S Bali, PhD (2006-present)Yuan-Tsong Chen, MD, PhD; Duke University Medical Center (2006-2021)Areeg El-Gharbawy, MD (2021-present)Jennifer L Goldstein, PhD, MS, CGC; University of North Carolina – Chapel Hill (2010-2021)Priya S Kishnani, MD (2021-present)Surekha Pendyal, MSc, Med, RD, FAND (2021-present)
14 October 2021 (sw) Comprehensive update posted live
25 August 2016 (sw) Comprehensive update posted live
19 September 2013 (me) Comprehensive update posted live
23 December 2010 (me) Comprehensive update posted live
2 September 2008 (me) Comprehensive update posted live
19 April 2006 (me) Review posted live
30 March 2005 (ytc) Original submission
• 14 October 2021 (sw) Comprehensive update posted live
• 25 August 2016 (sw) Comprehensive update posted live
• 19 September 2013 (me) Comprehensive update posted live
• 23 December 2010 (me) Comprehensive update posted live
• 2 September 2008 (me) Comprehensive update posted live
• 19 April 2006 (me) Review posted live
• 30 March 2005 (ytc) Original submission
## Acknowledgments
We acknowledge the
## Author History
Jennifer Austin, MS, MA, CGC (2016-present)Deeksha S Bali, PhD (2006-present)Yuan-Tsong Chen, MD, PhD; Duke University Medical Center (2006-2021)Areeg El-Gharbawy, MD (2021-present)Jennifer L Goldstein, PhD, MS, CGC; University of North Carolina – Chapel Hill (2010-2021)Priya S Kishnani, MD (2021-present)Surekha Pendyal, MSc, Med, RD, FAND (2021-present)
## Revision History
14 October 2021 (sw) Comprehensive update posted live
25 August 2016 (sw) Comprehensive update posted live
19 September 2013 (me) Comprehensive update posted live
23 December 2010 (me) Comprehensive update posted live
2 September 2008 (me) Comprehensive update posted live
19 April 2006 (me) Review posted live
30 March 2005 (ytc) Original submission
• 14 October 2021 (sw) Comprehensive update posted live
• 25 August 2016 (sw) Comprehensive update posted live
• 19 September 2013 (me) Comprehensive update posted live
• 23 December 2010 (me) Comprehensive update posted live
• 2 September 2008 (me) Comprehensive update posted live
• 19 April 2006 (me) Review posted live
• 30 March 2005 (ytc) Original submission
## References
## Literature Cited
|
[] |
19/4/2006
|
14/10/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
gsd2
|
gsd2
|
[
"Acid Alpha-Glucosidase Deficiency",
"Acid Maltase Deficiency",
"GAA Deficiency",
"Glycogenosis Type II",
"Glycogen Storage Disease Type II (GSD II)",
"Acid Alpha-Glucosidase Deficiency",
"Acid Maltase Deficiency",
"GAA Deficiency",
"Glycogen Storage Disease Type II (GSD II)",
"Glycogenosis Type II",
"Lysosomal alpha-glucosidase",
"GAA",
"Pompe Disease"
] |
Pompe Disease
|
Ethan Sperry, Nancy Leslie, Lisa Berry, Loren Pena
|
Summary Pompe disease can be classified by age of onset, organ involvement, severity, and rate of progression into infantile-onset Pompe disease (IOPD) (i.e., individuals with onset before age 12 months with cardiomyopathy) and late-onset Pompe disease (LOPD) (i.e., individuals with onset before age 12 months without cardiomyopathy, and all individuals with onset after age 12 months). Untreated individuals with IOPD typically have hypotonia, generalized muscle weakness, feeding difficulties, poor growth, and respiratory distress. Cardiomegaly and hypertrophic cardiomyopathy is usually identified in the first weeks of life and progress to left ventricular outflow obstruction and diminished lung volume. Progressive deposition of glycogen results in conduction defects with shortening of the PR interval on EKG. In untreated infants, death commonly occurs in the first two years of life from cardiopulmonary insufficiency. In those in whom enzyme replacement therapy (ERT) is initiated before age six months and before the need for ventilatory assistance, a majority have improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills compared to untreated individuals. LOPD can manifest from the first decade to as late as the seventh decade of life with progressive proximal muscle weakness primarily affecting the lower limbs, which may require use of a wheelchair. Respiratory insufficiency progressing to respiratory failure is a significant cause of morbidity and mortality. Some adults have developed arteriopathy, including dilatation of the ascending thoracic aorta. Scoliosis is also frequent. The diagnosis of Pompe disease is established in a proband who has deficiency of acid alpha-glucosidase (GAA) enzyme activity in isolated lymphocytes or mixed leukocytes and/or by identification of biallelic pathogenic (or likely pathogenic) variants in Pompe disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Pompe disease can be classified by age of onset, organ involvement, severity, and rate of progression:
Individuals with onset before age 12 months without cardiomyopathy
All individuals with onset after age 12 months
A diagnosis of Pompe disease may be suspected due to an
NBS for Pompe disease is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify acid alpha-glucosidase (GAA) enzyme activity. Pompe disease is included in the United States (US) Secretary of Health and Human Services
In the US most NBS laboratories determine their own cut-off levels for test results that are considered to be out of range and require further laboratory testing. For Pompe disease, follow-up testing typically includes molecular genetic testing (see
Further evaluations following an out-of-range NBS result while awaiting confirmatory testing may also include physical examination, echocardiography to assess for cardiac hypertrophy, a serum creatine kinase (CK) level, and urinary glucotetrasaccharide (Hex4).
A symptomatic individual can have either typical findings associated with later-onset Pompe disease or untreated infantile-onset Pompe disease resulting from any of the following: NBS not performed, false negative NBS result, symptoms prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result.
Poor feeding with poor growth
Motor delay / muscle weakness
Respiratory infections/difficulty
Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
Proximal muscular weakness
Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
The sensitivity of this assay is diminished in individuals with LOPD.
Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
The diagnosis of Pompe disease
As a general rule, the lower the GAA enzyme activity, the earlier the age of onset of disease:
Complete deficiency of GAA enzyme activity (<1% of normal controls) is associated with IOPD.
Partial deficiency of GAA enzyme activity (2%-40% of normal controls) is associated with LOPD.
The measurement of GAA enzyme activity in vitro may not reflect true in vivo activity, leading to what is known as pseudodeficiency.
The molecular diagnosis of Pompe
Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of Pompe disease, molecular genetic testing approaches can include
Note: Caution must be exercised in correlating results from molecular genetic testing and enzyme analysis in the absence of clinical features of Pompe disease because the presence of pseudodeficiency alleles (including NM_000152.3:c.1726 G>A [p.Gly576Ser] and NM_000152.3:c.2065G>A [p.Glu689Lys], which are relatively common in individuals of Asian ancestry) interferes with the interpretation of enzyme testing in NBS programs (confirmed by screening programs in Missouri and New York) [Kroos et al 2006, Lin et al 2017, Peruzzo et al 2019, de Faria et al 2021].
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Pompe Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020], Peruzzo et al [2019], and Moschetti et al [2024]
Several complex rearrangements in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Deletion of exon 18 comprises approximately 5%-7% of alleles [Van der Kraan et al 1994]. Although other exon and multiexon deletions have been reported, they are rare [McCready et al 2007, Pittis et al 2008, Bali et al 2012, Amiñoso et al 2013].
•
• Individuals with onset before age 12 months without cardiomyopathy
• All individuals with onset after age 12 months
• Individuals with onset before age 12 months without cardiomyopathy
• All individuals with onset after age 12 months
• Individuals with onset before age 12 months without cardiomyopathy
• All individuals with onset after age 12 months
•
• Poor feeding with poor growth
• Motor delay / muscle weakness
• Respiratory infections/difficulty
• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
• Poor feeding with poor growth
• Motor delay / muscle weakness
• Respiratory infections/difficulty
• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
•
• Proximal muscular weakness
• Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
• Proximal muscular weakness
• Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
• Poor feeding with poor growth
• Motor delay / muscle weakness
• Respiratory infections/difficulty
• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
• Proximal muscular weakness
• Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
• Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
• Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
• Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
• Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
• The sensitivity of this assay is diminished in individuals with LOPD.
• Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
• The sensitivity of this assay is diminished in individuals with LOPD.
• Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
• Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
• Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
• The sensitivity of this assay is diminished in individuals with LOPD.
• Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
• Complete deficiency of GAA enzyme activity (<1% of normal controls) is associated with IOPD.
• Partial deficiency of GAA enzyme activity (2%-40% of normal controls) is associated with LOPD.
• The measurement of GAA enzyme activity in vitro may not reflect true in vivo activity, leading to what is known as pseudodeficiency.
• Note: Caution must be exercised in correlating results from molecular genetic testing and enzyme analysis in the absence of clinical features of Pompe disease because the presence of pseudodeficiency alleles (including NM_000152.3:c.1726 G>A [p.Gly576Ser] and NM_000152.3:c.2065G>A [p.Glu689Lys], which are relatively common in individuals of Asian ancestry) interferes with the interpretation of enzyme testing in NBS programs (confirmed by screening programs in Missouri and New York) [Kroos et al 2006, Lin et al 2017, Peruzzo et al 2019, de Faria et al 2021].
• For an introduction to multigene panels click
## Suggestive Findings
A diagnosis of Pompe disease may be suspected due to an
NBS for Pompe disease is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify acid alpha-glucosidase (GAA) enzyme activity. Pompe disease is included in the United States (US) Secretary of Health and Human Services
In the US most NBS laboratories determine their own cut-off levels for test results that are considered to be out of range and require further laboratory testing. For Pompe disease, follow-up testing typically includes molecular genetic testing (see
Further evaluations following an out-of-range NBS result while awaiting confirmatory testing may also include physical examination, echocardiography to assess for cardiac hypertrophy, a serum creatine kinase (CK) level, and urinary glucotetrasaccharide (Hex4).
A symptomatic individual can have either typical findings associated with later-onset Pompe disease or untreated infantile-onset Pompe disease resulting from any of the following: NBS not performed, false negative NBS result, symptoms prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result.
Poor feeding with poor growth
Motor delay / muscle weakness
Respiratory infections/difficulty
Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
Proximal muscular weakness
Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
The sensitivity of this assay is diminished in individuals with LOPD.
Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
•
• Poor feeding with poor growth
• Motor delay / muscle weakness
• Respiratory infections/difficulty
• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
• Poor feeding with poor growth
• Motor delay / muscle weakness
• Respiratory infections/difficulty
• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
•
• Proximal muscular weakness
• Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
• Proximal muscular weakness
• Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
• Poor feeding with poor growth
• Motor delay / muscle weakness
• Respiratory infections/difficulty
• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
• Proximal muscular weakness
• Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
• Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
• Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
• Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
• Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
• The sensitivity of this assay is diminished in individuals with LOPD.
• Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
• The sensitivity of this assay is diminished in individuals with LOPD.
• Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
• Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
• Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
• The sensitivity of this assay is diminished in individuals with LOPD.
• Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
## Out-of-Range NBS Result
NBS for Pompe disease is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify acid alpha-glucosidase (GAA) enzyme activity. Pompe disease is included in the United States (US) Secretary of Health and Human Services
In the US most NBS laboratories determine their own cut-off levels for test results that are considered to be out of range and require further laboratory testing. For Pompe disease, follow-up testing typically includes molecular genetic testing (see
Further evaluations following an out-of-range NBS result while awaiting confirmatory testing may also include physical examination, echocardiography to assess for cardiac hypertrophy, a serum creatine kinase (CK) level, and urinary glucotetrasaccharide (Hex4).
## Symptomatic Individual
A symptomatic individual can have either typical findings associated with later-onset Pompe disease or untreated infantile-onset Pompe disease resulting from any of the following: NBS not performed, false negative NBS result, symptoms prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result.
Poor feeding with poor growth
Motor delay / muscle weakness
Respiratory infections/difficulty
Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
Proximal muscular weakness
Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
The sensitivity of this assay is diminished in individuals with LOPD.
Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
•
• Poor feeding with poor growth
• Motor delay / muscle weakness
• Respiratory infections/difficulty
• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
• Poor feeding with poor growth
• Motor delay / muscle weakness
• Respiratory infections/difficulty
• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
•
• Proximal muscular weakness
• Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
• Proximal muscular weakness
• Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
• Poor feeding with poor growth
• Motor delay / muscle weakness
• Respiratory infections/difficulty
• Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy)
• Proximal muscular weakness
• Respiratory insufficiency without clinically apparent cardiac involvement that may be more severe than expected for the level of skeletal myopathy
• Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
• Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
• Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
• Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
• The sensitivity of this assay is diminished in individuals with LOPD.
• Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
• The sensitivity of this assay is diminished in individuals with LOPD.
• Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
• Present in all individuals with IOPD and in some with LOPD (may be normal in some individuals with LOPD)
• Because elevated serum CK concentration is observed in many conditions, it must be considered nonspecific.
• The sensitivity of this assay is diminished in individuals with LOPD.
• Urinary glucotetrasaccharide has been useful in evaluating infants with an out-of-range result on NBS.
## Establishing the Diagnosis
The diagnosis of Pompe disease
As a general rule, the lower the GAA enzyme activity, the earlier the age of onset of disease:
Complete deficiency of GAA enzyme activity (<1% of normal controls) is associated with IOPD.
Partial deficiency of GAA enzyme activity (2%-40% of normal controls) is associated with LOPD.
The measurement of GAA enzyme activity in vitro may not reflect true in vivo activity, leading to what is known as pseudodeficiency.
The molecular diagnosis of Pompe
Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of Pompe disease, molecular genetic testing approaches can include
Note: Caution must be exercised in correlating results from molecular genetic testing and enzyme analysis in the absence of clinical features of Pompe disease because the presence of pseudodeficiency alleles (including NM_000152.3:c.1726 G>A [p.Gly576Ser] and NM_000152.3:c.2065G>A [p.Glu689Lys], which are relatively common in individuals of Asian ancestry) interferes with the interpretation of enzyme testing in NBS programs (confirmed by screening programs in Missouri and New York) [Kroos et al 2006, Lin et al 2017, Peruzzo et al 2019, de Faria et al 2021].
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Pompe Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020], Peruzzo et al [2019], and Moschetti et al [2024]
Several complex rearrangements in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Deletion of exon 18 comprises approximately 5%-7% of alleles [Van der Kraan et al 1994]. Although other exon and multiexon deletions have been reported, they are rare [McCready et al 2007, Pittis et al 2008, Bali et al 2012, Amiñoso et al 2013].
• Complete deficiency of GAA enzyme activity (<1% of normal controls) is associated with IOPD.
• Partial deficiency of GAA enzyme activity (2%-40% of normal controls) is associated with LOPD.
• The measurement of GAA enzyme activity in vitro may not reflect true in vivo activity, leading to what is known as pseudodeficiency.
• Note: Caution must be exercised in correlating results from molecular genetic testing and enzyme analysis in the absence of clinical features of Pompe disease because the presence of pseudodeficiency alleles (including NM_000152.3:c.1726 G>A [p.Gly576Ser] and NM_000152.3:c.2065G>A [p.Glu689Lys], which are relatively common in individuals of Asian ancestry) interferes with the interpretation of enzyme testing in NBS programs (confirmed by screening programs in Missouri and New York) [Kroos et al 2006, Lin et al 2017, Peruzzo et al 2019, de Faria et al 2021].
• For an introduction to multigene panels click
## Biochemical/Enzymatic Diagnosis
The diagnosis of Pompe disease
As a general rule, the lower the GAA enzyme activity, the earlier the age of onset of disease:
Complete deficiency of GAA enzyme activity (<1% of normal controls) is associated with IOPD.
Partial deficiency of GAA enzyme activity (2%-40% of normal controls) is associated with LOPD.
The measurement of GAA enzyme activity in vitro may not reflect true in vivo activity, leading to what is known as pseudodeficiency.
• Complete deficiency of GAA enzyme activity (<1% of normal controls) is associated with IOPD.
• Partial deficiency of GAA enzyme activity (2%-40% of normal controls) is associated with LOPD.
• The measurement of GAA enzyme activity in vitro may not reflect true in vivo activity, leading to what is known as pseudodeficiency.
## Molecular Diagnosis
The molecular diagnosis of Pompe
Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of Pompe disease, molecular genetic testing approaches can include
Note: Caution must be exercised in correlating results from molecular genetic testing and enzyme analysis in the absence of clinical features of Pompe disease because the presence of pseudodeficiency alleles (including NM_000152.3:c.1726 G>A [p.Gly576Ser] and NM_000152.3:c.2065G>A [p.Glu689Lys], which are relatively common in individuals of Asian ancestry) interferes with the interpretation of enzyme testing in NBS programs (confirmed by screening programs in Missouri and New York) [Kroos et al 2006, Lin et al 2017, Peruzzo et al 2019, de Faria et al 2021].
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Pompe Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020], Peruzzo et al [2019], and Moschetti et al [2024]
Several complex rearrangements in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Deletion of exon 18 comprises approximately 5%-7% of alleles [Van der Kraan et al 1994]. Although other exon and multiexon deletions have been reported, they are rare [McCready et al 2007, Pittis et al 2008, Bali et al 2012, Amiñoso et al 2013].
• Note: Caution must be exercised in correlating results from molecular genetic testing and enzyme analysis in the absence of clinical features of Pompe disease because the presence of pseudodeficiency alleles (including NM_000152.3:c.1726 G>A [p.Gly576Ser] and NM_000152.3:c.2065G>A [p.Glu689Lys], which are relatively common in individuals of Asian ancestry) interferes with the interpretation of enzyme testing in NBS programs (confirmed by screening programs in Missouri and New York) [Kroos et al 2006, Lin et al 2017, Peruzzo et al 2019, de Faria et al 2021].
• For an introduction to multigene panels click
##
When the phenotypic and laboratory findings suggest the diagnosis of Pompe disease, molecular genetic testing approaches can include
Note: Caution must be exercised in correlating results from molecular genetic testing and enzyme analysis in the absence of clinical features of Pompe disease because the presence of pseudodeficiency alleles (including NM_000152.3:c.1726 G>A [p.Gly576Ser] and NM_000152.3:c.2065G>A [p.Glu689Lys], which are relatively common in individuals of Asian ancestry) interferes with the interpretation of enzyme testing in NBS programs (confirmed by screening programs in Missouri and New York) [Kroos et al 2006, Lin et al 2017, Peruzzo et al 2019, de Faria et al 2021].
For an introduction to multigene panels click
• Note: Caution must be exercised in correlating results from molecular genetic testing and enzyme analysis in the absence of clinical features of Pompe disease because the presence of pseudodeficiency alleles (including NM_000152.3:c.1726 G>A [p.Gly576Ser] and NM_000152.3:c.2065G>A [p.Glu689Lys], which are relatively common in individuals of Asian ancestry) interferes with the interpretation of enzyme testing in NBS programs (confirmed by screening programs in Missouri and New York) [Kroos et al 2006, Lin et al 2017, Peruzzo et al 2019, de Faria et al 2021].
• For an introduction to multigene panels click
##
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Pompe Disease
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020], Peruzzo et al [2019], and Moschetti et al [2024]
Several complex rearrangements in
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Deletion of exon 18 comprises approximately 5%-7% of alleles [Van der Kraan et al 1994]. Although other exon and multiexon deletions have been reported, they are rare [McCready et al 2007, Pittis et al 2008, Bali et al 2012, Amiñoso et al 2013].
## Clinical Characteristics
Traditionally, Pompe disease has been separated into two major phenotypes – infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD) –based on age of onset, organ involvement (i.e., presence of cardiomyopathy), severity, and rate of progression. As a general rule, the earlier the onset of manifestations, the faster the rate of progression; thus, the two general classifications – IOPD and LOPD – tend to be clinically useful in determining prognosis and treatment options.
Although LOPD has been divided into childhood-, juvenile-, and adult-onset disease, many individuals with adult-onset disease recall symptoms beginning in childhood and, thus, late onset is often the preferred term for those presenting after age 12 months. Most likely, LOPD represents a clinical continuum in which age of onset cannot reliably distinguish subtype [Kishnani et al 2013].
Newborn screening (NBS) and the availability of enzyme replacement therapy (ERT) for affected individuals is changing the clinical course of individuals with Pompe disease.
Most of the literature on long-term clinical outcomes after initiation of ERT does not include significant numbers of individuals treated very early (those ascertained by NBS or known family history).
In those in whom ERT was initiated before age six months and before the need for ventilatory assistance, a majority had improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills compared to an untreated cohort.
Predictors of a poor response to ERT include increase in muscle glycogen during therapy, high IgG titers to alpha-glucosidase, and a negative cross-reactive immunologic material (CRIM) status. An individual is considered CRIM negative when that individual is unable to synthesize non-functional but immunoreactive protein; in this situation, providing ERT may induce an immune response in the affected individual, resulting in significantly decreased efficacy of ERT.
Prenatal ERT was carried out in a single individual with predicated IOPD based on family history and who was CRIM negative [Cohen et al 2022].
Six infusions of ERT were administered through the umbilical vein between 24 and 34 weeks' gestation.
At 13 months of postnatal life, this individual (who was subsequently treated with immunomodulation and ERT beginning on day one of life) was reported to be doing well, including having significantly better early measurements of left ventricular mass index in comparison to those of other affected neonates with CRIM-negative IOPD who were not treated prenatally.
Follow-up data on affected individuals revealed progressive skeletal muscle involvement with increasing age, particularly in those with later initiation of ERT and later initiation of higher-dose ERT [Chien et al 2020].
In a separate group of affected individuals who received hydrocortisone 2 mg/kg as a premedication for ERT [Yang et al 2023], motor function may be better preserved, although this group is younger than those described in Chien et al [2020].
ERT reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].
ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].
Assessment of cognitive abilities is difficult in children with IOPD who are younger than age five years; typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012].
Estimates of cognitive abilities at age 24 months using the Bayley scales showed preservation of cognitive abilities in infants ascertained by NBS and treated early with ERT [Lai et al 2016].
However, both MRI abnormalities and decline in full-scale IQ, performance IQ, and processing speed have been reported in a cohort of ERT-treated individuals, age 15-22.5 years [van den Dorpel et al 2024].
IOPD may be apparent in utero but, prior to NBS, was more often clinically recognized at a median age of four months in individuals with hypotonia, generalized muscle weakness, feeding difficulties, poor growth, and respiratory distress (see
Common Findings at Presentation of Infantile-Onset Pompe Disease in Individuals Who Were Not Diagnosed Through Newborn Screening
Hirschhorn & Reuser [2001], van den Hout et al [2003]
Enlargement of the heart can also result in diminished lung volume, atelectasis, and sometimes bronchial compression (see
Progressive deposition of glycogen results in conduction defects as seen by shortening of the PR interval on EKG.
Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease.
Nerve conduction velocity is typically normal for both motor and sensory nerves.
However, an evolving motor axonal neuropathy has been demonstrated in one child at age two years and in another at age six years [Burrow et al 2010, Schanzer et al 2019].
EMG and nerve conduction velocity (NCV) findings do not appear to be impacted by ERT.
ERT approaches are the standard of care for individuals with LOPD. Several ERTs are approved for LOPD (see Management,
In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
LOPD can manifest from the first decade to as late as the seventh decade of life with progressive proximal muscle weakness primarily affecting the lower limbs and respiratory insufficiency. Disease progression is often predicted by the age of onset, as progression is more rapid if symptoms are evident in childhood.
Clinical Manifestations in Untreated Late-Onset Pompe Disease
Based on Hirschhorn & Reuser [2001]
Affected individuals often become wheelchair users because of lower-limb weakness.
Affected adults often describe symptoms beginning in childhood that resulted in difficulty participating in sports.
Later, fatigue and difficulty with rising from a sitting position, climbing stairs, and walking prompt medical attention.
Echocardiography alone (without specific measurement of the diameter of the thoracic aorta) may not be sufficient to visualize this complication.
A case series by Zhao et al [2024] revealed arterial abnormalities in 23/30 individuals with LOPD:
Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
Vertebral dolichoectasia was found in 17/30.
Arterial stenosis was found in 14/30.
Aneurysms were found in 7/30.
Ectasia of the basilar and internal carotid arteries may be associated with clinical signs, such as transient ischemic attacks and third nerve paralysis [Sacconi et al 2010].
Combinations of pathogenic variants that result in complete absence of acid alpha-glucosidase (GAA) enzyme activity are seen more commonly in IOPD, whereas combinations of pathogenic variants that result in partial enzyme activity are seen more commonly in LOPD.
Observations about genotype-phenotype correlations with specific pathogenic variants (see
The pathogenic variant
The pathogenic variant
The pathogenic variant
The pathogenic variant
Proportion of Persons with Selected
LOPD = late-onset Pompe disease
Historically, IOPD (now defined as onset before age 12 months with cardiomyopathy) was further divided into the classic form (severe with onset age 12 months).
Since inclusion in NBS, new data suggests that Pompe disease is more common than previously thought. The birth prevalence from the state of California is estimated at 1:25,2000 (IOPD and LOPD combined), with the prevalence of LOPD being ~1:37,500 [Tang et al 2020]. The birth prevalence for African American infants continues to be the highest observed and is estimated to be 1:18,700 [Tang et al 2020]. Data from 206,741 newborns screened by NBS in northeast Italy estimated an overall incidence 1:18,795 (IOPD: 1:68,914; LOPD: 1:25,843) [Gragnaniello et al 2022]
• Most of the literature on long-term clinical outcomes after initiation of ERT does not include significant numbers of individuals treated very early (those ascertained by NBS or known family history).
• In those in whom ERT was initiated before age six months and before the need for ventilatory assistance, a majority had improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills compared to an untreated cohort.
• Predictors of a poor response to ERT include increase in muscle glycogen during therapy, high IgG titers to alpha-glucosidase, and a negative cross-reactive immunologic material (CRIM) status. An individual is considered CRIM negative when that individual is unable to synthesize non-functional but immunoreactive protein; in this situation, providing ERT may induce an immune response in the affected individual, resulting in significantly decreased efficacy of ERT.
• Six infusions of ERT were administered through the umbilical vein between 24 and 34 weeks' gestation.
• At 13 months of postnatal life, this individual (who was subsequently treated with immunomodulation and ERT beginning on day one of life) was reported to be doing well, including having significantly better early measurements of left ventricular mass index in comparison to those of other affected neonates with CRIM-negative IOPD who were not treated prenatally.
• Follow-up data on affected individuals revealed progressive skeletal muscle involvement with increasing age, particularly in those with later initiation of ERT and later initiation of higher-dose ERT [Chien et al 2020].
• In a separate group of affected individuals who received hydrocortisone 2 mg/kg as a premedication for ERT [Yang et al 2023], motor function may be better preserved, although this group is younger than those described in Chien et al [2020].
• ERT reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].
• ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].
• Assessment of cognitive abilities is difficult in children with IOPD who are younger than age five years; typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012].
• Estimates of cognitive abilities at age 24 months using the Bayley scales showed preservation of cognitive abilities in infants ascertained by NBS and treated early with ERT [Lai et al 2016].
• However, both MRI abnormalities and decline in full-scale IQ, performance IQ, and processing speed have been reported in a cohort of ERT-treated individuals, age 15-22.5 years [van den Dorpel et al 2024].
• Enlargement of the heart can also result in diminished lung volume, atelectasis, and sometimes bronchial compression (see
• Progressive deposition of glycogen results in conduction defects as seen by shortening of the PR interval on EKG.
• Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease.
• Nerve conduction velocity is typically normal for both motor and sensory nerves.
• However, an evolving motor axonal neuropathy has been demonstrated in one child at age two years and in another at age six years [Burrow et al 2010, Schanzer et al 2019].
• EMG and nerve conduction velocity (NCV) findings do not appear to be impacted by ERT.
• In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
• Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
• In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
• Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
• Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
• In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
• In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
• Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
• In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
• In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
• In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
• Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
• Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
• In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
• In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
• Affected individuals often become wheelchair users because of lower-limb weakness.
• Affected adults often describe symptoms beginning in childhood that resulted in difficulty participating in sports.
• Later, fatigue and difficulty with rising from a sitting position, climbing stairs, and walking prompt medical attention.
• Echocardiography alone (without specific measurement of the diameter of the thoracic aorta) may not be sufficient to visualize this complication.
• A case series by Zhao et al [2024] revealed arterial abnormalities in 23/30 individuals with LOPD:
• Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
• Vertebral dolichoectasia was found in 17/30.
• Arterial stenosis was found in 14/30.
• Aneurysms were found in 7/30.
• Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
• Vertebral dolichoectasia was found in 17/30.
• Arterial stenosis was found in 14/30.
• Aneurysms were found in 7/30.
• Ectasia of the basilar and internal carotid arteries may be associated with clinical signs, such as transient ischemic attacks and third nerve paralysis [Sacconi et al 2010].
• Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
• Vertebral dolichoectasia was found in 17/30.
• Arterial stenosis was found in 14/30.
• Aneurysms were found in 7/30.
• The pathogenic variant
• The pathogenic variant
• The pathogenic variant
• The pathogenic variant
## Clinical Description
Traditionally, Pompe disease has been separated into two major phenotypes – infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD) –based on age of onset, organ involvement (i.e., presence of cardiomyopathy), severity, and rate of progression. As a general rule, the earlier the onset of manifestations, the faster the rate of progression; thus, the two general classifications – IOPD and LOPD – tend to be clinically useful in determining prognosis and treatment options.
Although LOPD has been divided into childhood-, juvenile-, and adult-onset disease, many individuals with adult-onset disease recall symptoms beginning in childhood and, thus, late onset is often the preferred term for those presenting after age 12 months. Most likely, LOPD represents a clinical continuum in which age of onset cannot reliably distinguish subtype [Kishnani et al 2013].
Newborn screening (NBS) and the availability of enzyme replacement therapy (ERT) for affected individuals is changing the clinical course of individuals with Pompe disease.
Most of the literature on long-term clinical outcomes after initiation of ERT does not include significant numbers of individuals treated very early (those ascertained by NBS or known family history).
In those in whom ERT was initiated before age six months and before the need for ventilatory assistance, a majority had improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills compared to an untreated cohort.
Predictors of a poor response to ERT include increase in muscle glycogen during therapy, high IgG titers to alpha-glucosidase, and a negative cross-reactive immunologic material (CRIM) status. An individual is considered CRIM negative when that individual is unable to synthesize non-functional but immunoreactive protein; in this situation, providing ERT may induce an immune response in the affected individual, resulting in significantly decreased efficacy of ERT.
Prenatal ERT was carried out in a single individual with predicated IOPD based on family history and who was CRIM negative [Cohen et al 2022].
Six infusions of ERT were administered through the umbilical vein between 24 and 34 weeks' gestation.
At 13 months of postnatal life, this individual (who was subsequently treated with immunomodulation and ERT beginning on day one of life) was reported to be doing well, including having significantly better early measurements of left ventricular mass index in comparison to those of other affected neonates with CRIM-negative IOPD who were not treated prenatally.
Follow-up data on affected individuals revealed progressive skeletal muscle involvement with increasing age, particularly in those with later initiation of ERT and later initiation of higher-dose ERT [Chien et al 2020].
In a separate group of affected individuals who received hydrocortisone 2 mg/kg as a premedication for ERT [Yang et al 2023], motor function may be better preserved, although this group is younger than those described in Chien et al [2020].
ERT reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].
ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].
Assessment of cognitive abilities is difficult in children with IOPD who are younger than age five years; typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012].
Estimates of cognitive abilities at age 24 months using the Bayley scales showed preservation of cognitive abilities in infants ascertained by NBS and treated early with ERT [Lai et al 2016].
However, both MRI abnormalities and decline in full-scale IQ, performance IQ, and processing speed have been reported in a cohort of ERT-treated individuals, age 15-22.5 years [van den Dorpel et al 2024].
IOPD may be apparent in utero but, prior to NBS, was more often clinically recognized at a median age of four months in individuals with hypotonia, generalized muscle weakness, feeding difficulties, poor growth, and respiratory distress (see
Common Findings at Presentation of Infantile-Onset Pompe Disease in Individuals Who Were Not Diagnosed Through Newborn Screening
Hirschhorn & Reuser [2001], van den Hout et al [2003]
Enlargement of the heart can also result in diminished lung volume, atelectasis, and sometimes bronchial compression (see
Progressive deposition of glycogen results in conduction defects as seen by shortening of the PR interval on EKG.
Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease.
Nerve conduction velocity is typically normal for both motor and sensory nerves.
However, an evolving motor axonal neuropathy has been demonstrated in one child at age two years and in another at age six years [Burrow et al 2010, Schanzer et al 2019].
EMG and nerve conduction velocity (NCV) findings do not appear to be impacted by ERT.
ERT approaches are the standard of care for individuals with LOPD. Several ERTs are approved for LOPD (see Management,
In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
LOPD can manifest from the first decade to as late as the seventh decade of life with progressive proximal muscle weakness primarily affecting the lower limbs and respiratory insufficiency. Disease progression is often predicted by the age of onset, as progression is more rapid if symptoms are evident in childhood.
Clinical Manifestations in Untreated Late-Onset Pompe Disease
Based on Hirschhorn & Reuser [2001]
Affected individuals often become wheelchair users because of lower-limb weakness.
Affected adults often describe symptoms beginning in childhood that resulted in difficulty participating in sports.
Later, fatigue and difficulty with rising from a sitting position, climbing stairs, and walking prompt medical attention.
Echocardiography alone (without specific measurement of the diameter of the thoracic aorta) may not be sufficient to visualize this complication.
A case series by Zhao et al [2024] revealed arterial abnormalities in 23/30 individuals with LOPD:
Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
Vertebral dolichoectasia was found in 17/30.
Arterial stenosis was found in 14/30.
Aneurysms were found in 7/30.
Ectasia of the basilar and internal carotid arteries may be associated with clinical signs, such as transient ischemic attacks and third nerve paralysis [Sacconi et al 2010].
• Most of the literature on long-term clinical outcomes after initiation of ERT does not include significant numbers of individuals treated very early (those ascertained by NBS or known family history).
• In those in whom ERT was initiated before age six months and before the need for ventilatory assistance, a majority had improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills compared to an untreated cohort.
• Predictors of a poor response to ERT include increase in muscle glycogen during therapy, high IgG titers to alpha-glucosidase, and a negative cross-reactive immunologic material (CRIM) status. An individual is considered CRIM negative when that individual is unable to synthesize non-functional but immunoreactive protein; in this situation, providing ERT may induce an immune response in the affected individual, resulting in significantly decreased efficacy of ERT.
• Six infusions of ERT were administered through the umbilical vein between 24 and 34 weeks' gestation.
• At 13 months of postnatal life, this individual (who was subsequently treated with immunomodulation and ERT beginning on day one of life) was reported to be doing well, including having significantly better early measurements of left ventricular mass index in comparison to those of other affected neonates with CRIM-negative IOPD who were not treated prenatally.
• Follow-up data on affected individuals revealed progressive skeletal muscle involvement with increasing age, particularly in those with later initiation of ERT and later initiation of higher-dose ERT [Chien et al 2020].
• In a separate group of affected individuals who received hydrocortisone 2 mg/kg as a premedication for ERT [Yang et al 2023], motor function may be better preserved, although this group is younger than those described in Chien et al [2020].
• ERT reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].
• ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].
• Assessment of cognitive abilities is difficult in children with IOPD who are younger than age five years; typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012].
• Estimates of cognitive abilities at age 24 months using the Bayley scales showed preservation of cognitive abilities in infants ascertained by NBS and treated early with ERT [Lai et al 2016].
• However, both MRI abnormalities and decline in full-scale IQ, performance IQ, and processing speed have been reported in a cohort of ERT-treated individuals, age 15-22.5 years [van den Dorpel et al 2024].
• Enlargement of the heart can also result in diminished lung volume, atelectasis, and sometimes bronchial compression (see
• Progressive deposition of glycogen results in conduction defects as seen by shortening of the PR interval on EKG.
• Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease.
• Nerve conduction velocity is typically normal for both motor and sensory nerves.
• However, an evolving motor axonal neuropathy has been demonstrated in one child at age two years and in another at age six years [Burrow et al 2010, Schanzer et al 2019].
• EMG and nerve conduction velocity (NCV) findings do not appear to be impacted by ERT.
• In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
• Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
• In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
• Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
• Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
• In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
• In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
• Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
• In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
• In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
• In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
• Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
• Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
• In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
• In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
• Affected individuals often become wheelchair users because of lower-limb weakness.
• Affected adults often describe symptoms beginning in childhood that resulted in difficulty participating in sports.
• Later, fatigue and difficulty with rising from a sitting position, climbing stairs, and walking prompt medical attention.
• Echocardiography alone (without specific measurement of the diameter of the thoracic aorta) may not be sufficient to visualize this complication.
• A case series by Zhao et al [2024] revealed arterial abnormalities in 23/30 individuals with LOPD:
• Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
• Vertebral dolichoectasia was found in 17/30.
• Arterial stenosis was found in 14/30.
• Aneurysms were found in 7/30.
• Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
• Vertebral dolichoectasia was found in 17/30.
• Arterial stenosis was found in 14/30.
• Aneurysms were found in 7/30.
• Ectasia of the basilar and internal carotid arteries may be associated with clinical signs, such as transient ischemic attacks and third nerve paralysis [Sacconi et al 2010].
• Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
• Vertebral dolichoectasia was found in 17/30.
• Arterial stenosis was found in 14/30.
• Aneurysms were found in 7/30.
## IOPD with Prompt Initiation of Appropriate Management
Prenatal ERT was carried out in a single individual with predicated IOPD based on family history and who was CRIM negative [Cohen et al 2022].
Six infusions of ERT were administered through the umbilical vein between 24 and 34 weeks' gestation.
At 13 months of postnatal life, this individual (who was subsequently treated with immunomodulation and ERT beginning on day one of life) was reported to be doing well, including having significantly better early measurements of left ventricular mass index in comparison to those of other affected neonates with CRIM-negative IOPD who were not treated prenatally.
Follow-up data on affected individuals revealed progressive skeletal muscle involvement with increasing age, particularly in those with later initiation of ERT and later initiation of higher-dose ERT [Chien et al 2020].
In a separate group of affected individuals who received hydrocortisone 2 mg/kg as a premedication for ERT [Yang et al 2023], motor function may be better preserved, although this group is younger than those described in Chien et al [2020].
ERT reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].
ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].
Assessment of cognitive abilities is difficult in children with IOPD who are younger than age five years; typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012].
Estimates of cognitive abilities at age 24 months using the Bayley scales showed preservation of cognitive abilities in infants ascertained by NBS and treated early with ERT [Lai et al 2016].
However, both MRI abnormalities and decline in full-scale IQ, performance IQ, and processing speed have been reported in a cohort of ERT-treated individuals, age 15-22.5 years [van den Dorpel et al 2024].
• Six infusions of ERT were administered through the umbilical vein between 24 and 34 weeks' gestation.
• At 13 months of postnatal life, this individual (who was subsequently treated with immunomodulation and ERT beginning on day one of life) was reported to be doing well, including having significantly better early measurements of left ventricular mass index in comparison to those of other affected neonates with CRIM-negative IOPD who were not treated prenatally.
• Follow-up data on affected individuals revealed progressive skeletal muscle involvement with increasing age, particularly in those with later initiation of ERT and later initiation of higher-dose ERT [Chien et al 2020].
• In a separate group of affected individuals who received hydrocortisone 2 mg/kg as a premedication for ERT [Yang et al 2023], motor function may be better preserved, although this group is younger than those described in Chien et al [2020].
• ERT reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].
• ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].
• Assessment of cognitive abilities is difficult in children with IOPD who are younger than age five years; typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012].
• Estimates of cognitive abilities at age 24 months using the Bayley scales showed preservation of cognitive abilities in infants ascertained by NBS and treated early with ERT [Lai et al 2016].
• However, both MRI abnormalities and decline in full-scale IQ, performance IQ, and processing speed have been reported in a cohort of ERT-treated individuals, age 15-22.5 years [van den Dorpel et al 2024].
##
Prenatal ERT was carried out in a single individual with predicated IOPD based on family history and who was CRIM negative [Cohen et al 2022].
Six infusions of ERT were administered through the umbilical vein between 24 and 34 weeks' gestation.
At 13 months of postnatal life, this individual (who was subsequently treated with immunomodulation and ERT beginning on day one of life) was reported to be doing well, including having significantly better early measurements of left ventricular mass index in comparison to those of other affected neonates with CRIM-negative IOPD who were not treated prenatally.
• Six infusions of ERT were administered through the umbilical vein between 24 and 34 weeks' gestation.
• At 13 months of postnatal life, this individual (who was subsequently treated with immunomodulation and ERT beginning on day one of life) was reported to be doing well, including having significantly better early measurements of left ventricular mass index in comparison to those of other affected neonates with CRIM-negative IOPD who were not treated prenatally.
##
Follow-up data on affected individuals revealed progressive skeletal muscle involvement with increasing age, particularly in those with later initiation of ERT and later initiation of higher-dose ERT [Chien et al 2020].
In a separate group of affected individuals who received hydrocortisone 2 mg/kg as a premedication for ERT [Yang et al 2023], motor function may be better preserved, although this group is younger than those described in Chien et al [2020].
ERT reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].
ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].
Assessment of cognitive abilities is difficult in children with IOPD who are younger than age five years; typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012].
Estimates of cognitive abilities at age 24 months using the Bayley scales showed preservation of cognitive abilities in infants ascertained by NBS and treated early with ERT [Lai et al 2016].
However, both MRI abnormalities and decline in full-scale IQ, performance IQ, and processing speed have been reported in a cohort of ERT-treated individuals, age 15-22.5 years [van den Dorpel et al 2024].
• Follow-up data on affected individuals revealed progressive skeletal muscle involvement with increasing age, particularly in those with later initiation of ERT and later initiation of higher-dose ERT [Chien et al 2020].
• In a separate group of affected individuals who received hydrocortisone 2 mg/kg as a premedication for ERT [Yang et al 2023], motor function may be better preserved, although this group is younger than those described in Chien et al [2020].
• ERT reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].
• ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].
• Assessment of cognitive abilities is difficult in children with IOPD who are younger than age five years; typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012].
• Estimates of cognitive abilities at age 24 months using the Bayley scales showed preservation of cognitive abilities in infants ascertained by NBS and treated early with ERT [Lai et al 2016].
• However, both MRI abnormalities and decline in full-scale IQ, performance IQ, and processing speed have been reported in a cohort of ERT-treated individuals, age 15-22.5 years [van den Dorpel et al 2024].
## Untreated IOPD
IOPD may be apparent in utero but, prior to NBS, was more often clinically recognized at a median age of four months in individuals with hypotonia, generalized muscle weakness, feeding difficulties, poor growth, and respiratory distress (see
Common Findings at Presentation of Infantile-Onset Pompe Disease in Individuals Who Were Not Diagnosed Through Newborn Screening
Hirschhorn & Reuser [2001], van den Hout et al [2003]
Enlargement of the heart can also result in diminished lung volume, atelectasis, and sometimes bronchial compression (see
Progressive deposition of glycogen results in conduction defects as seen by shortening of the PR interval on EKG.
Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease.
Nerve conduction velocity is typically normal for both motor and sensory nerves.
However, an evolving motor axonal neuropathy has been demonstrated in one child at age two years and in another at age six years [Burrow et al 2010, Schanzer et al 2019].
EMG and nerve conduction velocity (NCV) findings do not appear to be impacted by ERT.
• Enlargement of the heart can also result in diminished lung volume, atelectasis, and sometimes bronchial compression (see
• Progressive deposition of glycogen results in conduction defects as seen by shortening of the PR interval on EKG.
• Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease.
• Nerve conduction velocity is typically normal for both motor and sensory nerves.
• However, an evolving motor axonal neuropathy has been demonstrated in one child at age two years and in another at age six years [Burrow et al 2010, Schanzer et al 2019].
• EMG and nerve conduction velocity (NCV) findings do not appear to be impacted by ERT.
## LOPD Treated with ERT
ERT approaches are the standard of care for individuals with LOPD. Several ERTs are approved for LOPD (see Management,
In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
• In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
• Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
• In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
• Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
• Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
• In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
• In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
• Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
• In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
• In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
• In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78-week evaluation point [van der Ploeg et al 2010].
• Similar findings were demonstrated in an open-label trial and in longitudinal follow-up studies [Strothotte et al 2010, Schoser et al 2017, Stockton et al 2020, Lee et al 2022, Sarah et al 2022, Winkler et al 2022].
• Both products have been studied in randomized double-blind trials with algulcosidase alfa as the active comparator (COMET and PROPEL trials, respectively).
• In the COMET trial, avalglucosidase alfa met the non-inferiority metric in percent predicted forced vital capacity from baseline to the alglucosidase alfa endpoint [Diaz-Manera et al 2021], and a 97-week single-arm extension study demonstrated maintenance or improvement of the endpoints [Kishnani et al 2023].
• In the PROPEL trial, cipagluosidase alfa with miglustat did not meet the superiority endpoint to alglucosidase alfa plus placebo for improvement in the six-minute walk test [Schoser et al 2021], although a single-arm 104-week extension study showed continued improvement or stabilization of functional and pulmonary endpoints [Schoser et al 2024].
## Untreated LOPD
LOPD can manifest from the first decade to as late as the seventh decade of life with progressive proximal muscle weakness primarily affecting the lower limbs and respiratory insufficiency. Disease progression is often predicted by the age of onset, as progression is more rapid if symptoms are evident in childhood.
Clinical Manifestations in Untreated Late-Onset Pompe Disease
Based on Hirschhorn & Reuser [2001]
Affected individuals often become wheelchair users because of lower-limb weakness.
Affected adults often describe symptoms beginning in childhood that resulted in difficulty participating in sports.
Later, fatigue and difficulty with rising from a sitting position, climbing stairs, and walking prompt medical attention.
Echocardiography alone (without specific measurement of the diameter of the thoracic aorta) may not be sufficient to visualize this complication.
A case series by Zhao et al [2024] revealed arterial abnormalities in 23/30 individuals with LOPD:
Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
Vertebral dolichoectasia was found in 17/30.
Arterial stenosis was found in 14/30.
Aneurysms were found in 7/30.
Ectasia of the basilar and internal carotid arteries may be associated with clinical signs, such as transient ischemic attacks and third nerve paralysis [Sacconi et al 2010].
• Affected individuals often become wheelchair users because of lower-limb weakness.
• Affected adults often describe symptoms beginning in childhood that resulted in difficulty participating in sports.
• Later, fatigue and difficulty with rising from a sitting position, climbing stairs, and walking prompt medical attention.
• Echocardiography alone (without specific measurement of the diameter of the thoracic aorta) may not be sufficient to visualize this complication.
• A case series by Zhao et al [2024] revealed arterial abnormalities in 23/30 individuals with LOPD:
• Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
• Vertebral dolichoectasia was found in 17/30.
• Arterial stenosis was found in 14/30.
• Aneurysms were found in 7/30.
• Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
• Vertebral dolichoectasia was found in 17/30.
• Arterial stenosis was found in 14/30.
• Aneurysms were found in 7/30.
• Ectasia of the basilar and internal carotid arteries may be associated with clinical signs, such as transient ischemic attacks and third nerve paralysis [Sacconi et al 2010].
• Dilative arteriopathy was found in 19/30, including eight with dilatation of the anterior circulation arteries.
• Vertebral dolichoectasia was found in 17/30.
• Arterial stenosis was found in 14/30.
• Aneurysms were found in 7/30.
## Genotype-Phenotype Correlations
Combinations of pathogenic variants that result in complete absence of acid alpha-glucosidase (GAA) enzyme activity are seen more commonly in IOPD, whereas combinations of pathogenic variants that result in partial enzyme activity are seen more commonly in LOPD.
Observations about genotype-phenotype correlations with specific pathogenic variants (see
The pathogenic variant
The pathogenic variant
The pathogenic variant
The pathogenic variant
Proportion of Persons with Selected
LOPD = late-onset Pompe disease
• The pathogenic variant
• The pathogenic variant
• The pathogenic variant
• The pathogenic variant
## Nomenclature
Historically, IOPD (now defined as onset before age 12 months with cardiomyopathy) was further divided into the classic form (severe with onset age 12 months).
## Prevalence
Since inclusion in NBS, new data suggests that Pompe disease is more common than previously thought. The birth prevalence from the state of California is estimated at 1:25,2000 (IOPD and LOPD combined), with the prevalence of LOPD being ~1:37,500 [Tang et al 2020]. The birth prevalence for African American infants continues to be the highest observed and is estimated to be 1:18,700 [Tang et al 2020]. Data from 206,741 newborns screened by NBS in northeast Italy estimated an overall incidence 1:18,795 (IOPD: 1:68,914; LOPD: 1:25,843) [Gragnaniello et al 2022]
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Infantile-Onset Pompe Disease
Hypotonia, hypertrophic cardiomyopathy, & myopathy as a result of excessive glycogen storage
Males are more severely affected than females & typical age of presentation w/cardiomyopathy & weakness is in mid-adolescence, although a few persons w/infantile onset have been reported.
ID may be present, which is unusual in Pompe disease.
Typically defined by presence of unexplained LVH. Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of ↑ LV wall thickness, such as pressure overload or storage/infiltrative disorders.
Not assoc w/hypotonia or pronounced muscle weakness
Muscle weakness & cardiomyopathy w/o ↑ serum CK concentration
Phenotypes vary widely, incl asymptomatic females ascertained through NBS of their newborns.
Acutely symptomatic infants may have encephalopathy or coma, which is unusual in Pompe disease.
Hypotonia, feeding difficulties, progressive proximal muscle weakness, & areflexia
No cardiac involvement
Lack of cardiomegaly should help distinguish SMA I from IOPD.
Mitochondrial / respiratory chain disorders show wide variation in clinical presentation & may include hypotonia, respiratory failure, cardiomyopathy, hepatomegaly, seizures, deafness, & ↑ serum CK concentration.
Mitochondrial disorders are often distinguishable from Pompe disease by absence of hypotonia & presence of cognitive involvement.
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; ID = intellectual disability; IOPD = infantile-onset Pompe disease; LVH = left ventricular hypertrophy; MT = mitochondrial; MOI = mode of inheritance; NBS = newborn screening; XL = X-linked
See
Nonsyndromic hypertrophic cardiomyopathy is typically inherited in an autosomal dominant manner; pathogenic variants in genes associated with autosomal inheritance have been reported in rare families.
McCormick et al [2018]
The early involvement of the respiratory muscles is often useful in distinguishing LOPD from many neuromuscular disorders.
Genes of Interest in the Differential Diagnosis of Late-Onset Pompe Disease
Progressive proximal muscle weakness, respiratory insufficiency, & difficulty ambulating
Primarily affects males.
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; MOI = mode of inheritance; XL = X-linked
See OMIM Phenotypic Series
• Hypotonia, hypertrophic cardiomyopathy, & myopathy as a result of excessive glycogen storage
• Males are more severely affected than females & typical age of presentation w/cardiomyopathy & weakness is in mid-adolescence, although a few persons w/infantile onset have been reported.
• ID may be present, which is unusual in Pompe disease.
• Typically defined by presence of unexplained LVH. Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of ↑ LV wall thickness, such as pressure overload or storage/infiltrative disorders.
• Not assoc w/hypotonia or pronounced muscle weakness
• Muscle weakness & cardiomyopathy w/o ↑ serum CK concentration
• Phenotypes vary widely, incl asymptomatic females ascertained through NBS of their newborns.
• Acutely symptomatic infants may have encephalopathy or coma, which is unusual in Pompe disease.
• Hypotonia, feeding difficulties, progressive proximal muscle weakness, & areflexia
• No cardiac involvement
• Lack of cardiomegaly should help distinguish SMA I from IOPD.
• Mitochondrial / respiratory chain disorders show wide variation in clinical presentation & may include hypotonia, respiratory failure, cardiomyopathy, hepatomegaly, seizures, deafness, & ↑ serum CK concentration.
• Mitochondrial disorders are often distinguishable from Pompe disease by absence of hypotonia & presence of cognitive involvement.
• Progressive proximal muscle weakness, respiratory insufficiency, & difficulty ambulating
• Primarily affects males.
## Infantile-Onset Pompe Disease (IOPD)
Genes of Interest in the Differential Diagnosis of Infantile-Onset Pompe Disease
Hypotonia, hypertrophic cardiomyopathy, & myopathy as a result of excessive glycogen storage
Males are more severely affected than females & typical age of presentation w/cardiomyopathy & weakness is in mid-adolescence, although a few persons w/infantile onset have been reported.
ID may be present, which is unusual in Pompe disease.
Typically defined by presence of unexplained LVH. Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of ↑ LV wall thickness, such as pressure overload or storage/infiltrative disorders.
Not assoc w/hypotonia or pronounced muscle weakness
Muscle weakness & cardiomyopathy w/o ↑ serum CK concentration
Phenotypes vary widely, incl asymptomatic females ascertained through NBS of their newborns.
Acutely symptomatic infants may have encephalopathy or coma, which is unusual in Pompe disease.
Hypotonia, feeding difficulties, progressive proximal muscle weakness, & areflexia
No cardiac involvement
Lack of cardiomegaly should help distinguish SMA I from IOPD.
Mitochondrial / respiratory chain disorders show wide variation in clinical presentation & may include hypotonia, respiratory failure, cardiomyopathy, hepatomegaly, seizures, deafness, & ↑ serum CK concentration.
Mitochondrial disorders are often distinguishable from Pompe disease by absence of hypotonia & presence of cognitive involvement.
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; ID = intellectual disability; IOPD = infantile-onset Pompe disease; LVH = left ventricular hypertrophy; MT = mitochondrial; MOI = mode of inheritance; NBS = newborn screening; XL = X-linked
See
Nonsyndromic hypertrophic cardiomyopathy is typically inherited in an autosomal dominant manner; pathogenic variants in genes associated with autosomal inheritance have been reported in rare families.
McCormick et al [2018]
• Hypotonia, hypertrophic cardiomyopathy, & myopathy as a result of excessive glycogen storage
• Males are more severely affected than females & typical age of presentation w/cardiomyopathy & weakness is in mid-adolescence, although a few persons w/infantile onset have been reported.
• ID may be present, which is unusual in Pompe disease.
• Typically defined by presence of unexplained LVH. Such LVH occurs in a non-dilated ventricle in the absence of other cardiac or systemic disease capable of producing the observed magnitude of ↑ LV wall thickness, such as pressure overload or storage/infiltrative disorders.
• Not assoc w/hypotonia or pronounced muscle weakness
• Muscle weakness & cardiomyopathy w/o ↑ serum CK concentration
• Phenotypes vary widely, incl asymptomatic females ascertained through NBS of their newborns.
• Acutely symptomatic infants may have encephalopathy or coma, which is unusual in Pompe disease.
• Hypotonia, feeding difficulties, progressive proximal muscle weakness, & areflexia
• No cardiac involvement
• Lack of cardiomegaly should help distinguish SMA I from IOPD.
• Mitochondrial / respiratory chain disorders show wide variation in clinical presentation & may include hypotonia, respiratory failure, cardiomyopathy, hepatomegaly, seizures, deafness, & ↑ serum CK concentration.
• Mitochondrial disorders are often distinguishable from Pompe disease by absence of hypotonia & presence of cognitive involvement.
## Late-Onset Pompe Disease (LOPD)
The early involvement of the respiratory muscles is often useful in distinguishing LOPD from many neuromuscular disorders.
Genes of Interest in the Differential Diagnosis of Late-Onset Pompe Disease
Progressive proximal muscle weakness, respiratory insufficiency, & difficulty ambulating
Primarily affects males.
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; MOI = mode of inheritance; XL = X-linked
See OMIM Phenotypic Series
• Progressive proximal muscle weakness, respiratory insufficiency, & difficulty ambulating
• Primarily affects males.
## Management
Clinical practice guidelines for Pompe disease have been published:
Guidelines for individuals ascertained by newborn screening [Kronn et al 2017]
Guidelines for infantile-onset Pompe disease (IOPD) [American College of Medical Genetics expert panel; see Kishnani et al 2006]
Guidelines for late-onset Pompe disease (LOPD) [Cupler et al 2012]
To establish the extent of disease and needs in an individual diagnosed with Pompe disease, the evaluations summarized in
Infantile-Onset Pompe Disease: Recommended Evaluations Following Initial Diagnosis
Most affected persons demonstrate pulmonary insufficiency.
Assessing ventilatory capacity in supine position can detect early ventilatory insufficiency.
Incl for facial hypotonia, macroglossia, tongue weakness, &/or poor oral motor skills
Consider videofluoroscopic swallow study.
Assess for signs/symptoms of GERD.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support
Home nursing referral
CK = creatine kinase; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; pCO
van der Beek et al [2011], Cupler et al [2012]
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Late-Onset Pompe Disease: Recommended Evaluations Following Initial Diagnosis
To obtain baseline eval of lungs & cardiac silhouette
Cardiomegaly is rare.
To guide subsequent therapies
Difficulty w/communication is common.
Gross motor & fine motor skills
Contractures and scoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; CK = creatine kinase; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Sacconi et al [2014]
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for Pompe disease.
Although enzyme replacement therapy (ERT) should be initiated as soon as the diagnosis of IOPD or symptomatic Pompe disease is established, it is appropriate to determine
Targeted Treatment of Pompe Disease
Weight <30kg: 40mg/kg every other week
Weight ≥30kg: 20mg/kg every other week
Cipaglucosidase alfa: 20mg/kg every other week
Miglustat dosing is by weight category; refer to product insert
IOPD = infantile-onset Pompe disease; LOPD = late-onset Pompe disease
Multiple immunomodulation protocols are in use, most of which use rituximab with additional drugs in cases of CRIM-negative IOPD (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013].
In utero alglucosidase alfa therapy (20 mg/kg of estimated fetal weight) was given to an affected fetus every two weeks from 24 5/7 weeks' gestation to 34 5/7 weeks' gestation as part of a clinical trial (see
Determining CRIM status prior to initiating ERT is recommended. Multiple immunomodulation protocols are in use, most of which use rituximab with additional drugs (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013].
Two ways to determine the CRIM status of an individual with Pompe disease are as follows:
GAA protein quantitation performed by an antibody-based method in cultured fibroblasts
Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM negative) [Bali et al 2012]
Geographic areas in which CRIM-negative status is common include the United States and the Middle East [Messinger et al 2012].
Across all infusion medications used for Pompe disease, there is a trend toward heightened adverse reactions in individuals who are actively ill at the time of infusion.
Similarly, individuals who have had a previous adverse reaction more commonly report subsequent adverse reactions.
Taken together, providers may wish to consider deferring an infusion for individuals who are actively ill with viral or bacterial illness.
For individuals experiencing more severe infusion-associated reactions, pausing infusions and/or adjusting total duration of the infusion can promote improved tolerance.
Investigation of immunoglobulin (Ig) E-mediated reactions could be helpful in situations where significant, or progressive, intolerance of the infusion is noted.
Development of IgE antibodies is less common but may be associated with anaphylaxis requiring life support measures.
Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see
For these reasons – and because many individuals with IOPD have preexisting compromise of respiratory and cardiac function – initiation of therapy in centers equipped to provide emergency care is recommended.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Pompe Disease: Supportive Treatment of Manifestations
Persons w/hypertrophic cardiomyopathy are at high risk for tachyarrhythmia & sudden death.
It is unclear if persons on ERT w/subsequent improvement in cardiac function remain at ↑ risk of arrhythmia.
Proximal motor weakness can result in contractures of the pelvic girdle in infants & children, necessitating aggressive mgmt incl surgery.
Untreated persons often progress to requiring a wheelchair.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Untreated infants may require specialized diets & maximal nutritional support.
Persons w/LOPD may also develop feeding concerns & are often managed on a soft diet, w/a few requiring gastric or jejunal feedings.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; ERT = enzyme replacement therapy; LOPD = late-onset Pompe disease; OT = occupational therapy; PT = physical therapy
Kronn et al [2017]
Roberts et al [2011]
Jones et al [2011]
van Capelle et al [2010]
Updated management and surveillance guidelines have been published by the Pompe Disease Newborn Screening Working Group [Kronn et al 2017], summarized in
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Pompe Disease: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
IOPD: every 2-3 yrs until puberty, then every 1-2 yrs
LOPD: Consider annual screening.
IOPD: consider initial screening prior to starting ERT & then every 5 yrs thereafter.
LOPD: at initial visit & at least every 5 yrs thereafter.
BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CK = creatine kinase; DXA = dual-energy x-ray absorptiometry; IOPD = infantile-onset Pompe disease; LOPD = late-onset Pompe disease
Sacconi et al [2014] noted that ERT did not prevent development of significant conduction abnormalities in four of 131 adults with LOPD. Pfrimmer et al [2024] noted that around half of individuals with IOPD in their study on long-term ERT developed cardiac arrhythmias.
Viamonte et al [2020]
Hensel et al [2015]
To monitor for secondary complications related to cardiac and/or pulmonary impairment as well as medication effects
Use of standard drugs for treatment of cardiac manifestations may be contraindicated in certain stages of the disease. The use of digoxin, ionotropes, diuretics, and afterload-reducing agents may worsen left ventricular outflow obstruction, although they may be indicated in later stages of the disease.
Hypotension and volume depletion should be avoided.
Anesthesia should be used only when absolutely necessary because reduced cardiovascular return and underlying respiratory insufficiency pose significant risks.
Exposure to infectious agents is to be avoided.
See
Most individuals with IOPD have not reproduced.
Many adults with LOPD have reproduced. Several women have been treated with ERT during pregnancy and lactation with no reported adverse effects on the fetus and no adverse events during infusions [de Vries et al 2011, Holbeck-Brendel & Poulsen 2017, Goker-Alpan et al 2020]. As would be expected in a woman with a myopathy and respiratory insufficiency, the growing fetus may pose additional complications to the mother's health. Close respiratory and cardiac surveillance should be initiated in consultation with maternal-fetal medicine specialists.
Search
• Guidelines for individuals ascertained by newborn screening [Kronn et al 2017]
• Guidelines for infantile-onset Pompe disease (IOPD) [American College of Medical Genetics expert panel; see Kishnani et al 2006]
• Guidelines for late-onset Pompe disease (LOPD) [Cupler et al 2012]
• Most affected persons demonstrate pulmonary insufficiency.
• Assessing ventilatory capacity in supine position can detect early ventilatory insufficiency.
• Incl for facial hypotonia, macroglossia, tongue weakness, &/or poor oral motor skills
• Consider videofluoroscopic swallow study.
• Assess for signs/symptoms of GERD.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support
• Home nursing referral
• To obtain baseline eval of lungs & cardiac silhouette
• Cardiomegaly is rare.
• To guide subsequent therapies
• Difficulty w/communication is common.
• Gross motor & fine motor skills
• Contractures and scoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support
• Home nursing referral
• Weight <30kg: 40mg/kg every other week
• Weight ≥30kg: 20mg/kg every other week
• Cipaglucosidase alfa: 20mg/kg every other week
• Miglustat dosing is by weight category; refer to product insert
• GAA protein quantitation performed by an antibody-based method in cultured fibroblasts
• Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM negative) [Bali et al 2012]
• Across all infusion medications used for Pompe disease, there is a trend toward heightened adverse reactions in individuals who are actively ill at the time of infusion.
• Similarly, individuals who have had a previous adverse reaction more commonly report subsequent adverse reactions.
• Taken together, providers may wish to consider deferring an infusion for individuals who are actively ill with viral or bacterial illness.
• For individuals experiencing more severe infusion-associated reactions, pausing infusions and/or adjusting total duration of the infusion can promote improved tolerance.
• Investigation of immunoglobulin (Ig) E-mediated reactions could be helpful in situations where significant, or progressive, intolerance of the infusion is noted.
• Development of IgE antibodies is less common but may be associated with anaphylaxis requiring life support measures.
• Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see
• Persons w/hypertrophic cardiomyopathy are at high risk for tachyarrhythmia & sudden death.
• It is unclear if persons on ERT w/subsequent improvement in cardiac function remain at ↑ risk of arrhythmia.
• Proximal motor weakness can result in contractures of the pelvic girdle in infants & children, necessitating aggressive mgmt incl surgery.
• Untreated persons often progress to requiring a wheelchair.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
• Untreated infants may require specialized diets & maximal nutritional support.
• Persons w/LOPD may also develop feeding concerns & are often managed on a soft diet, w/a few requiring gastric or jejunal feedings.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• IOPD: every 2-3 yrs until puberty, then every 1-2 yrs
• LOPD: Consider annual screening.
• IOPD: consider initial screening prior to starting ERT & then every 5 yrs thereafter.
• LOPD: at initial visit & at least every 5 yrs thereafter.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Pompe disease, the evaluations summarized in
Infantile-Onset Pompe Disease: Recommended Evaluations Following Initial Diagnosis
Most affected persons demonstrate pulmonary insufficiency.
Assessing ventilatory capacity in supine position can detect early ventilatory insufficiency.
Incl for facial hypotonia, macroglossia, tongue weakness, &/or poor oral motor skills
Consider videofluoroscopic swallow study.
Assess for signs/symptoms of GERD.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support
Home nursing referral
CK = creatine kinase; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; pCO
van der Beek et al [2011], Cupler et al [2012]
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Late-Onset Pompe Disease: Recommended Evaluations Following Initial Diagnosis
To obtain baseline eval of lungs & cardiac silhouette
Cardiomegaly is rare.
To guide subsequent therapies
Difficulty w/communication is common.
Gross motor & fine motor skills
Contractures and scoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; CK = creatine kinase; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Sacconi et al [2014]
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Most affected persons demonstrate pulmonary insufficiency.
• Assessing ventilatory capacity in supine position can detect early ventilatory insufficiency.
• Incl for facial hypotonia, macroglossia, tongue weakness, &/or poor oral motor skills
• Consider videofluoroscopic swallow study.
• Assess for signs/symptoms of GERD.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support
• Home nursing referral
• To obtain baseline eval of lungs & cardiac silhouette
• Cardiomegaly is rare.
• To guide subsequent therapies
• Difficulty w/communication is common.
• Gross motor & fine motor skills
• Contractures and scoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for Pompe disease.
Although enzyme replacement therapy (ERT) should be initiated as soon as the diagnosis of IOPD or symptomatic Pompe disease is established, it is appropriate to determine
Targeted Treatment of Pompe Disease
Weight <30kg: 40mg/kg every other week
Weight ≥30kg: 20mg/kg every other week
Cipaglucosidase alfa: 20mg/kg every other week
Miglustat dosing is by weight category; refer to product insert
IOPD = infantile-onset Pompe disease; LOPD = late-onset Pompe disease
Multiple immunomodulation protocols are in use, most of which use rituximab with additional drugs in cases of CRIM-negative IOPD (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013].
In utero alglucosidase alfa therapy (20 mg/kg of estimated fetal weight) was given to an affected fetus every two weeks from 24 5/7 weeks' gestation to 34 5/7 weeks' gestation as part of a clinical trial (see
Determining CRIM status prior to initiating ERT is recommended. Multiple immunomodulation protocols are in use, most of which use rituximab with additional drugs (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013].
Two ways to determine the CRIM status of an individual with Pompe disease are as follows:
GAA protein quantitation performed by an antibody-based method in cultured fibroblasts
Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM negative) [Bali et al 2012]
Geographic areas in which CRIM-negative status is common include the United States and the Middle East [Messinger et al 2012].
Across all infusion medications used for Pompe disease, there is a trend toward heightened adverse reactions in individuals who are actively ill at the time of infusion.
Similarly, individuals who have had a previous adverse reaction more commonly report subsequent adverse reactions.
Taken together, providers may wish to consider deferring an infusion for individuals who are actively ill with viral or bacterial illness.
For individuals experiencing more severe infusion-associated reactions, pausing infusions and/or adjusting total duration of the infusion can promote improved tolerance.
Investigation of immunoglobulin (Ig) E-mediated reactions could be helpful in situations where significant, or progressive, intolerance of the infusion is noted.
Development of IgE antibodies is less common but may be associated with anaphylaxis requiring life support measures.
Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see
For these reasons – and because many individuals with IOPD have preexisting compromise of respiratory and cardiac function – initiation of therapy in centers equipped to provide emergency care is recommended.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Pompe Disease: Supportive Treatment of Manifestations
Persons w/hypertrophic cardiomyopathy are at high risk for tachyarrhythmia & sudden death.
It is unclear if persons on ERT w/subsequent improvement in cardiac function remain at ↑ risk of arrhythmia.
Proximal motor weakness can result in contractures of the pelvic girdle in infants & children, necessitating aggressive mgmt incl surgery.
Untreated persons often progress to requiring a wheelchair.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Untreated infants may require specialized diets & maximal nutritional support.
Persons w/LOPD may also develop feeding concerns & are often managed on a soft diet, w/a few requiring gastric or jejunal feedings.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; ERT = enzyme replacement therapy; LOPD = late-onset Pompe disease; OT = occupational therapy; PT = physical therapy
Kronn et al [2017]
Roberts et al [2011]
Jones et al [2011]
van Capelle et al [2010]
• Weight <30kg: 40mg/kg every other week
• Weight ≥30kg: 20mg/kg every other week
• Cipaglucosidase alfa: 20mg/kg every other week
• Miglustat dosing is by weight category; refer to product insert
• GAA protein quantitation performed by an antibody-based method in cultured fibroblasts
• Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM negative) [Bali et al 2012]
• Across all infusion medications used for Pompe disease, there is a trend toward heightened adverse reactions in individuals who are actively ill at the time of infusion.
• Similarly, individuals who have had a previous adverse reaction more commonly report subsequent adverse reactions.
• Taken together, providers may wish to consider deferring an infusion for individuals who are actively ill with viral or bacterial illness.
• For individuals experiencing more severe infusion-associated reactions, pausing infusions and/or adjusting total duration of the infusion can promote improved tolerance.
• Investigation of immunoglobulin (Ig) E-mediated reactions could be helpful in situations where significant, or progressive, intolerance of the infusion is noted.
• Development of IgE antibodies is less common but may be associated with anaphylaxis requiring life support measures.
• Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see
• Persons w/hypertrophic cardiomyopathy are at high risk for tachyarrhythmia & sudden death.
• It is unclear if persons on ERT w/subsequent improvement in cardiac function remain at ↑ risk of arrhythmia.
• Proximal motor weakness can result in contractures of the pelvic girdle in infants & children, necessitating aggressive mgmt incl surgery.
• Untreated persons often progress to requiring a wheelchair.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
• Untreated infants may require specialized diets & maximal nutritional support.
• Persons w/LOPD may also develop feeding concerns & are often managed on a soft diet, w/a few requiring gastric or jejunal feedings.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
## Targeted Therapies
Although enzyme replacement therapy (ERT) should be initiated as soon as the diagnosis of IOPD or symptomatic Pompe disease is established, it is appropriate to determine
Targeted Treatment of Pompe Disease
Weight <30kg: 40mg/kg every other week
Weight ≥30kg: 20mg/kg every other week
Cipaglucosidase alfa: 20mg/kg every other week
Miglustat dosing is by weight category; refer to product insert
IOPD = infantile-onset Pompe disease; LOPD = late-onset Pompe disease
Multiple immunomodulation protocols are in use, most of which use rituximab with additional drugs in cases of CRIM-negative IOPD (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013].
In utero alglucosidase alfa therapy (20 mg/kg of estimated fetal weight) was given to an affected fetus every two weeks from 24 5/7 weeks' gestation to 34 5/7 weeks' gestation as part of a clinical trial (see
Determining CRIM status prior to initiating ERT is recommended. Multiple immunomodulation protocols are in use, most of which use rituximab with additional drugs (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013].
Two ways to determine the CRIM status of an individual with Pompe disease are as follows:
GAA protein quantitation performed by an antibody-based method in cultured fibroblasts
Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM negative) [Bali et al 2012]
Geographic areas in which CRIM-negative status is common include the United States and the Middle East [Messinger et al 2012].
Across all infusion medications used for Pompe disease, there is a trend toward heightened adverse reactions in individuals who are actively ill at the time of infusion.
Similarly, individuals who have had a previous adverse reaction more commonly report subsequent adverse reactions.
Taken together, providers may wish to consider deferring an infusion for individuals who are actively ill with viral or bacterial illness.
For individuals experiencing more severe infusion-associated reactions, pausing infusions and/or adjusting total duration of the infusion can promote improved tolerance.
Investigation of immunoglobulin (Ig) E-mediated reactions could be helpful in situations where significant, or progressive, intolerance of the infusion is noted.
Development of IgE antibodies is less common but may be associated with anaphylaxis requiring life support measures.
Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see
For these reasons – and because many individuals with IOPD have preexisting compromise of respiratory and cardiac function – initiation of therapy in centers equipped to provide emergency care is recommended.
• Weight <30kg: 40mg/kg every other week
• Weight ≥30kg: 20mg/kg every other week
• Cipaglucosidase alfa: 20mg/kg every other week
• Miglustat dosing is by weight category; refer to product insert
• GAA protein quantitation performed by an antibody-based method in cultured fibroblasts
• Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM negative) [Bali et al 2012]
• Across all infusion medications used for Pompe disease, there is a trend toward heightened adverse reactions in individuals who are actively ill at the time of infusion.
• Similarly, individuals who have had a previous adverse reaction more commonly report subsequent adverse reactions.
• Taken together, providers may wish to consider deferring an infusion for individuals who are actively ill with viral or bacterial illness.
• For individuals experiencing more severe infusion-associated reactions, pausing infusions and/or adjusting total duration of the infusion can promote improved tolerance.
• Investigation of immunoglobulin (Ig) E-mediated reactions could be helpful in situations where significant, or progressive, intolerance of the infusion is noted.
• Development of IgE antibodies is less common but may be associated with anaphylaxis requiring life support measures.
• Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see
##
Determining CRIM status prior to initiating ERT is recommended. Multiple immunomodulation protocols are in use, most of which use rituximab with additional drugs (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013].
Two ways to determine the CRIM status of an individual with Pompe disease are as follows:
GAA protein quantitation performed by an antibody-based method in cultured fibroblasts
Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM negative) [Bali et al 2012]
Geographic areas in which CRIM-negative status is common include the United States and the Middle East [Messinger et al 2012].
• GAA protein quantitation performed by an antibody-based method in cultured fibroblasts
• Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM negative) [Bali et al 2012]
##
Across all infusion medications used for Pompe disease, there is a trend toward heightened adverse reactions in individuals who are actively ill at the time of infusion.
Similarly, individuals who have had a previous adverse reaction more commonly report subsequent adverse reactions.
Taken together, providers may wish to consider deferring an infusion for individuals who are actively ill with viral or bacterial illness.
For individuals experiencing more severe infusion-associated reactions, pausing infusions and/or adjusting total duration of the infusion can promote improved tolerance.
Investigation of immunoglobulin (Ig) E-mediated reactions could be helpful in situations where significant, or progressive, intolerance of the infusion is noted.
Development of IgE antibodies is less common but may be associated with anaphylaxis requiring life support measures.
Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see
For these reasons – and because many individuals with IOPD have preexisting compromise of respiratory and cardiac function – initiation of therapy in centers equipped to provide emergency care is recommended.
• Across all infusion medications used for Pompe disease, there is a trend toward heightened adverse reactions in individuals who are actively ill at the time of infusion.
• Similarly, individuals who have had a previous adverse reaction more commonly report subsequent adverse reactions.
• Taken together, providers may wish to consider deferring an infusion for individuals who are actively ill with viral or bacterial illness.
• For individuals experiencing more severe infusion-associated reactions, pausing infusions and/or adjusting total duration of the infusion can promote improved tolerance.
• Investigation of immunoglobulin (Ig) E-mediated reactions could be helpful in situations where significant, or progressive, intolerance of the infusion is noted.
• Development of IgE antibodies is less common but may be associated with anaphylaxis requiring life support measures.
• Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Pompe Disease: Supportive Treatment of Manifestations
Persons w/hypertrophic cardiomyopathy are at high risk for tachyarrhythmia & sudden death.
It is unclear if persons on ERT w/subsequent improvement in cardiac function remain at ↑ risk of arrhythmia.
Proximal motor weakness can result in contractures of the pelvic girdle in infants & children, necessitating aggressive mgmt incl surgery.
Untreated persons often progress to requiring a wheelchair.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Untreated infants may require specialized diets & maximal nutritional support.
Persons w/LOPD may also develop feeding concerns & are often managed on a soft diet, w/a few requiring gastric or jejunal feedings.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; ERT = enzyme replacement therapy; LOPD = late-onset Pompe disease; OT = occupational therapy; PT = physical therapy
Kronn et al [2017]
Roberts et al [2011]
Jones et al [2011]
van Capelle et al [2010]
• Persons w/hypertrophic cardiomyopathy are at high risk for tachyarrhythmia & sudden death.
• It is unclear if persons on ERT w/subsequent improvement in cardiac function remain at ↑ risk of arrhythmia.
• Proximal motor weakness can result in contractures of the pelvic girdle in infants & children, necessitating aggressive mgmt incl surgery.
• Untreated persons often progress to requiring a wheelchair.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
• Untreated infants may require specialized diets & maximal nutritional support.
• Persons w/LOPD may also develop feeding concerns & are often managed on a soft diet, w/a few requiring gastric or jejunal feedings.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or
## Surveillance
Updated management and surveillance guidelines have been published by the Pompe Disease Newborn Screening Working Group [Kronn et al 2017], summarized in
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Pompe Disease: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
IOPD: every 2-3 yrs until puberty, then every 1-2 yrs
LOPD: Consider annual screening.
IOPD: consider initial screening prior to starting ERT & then every 5 yrs thereafter.
LOPD: at initial visit & at least every 5 yrs thereafter.
BNP = B-type natriuretic peptide; BUN = blood urea nitrogen; CK = creatine kinase; DXA = dual-energy x-ray absorptiometry; IOPD = infantile-onset Pompe disease; LOPD = late-onset Pompe disease
Sacconi et al [2014] noted that ERT did not prevent development of significant conduction abnormalities in four of 131 adults with LOPD. Pfrimmer et al [2024] noted that around half of individuals with IOPD in their study on long-term ERT developed cardiac arrhythmias.
Viamonte et al [2020]
Hensel et al [2015]
To monitor for secondary complications related to cardiac and/or pulmonary impairment as well as medication effects
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• IOPD: every 2-3 yrs until puberty, then every 1-2 yrs
• LOPD: Consider annual screening.
• IOPD: consider initial screening prior to starting ERT & then every 5 yrs thereafter.
• LOPD: at initial visit & at least every 5 yrs thereafter.
## Agents/Circumstances to Avoid
Use of standard drugs for treatment of cardiac manifestations may be contraindicated in certain stages of the disease. The use of digoxin, ionotropes, diuretics, and afterload-reducing agents may worsen left ventricular outflow obstruction, although they may be indicated in later stages of the disease.
Hypotension and volume depletion should be avoided.
Anesthesia should be used only when absolutely necessary because reduced cardiovascular return and underlying respiratory insufficiency pose significant risks.
Exposure to infectious agents is to be avoided.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Most individuals with IOPD have not reproduced.
Many adults with LOPD have reproduced. Several women have been treated with ERT during pregnancy and lactation with no reported adverse effects on the fetus and no adverse events during infusions [de Vries et al 2011, Holbeck-Brendel & Poulsen 2017, Goker-Alpan et al 2020]. As would be expected in a woman with a myopathy and respiratory insufficiency, the growing fetus may pose additional complications to the mother's health. Close respiratory and cardiac surveillance should be initiated in consultation with maternal-fetal medicine specialists.
## Therapies Under Investigation
Search
## Genetic Counseling
Pompe disease is inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Sib pair concordance in IOPD is high in children with null pathogenic variants [Hirschhorn & Reuser 2001]. Age and severity of manifestations in LOPD may vary among affected sibs.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Note: Measurement of acid alpha-glucosidase enzyme activity in skin fibroblasts, muscle, or peripheral blood leukocytes is
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
The American College of Medical Genetics and Genomics includes Pompe disease among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [Gregg et al 2021].
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Sib pair concordance in IOPD is high in children with null pathogenic variants [Hirschhorn & Reuser 2001]. Age and severity of manifestations in LOPD may vary among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The American College of Medical Genetics and Genomics includes Pompe disease among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [Gregg et al 2021].
## Mode of Inheritance
Pompe disease is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Sib pair concordance in IOPD is high in children with null pathogenic variants [Hirschhorn & Reuser 2001]. Age and severity of manifestations in LOPD may vary among affected sibs.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual are presumed to be heterozygous for a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Sib pair concordance in IOPD is high in children with null pathogenic variants [Hirschhorn & Reuser 2001]. Age and severity of manifestations in LOPD may vary among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Note: Measurement of acid alpha-glucosidase enzyme activity in skin fibroblasts, muscle, or peripheral blood leukocytes is
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
The American College of Medical Genetics and Genomics includes Pompe disease among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [Gregg et al 2021].
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The American College of Medical Genetics and Genomics includes Pompe disease among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [Gregg et al 2021].
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Health Resources & Services Administration
•
•
•
•
•
•
•
•
•
• Health Resources & Services Administration
•
•
•
## Molecular Genetics
Pompe Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Pompe Disease (
Acid alpha-glucosidase (GAA) is a lysosomal enzyme that catalyzes α-1,4- and α-1,6-glucosidic linkages at acid pH. There are seven glycosylation sites. The immature protein consists of 952 amino acids with a predicted non-glycosylated weight of 105 kd. The mature enzyme exists in either 76-kd or 70-kd form as a monomer. Pathogenic variants in
Variants that lead to ↓ GAA enzyme activity w/o causing Pompe disease
These two variants are common in persons of Asian ancestry.
Variant frequently assoc w/IOPD
Although present in several different ancestral backgrounds, this variant has been observed in up to 60% of persons of African descent with a common haplotype, suggesting a founder effect (see
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Variants that lead to ↓ GAA enzyme activity w/o causing Pompe disease
• These two variants are common in persons of Asian ancestry.
• Variant frequently assoc w/IOPD
• Although present in several different ancestral backgrounds, this variant has been observed in up to 60% of persons of African descent with a common haplotype, suggesting a founder effect (see
## Molecular Pathogenesis
Acid alpha-glucosidase (GAA) is a lysosomal enzyme that catalyzes α-1,4- and α-1,6-glucosidic linkages at acid pH. There are seven glycosylation sites. The immature protein consists of 952 amino acids with a predicted non-glycosylated weight of 105 kd. The mature enzyme exists in either 76-kd or 70-kd form as a monomer. Pathogenic variants in
Variants that lead to ↓ GAA enzyme activity w/o causing Pompe disease
These two variants are common in persons of Asian ancestry.
Variant frequently assoc w/IOPD
Although present in several different ancestral backgrounds, this variant has been observed in up to 60% of persons of African descent with a common haplotype, suggesting a founder effect (see
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Variants that lead to ↓ GAA enzyme activity w/o causing Pompe disease
• These two variants are common in persons of Asian ancestry.
• Variant frequently assoc w/IOPD
• Although present in several different ancestral backgrounds, this variant has been observed in up to 60% of persons of African descent with a common haplotype, suggesting a founder effect (see
## Chapter Notes
Laurie Bailey, MS; Cincinnati Children's Hospital Medical Center (2017-2025)Lisa Berry, MS (2025-present)Nancy Leslie, MD (2007-present)Loren Pena, MD, PhD (2025-present)Ethan Sperry, MD, PhD (2025-present)Brad Tinkle, MD, PhD; Advocate Children’s Hospital, Illinois (2007-2017)
21 August 2025 (ma) Comprehensive update posted live
11 May 2017 (bp) Comprehensive update posted live
9 May 2013 (me) Comprehensive update posted live
12 August 2010 (me) Comprehensive update posted live
31 August 2007 (me) Review posted live
8 January 2007 (bt) Original submission
• 21 August 2025 (ma) Comprehensive update posted live
• 11 May 2017 (bp) Comprehensive update posted live
• 9 May 2013 (me) Comprehensive update posted live
• 12 August 2010 (me) Comprehensive update posted live
• 31 August 2007 (me) Review posted live
• 8 January 2007 (bt) Original submission
## Author Notes
## Author History
Laurie Bailey, MS; Cincinnati Children's Hospital Medical Center (2017-2025)Lisa Berry, MS (2025-present)Nancy Leslie, MD (2007-present)Loren Pena, MD, PhD (2025-present)Ethan Sperry, MD, PhD (2025-present)Brad Tinkle, MD, PhD; Advocate Children’s Hospital, Illinois (2007-2017)
## Revision History
21 August 2025 (ma) Comprehensive update posted live
11 May 2017 (bp) Comprehensive update posted live
9 May 2013 (me) Comprehensive update posted live
12 August 2010 (me) Comprehensive update posted live
31 August 2007 (me) Review posted live
8 January 2007 (bt) Original submission
• 21 August 2025 (ma) Comprehensive update posted live
• 11 May 2017 (bp) Comprehensive update posted live
• 9 May 2013 (me) Comprehensive update posted live
• 12 August 2010 (me) Comprehensive update posted live
• 31 August 2007 (me) Review posted live
• 8 January 2007 (bt) Original submission
## Key Sections in This
## References
American College of Medical Genetics. Pompe disease diagnosis and management guideline. Available
Cupler EJ, Berger KI, Leshner RT, Wolfe GI, Han JJ, Barohn RJ, Kissel JT; AANEM Consensus Committee on Late-Onset Pompe Disease. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve. 2012;45:319-33.
Kronn DF, Day-Salvatore D, Hwu WL, Jones SA, Nakamura K, Okuyama T, Swoboda KJ, Kishnani PS; Pompe Disease Newborn Screening working group. management of confirmed newborn-screened patients with Pompe disease across the disease spectrum. Pediatrics. 2017;140:S24-S45.
• American College of Medical Genetics. Pompe disease diagnosis and management guideline. Available
• Cupler EJ, Berger KI, Leshner RT, Wolfe GI, Han JJ, Barohn RJ, Kissel JT; AANEM Consensus Committee on Late-Onset Pompe Disease. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve. 2012;45:319-33.
• Kronn DF, Day-Salvatore D, Hwu WL, Jones SA, Nakamura K, Okuyama T, Swoboda KJ, Kishnani PS; Pompe Disease Newborn Screening working group. management of confirmed newborn-screened patients with Pompe disease across the disease spectrum. Pediatrics. 2017;140:S24-S45.
## Published Guidelines / Consensus Statements
American College of Medical Genetics. Pompe disease diagnosis and management guideline. Available
Cupler EJ, Berger KI, Leshner RT, Wolfe GI, Han JJ, Barohn RJ, Kissel JT; AANEM Consensus Committee on Late-Onset Pompe Disease. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve. 2012;45:319-33.
Kronn DF, Day-Salvatore D, Hwu WL, Jones SA, Nakamura K, Okuyama T, Swoboda KJ, Kishnani PS; Pompe Disease Newborn Screening working group. management of confirmed newborn-screened patients with Pompe disease across the disease spectrum. Pediatrics. 2017;140:S24-S45.
• American College of Medical Genetics. Pompe disease diagnosis and management guideline. Available
• Cupler EJ, Berger KI, Leshner RT, Wolfe GI, Han JJ, Barohn RJ, Kissel JT; AANEM Consensus Committee on Late-Onset Pompe Disease. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve. 2012;45:319-33.
• Kronn DF, Day-Salvatore D, Hwu WL, Jones SA, Nakamura K, Okuyama T, Swoboda KJ, Kishnani PS; Pompe Disease Newborn Screening working group. management of confirmed newborn-screened patients with Pompe disease across the disease spectrum. Pediatrics. 2017;140:S24-S45.
## Literature Cited
|
[] |
31/8/2007
|
21/8/2025
|
5/8/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
gsd3
|
gsd3
|
[
"Cori Disease",
"Debrancher Deficiency",
"Forbes Disease",
"Glycogen Debranching Enzyme (GDE) Deficiency",
"Cori Disease",
"Debrancher Deficiency",
"Forbes Disease",
"Glycogen Debranching Enzyme (GDE) Deficiency",
"Glycogen Storage Disease Type IIIa (GSD IIIa)",
"Glycogen Storage Disease Type IIIb (GSD IIIb)",
"Glycogen debranching enzyme",
"AGL",
"Glycogen Storage Disease Type III"
] |
Glycogen Storage Disease Type III
|
Andrea B Schreuder, Alessandro Rossi, Sarah C Grünert, Terry GJ Derks
|
Summary Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement. GSD IIIa is the most common subtype, present in about 85% of affected individuals; it manifests with liver and muscle involvement. GSD IIIb, with liver involvement only, comprises about 15% of all affected individuals. In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive, with fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Most individuals develop cardiac involvement with cardiac hypertrophy and/or cardiomyopathy. Skeletal myopathy manifesting as weakness may be evident in childhood and slowly progresses, typically becoming prominent in the third to fourth decade. The overall prognosis is favorable but cannot be predicted on an individual basis. Long-term complications such as muscular and cardiac symptoms as well as liver fibrosis/cirrhosis and hepatocellular carcinoma may have a severe impact on prognosis and quality of life. To date, it is unknown if long-term complications can be alleviated and/or avoided by dietary interventions. The diagnosis of GSD III is established in a proband by identification of biallelic pathogenic variants in GSD III is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
GSD IIIa (~85% of all GSD III). Liver and muscle involvement, resulting from enzyme deficiency in both liver and muscle
GSD IIIb (~15% of all GSD III). Only liver involvement, resulting from enzyme deficiency in liver only
For synonyms and outdated names see
• GSD IIIa (~85% of all GSD III). Liver and muscle involvement, resulting from enzyme deficiency in both liver and muscle
• GSD IIIb (~15% of all GSD III). Only liver involvement, resulting from enzyme deficiency in liver only
## Diagnosis
Glycogen storage disease type III (GSD III)
Hepatomegaly (presenting feature in ~98%, typically in infancy or early childhood)
Failure to thrive / short stature (presenting feature in ~49%)
Hepatic cirrhosis and hepatic adenomas (in adolescence and adulthood)
Weakness / myopathy
Exercise intolerance
Hypertrophic cardiomyopathy
Ketotic hypoglycemia or ketotic normoglycemia with fasting; elevated ketone concentrations after an overnight fast in untreated individuals
Elevated creatine kinase (once toddlers become active)
Hyperlipidemia, elevated serum triglycerides, and/or cholesterol postprandially initially increases and subsequently decreases, reaching lowest concentrations preprandially.
Elevated transaminase levels
Uric acid and lactate are usually normal [
Note: Blood glucose, ketones, lactate, and lipid levels are affected by diet and timing of blood draw and proximity to the last meal and/or duration of fasting.
The diagnosis of GSD III
Molecular genetic testing approaches include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type III
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The debranching enzyme is a single polypeptide with two catalytic sites, amylo-1,6-glucosidase (EC 3.2.1.33) and 4-alpha-glucanotransferase (EC 2.4.1.25). If molecular genetic testing is inconclusive, debranching enzyme activity can be measured enzymatically, ideally in tissues that are obtained as noninvasively as possible. Liver or muscle biopsy is rarely required to establish the diagnosis of GSD III.
Note: (1) Analysis of debranching enzyme activity in white blood cells is not available in the United States. (2) To distinguish GSD IIIa (liver and muscle involvement; 85% of affected individuals) from GSD IIIb (liver only; 15% of affected individuals), muscle biopsy may be considered to measure debranching enzyme activity and glycogen content since normal serum CK concentrations do not preclude muscle involvement, and information on genotype-phenotype correlations is insufficient for clinical subtyping.
• Hepatomegaly (presenting feature in ~98%, typically in infancy or early childhood)
• Failure to thrive / short stature (presenting feature in ~49%)
• Hepatic cirrhosis and hepatic adenomas (in adolescence and adulthood)
• Weakness / myopathy
• Exercise intolerance
• Hypertrophic cardiomyopathy
• Ketotic hypoglycemia or ketotic normoglycemia with fasting; elevated ketone concentrations after an overnight fast in untreated individuals
• Elevated creatine kinase (once toddlers become active)
• Hyperlipidemia, elevated serum triglycerides, and/or cholesterol postprandially initially increases and subsequently decreases, reaching lowest concentrations preprandially.
• Elevated transaminase levels
• Uric acid and lactate are usually normal [
• For an introduction to multigene panels click
## Suggestive Findings
Glycogen storage disease type III (GSD III)
Hepatomegaly (presenting feature in ~98%, typically in infancy or early childhood)
Failure to thrive / short stature (presenting feature in ~49%)
Hepatic cirrhosis and hepatic adenomas (in adolescence and adulthood)
Weakness / myopathy
Exercise intolerance
Hypertrophic cardiomyopathy
Ketotic hypoglycemia or ketotic normoglycemia with fasting; elevated ketone concentrations after an overnight fast in untreated individuals
Elevated creatine kinase (once toddlers become active)
Hyperlipidemia, elevated serum triglycerides, and/or cholesterol postprandially initially increases and subsequently decreases, reaching lowest concentrations preprandially.
Elevated transaminase levels
Uric acid and lactate are usually normal [
Note: Blood glucose, ketones, lactate, and lipid levels are affected by diet and timing of blood draw and proximity to the last meal and/or duration of fasting.
• Hepatomegaly (presenting feature in ~98%, typically in infancy or early childhood)
• Failure to thrive / short stature (presenting feature in ~49%)
• Hepatic cirrhosis and hepatic adenomas (in adolescence and adulthood)
• Weakness / myopathy
• Exercise intolerance
• Hypertrophic cardiomyopathy
• Ketotic hypoglycemia or ketotic normoglycemia with fasting; elevated ketone concentrations after an overnight fast in untreated individuals
• Elevated creatine kinase (once toddlers become active)
• Hyperlipidemia, elevated serum triglycerides, and/or cholesterol postprandially initially increases and subsequently decreases, reaching lowest concentrations preprandially.
• Elevated transaminase levels
• Uric acid and lactate are usually normal [
## Establishing the Diagnosis
The diagnosis of GSD III
Molecular genetic testing approaches include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type III
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The debranching enzyme is a single polypeptide with two catalytic sites, amylo-1,6-glucosidase (EC 3.2.1.33) and 4-alpha-glucanotransferase (EC 2.4.1.25). If molecular genetic testing is inconclusive, debranching enzyme activity can be measured enzymatically, ideally in tissues that are obtained as noninvasively as possible. Liver or muscle biopsy is rarely required to establish the diagnosis of GSD III.
Note: (1) Analysis of debranching enzyme activity in white blood cells is not available in the United States. (2) To distinguish GSD IIIa (liver and muscle involvement; 85% of affected individuals) from GSD IIIb (liver only; 15% of affected individuals), muscle biopsy may be considered to measure debranching enzyme activity and glycogen content since normal serum CK concentrations do not preclude muscle involvement, and information on genotype-phenotype correlations is insufficient for clinical subtyping.
• For an introduction to multigene panels click
## Molecular Diagnosis
Molecular genetic testing approaches include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type III
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Analysis of Debranching Enzyme Activity
The debranching enzyme is a single polypeptide with two catalytic sites, amylo-1,6-glucosidase (EC 3.2.1.33) and 4-alpha-glucanotransferase (EC 2.4.1.25). If molecular genetic testing is inconclusive, debranching enzyme activity can be measured enzymatically, ideally in tissues that are obtained as noninvasively as possible. Liver or muscle biopsy is rarely required to establish the diagnosis of GSD III.
Note: (1) Analysis of debranching enzyme activity in white blood cells is not available in the United States. (2) To distinguish GSD IIIa (liver and muscle involvement; 85% of affected individuals) from GSD IIIb (liver only; 15% of affected individuals), muscle biopsy may be considered to measure debranching enzyme activity and glycogen content since normal serum CK concentrations do not preclude muscle involvement, and information on genotype-phenotype correlations is insufficient for clinical subtyping.
## Clinical Characteristics
Glycogen storage disease type III (GSD III) is characterized by variable liver, skeletal muscle, and cardiac muscle involvement. GSD IIIa (~85% of all GSD III) is characterized by liver and muscle involvement, and GSD IIIb (~15% of all GSD III) is characterized by liver involvement only, typically present in childhood with hepatomegaly and ketotic hypoglycemia with markedly elevated liver transaminases and hypertriglyceridemia.
Liver histology shows prominent distension of hepatocytes by glycogen; fibrous septa and periportal fibrosis are frequently present. Fibrosis increases over time and is typically greater in individuals with GSD III than in the other forms of GSD (
Elevated prothrombin time and low serum concentration of albumin are noted in those with GSD III who develop cirrhosis [
Hepatic adenomas are reported in 6.9% of individuals [
In GSD III, hepatic cirrhosis (not adenomas) leads to hepatocellular carcinoma [
Altered perfusion [
Myopathy may be partially avoided, and existing skeletal myopathy can be improved with high-protein diet and avoidance of excessive carbohydrate intake [
Cardiomyopathy often appears during childhood; rarely, it has been documented in the first year of life. Its clinical significance is uncertain, as most affected individuals are asymptomatic; however, severe cardiac dysfunction, congestive heart failure, and sudden death have occasionally been reported [
Cardiac myopathies can be improved with high-protein diet and avoidance of excessive carbohydrate intake [
There is a clear genotype-phenotype correlation with at least two pathogenic variants in exon 3 (
No clear genotype-phenotype correlations between other
Abnormal glycogen with short outer chains was first reported by
Other terms used to refer to GSD III include AGL deficiency and amylo-1,6-glucosidase deficiency.
GSD III is rare, with an estimated prevalence of 1:100,000.
Certain populations have an increased prevalence as the result of a founder effect:
The Inuit population in Nunavik (Canada) (~1:2,500) [
The Faroese (~1:3,100) [
North African Jews from Israel (~1:5,400) [
• The Inuit population in Nunavik (Canada) (~1:2,500) [
• The Faroese (~1:3,100) [
• North African Jews from Israel (~1:5,400) [
## Clinical Description
Glycogen storage disease type III (GSD III) is characterized by variable liver, skeletal muscle, and cardiac muscle involvement. GSD IIIa (~85% of all GSD III) is characterized by liver and muscle involvement, and GSD IIIb (~15% of all GSD III) is characterized by liver involvement only, typically present in childhood with hepatomegaly and ketotic hypoglycemia with markedly elevated liver transaminases and hypertriglyceridemia.
Liver histology shows prominent distension of hepatocytes by glycogen; fibrous septa and periportal fibrosis are frequently present. Fibrosis increases over time and is typically greater in individuals with GSD III than in the other forms of GSD (
Elevated prothrombin time and low serum concentration of albumin are noted in those with GSD III who develop cirrhosis [
Hepatic adenomas are reported in 6.9% of individuals [
In GSD III, hepatic cirrhosis (not adenomas) leads to hepatocellular carcinoma [
Altered perfusion [
Myopathy may be partially avoided, and existing skeletal myopathy can be improved with high-protein diet and avoidance of excessive carbohydrate intake [
Cardiomyopathy often appears during childhood; rarely, it has been documented in the first year of life. Its clinical significance is uncertain, as most affected individuals are asymptomatic; however, severe cardiac dysfunction, congestive heart failure, and sudden death have occasionally been reported [
Cardiac myopathies can be improved with high-protein diet and avoidance of excessive carbohydrate intake [
## Genotype-Phenotype Correlations
There is a clear genotype-phenotype correlation with at least two pathogenic variants in exon 3 (
No clear genotype-phenotype correlations between other
## Nomenclature
Abnormal glycogen with short outer chains was first reported by
Other terms used to refer to GSD III include AGL deficiency and amylo-1,6-glucosidase deficiency.
## Prevalence
GSD III is rare, with an estimated prevalence of 1:100,000.
Certain populations have an increased prevalence as the result of a founder effect:
The Inuit population in Nunavik (Canada) (~1:2,500) [
The Faroese (~1:3,100) [
North African Jews from Israel (~1:5,400) [
• The Inuit population in Nunavik (Canada) (~1:2,500) [
• The Faroese (~1:3,100) [
• North African Jews from Israel (~1:5,400) [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Findings in glycogen storage disease type III (GSD III) that may help distinguish it from other forms of GSD presenting with fasting intolerance-related signs and symptoms include the following:
A history of hepatomegaly, hypoglycemia, and failure to thrive in childhood
Elevated serum creatine kinase (CK) in the setting of a hepatic GSD in a young child
Remarkably elevated serum transaminases (often ~500 U/L) prior to commencement of treatment. No other GSD is associated with such marked elevation of aspartate aminotransferase and alanine transaminase [
Elevated excretion of urinary glucose tetrasaccharide [
Liver histology. Fibrosis increases over time in GSD III and is typically greater than in the other forms of GSD: fibrosis is not a feature of
Selected examples of metabolic disorders that present with signs and symptoms related to fasting intolerance are reviewed in
Selected Metabolic Disorders Presenting with Fasting Intolerance in the Differential Diagnosis of GSD III
ALT = alanine transaminase; AR = autosomal recessive; AST = aspartate aminotransferase; CK = creatine kinase; GI = gastrointestinal; GSD = glycogen storage disease; MADD = multiple acyl-CoA dehydrogenase deficiency; MCAD = medium-chain acyl-coenzyme A dehydrogenase; MOI = mode of inheritance; VLCAD = very long-chain acyl-coenzyme a dehydrogenase deficiency; XL = X-linked
Phosphorylase kinase (PhK) is responsible for activation of hepatic glycogen phosphorylase that cleaves the terminal glucose moieties from the glycogen chain.
MADD is caused by biallelic pathogenic variants in
• A history of hepatomegaly, hypoglycemia, and failure to thrive in childhood
• Elevated serum creatine kinase (CK) in the setting of a hepatic GSD in a young child
• Remarkably elevated serum transaminases (often ~500 U/L) prior to commencement of treatment. No other GSD is associated with such marked elevation of aspartate aminotransferase and alanine transaminase [
• Elevated excretion of urinary glucose tetrasaccharide [
• Liver histology. Fibrosis increases over time in GSD III and is typically greater than in the other forms of GSD: fibrosis is not a feature of
## Management
Based on the 2010 ACMG practice guidelines, the investigations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Glycogen Storage Disease Type III
Glucose, AST, ALT, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, international normalized ratio, albumin, bilirubin, creatinine
Consultation w/biochemical geneticist
Liver ultrasound to assess liver size & structure
CK
Developmental assessment (incl gross & fine motor assessment)
Neuromuscular consultation, incl strength, endurance, exercise tolerance, & pain assessment
PT consultation
Neuromuscular assessment (e.g., muscle ultrasound, dynamometry) should be performed subsequently based on physical status, function, symptoms, or need.
Electromyography/nerve conduction tests in those w/suspected peripheral neuropathy
CK-MB, troponin I/T, NT-proBNP
Electrocardiogram
Echocardiogram
Measure length/height, weight; BMI.
Eval of nutritional status
Assess & optimize dietary intake for exercise & activity levels.
Serum calcium & 25(OH)-vitamin D
Bone mineral density
Orthopedic consultation as needed
Females w/GSD III may develop polycystic ovaries from a young age.
Avoid estrogen (may contribute to hepatocellular neoplasm).
Community or
Social work involvement for parental support;
Home nursing referral;
Emergency letters to prevent/ manage metabolic decompensation.
ALT = alanine transaminase; AST = aspartate aminotransferase; BMI = body mass index; BNP = B-type natriuretic peptide; CK = creatine kinase; GSD = glycogen storage disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MOI = mode of inheritance; NT = N-terminal; PT = physical therapist
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
As an alternative for uncooked cornstarch, Glycosade
Skeletal muscle metabolism may be impaired during exercise in GSD III. Consumption of maltodextrin or rapidly absorbable carbohydrates can prevent hypoglycemia during physical activity. Fructose or sucrose prior to exercise may improve exercise tolerance but does not completely prevent exercise-induced damage [
Titration of protein and cornstarch in the diet is the primary treatment for elevated cholesterol and triglyceride concentrations, which usually result from suboptimal metabolic control.
It has been shown that high-fat diet can reduce cardiomyopathy in individuals with GSD III [
Recommended Surveillance for Individuals with Glycogen Storage Disease Type III
Measure blood glucose preprandially.
Measure blood ketones on waking using a portable blood ketone meter
Continuous glucose monitoring can be helpful for many.
Direct & functional neuromuscular assessment of strength & endurance
Assessment of exercise tolerance & pain
PT assessment in children incl gross & fine motor skills
In adults: musculoskeletal assessment for alterations in alignment (hypermobility, ↑ width of base of support, anterior pelvic tilt, genu valgum & recurvatum, hindfoot valgus, & forefoot varus) & assessment for adaptive equipment
Annual neuromuscular, PT, & musculoskeletal assessments in adults based on signs/symptoms
Follow-up assessments (e.g., muscle ultrasound, dynamometry) based on physical status, function, & symptoms
Note: Statins can worsen myopathy.
NT-proBNP, CK-MB
Electrocardiogram
Echocardiogram
Additional investigations (e.g., heart MRI) may be indicated.
GSD IIIa: every 12-24 mos
GSD IIIb: every 5 yrs
Note: Exercise restriction is usually not recommended.
Measure height, weight, & head circumference to monitor growth.
Assess & optimize dietary intake for exercise & activity levels.
In females at each visit, as females w/GSD III may develop polycystic ovaries from a young age
Avoid estrogen (may contribute to hepatocellular neoplasm).
ALT = alanine transaminase; AST = aspartate aminotransferase; B-type natriuretic peptide = BNP; CK = creatine kinase; NT = N-terminal; PT = physical therapy
Hypoglycemia is uncommon in older children and adults on waking since counterregulation can raise blood glucose concentrations; however, monitoring blood glucose concentrations preprandially can reveal periods of suboptimal control.
Elevated ketones reflect poor metabolic control, as ketones are produced when glucose is unavailable and instead fatty acid oxidation is used as a source of energy.
Avoid the following:
High carbohydrate intake. Excess sugar is stored as glycogen, which cannot be broken down, resulting in hepatomegaly.
Steroid-based drugs, which interfere with glucose metabolism and utilization. Long-term steroid usage itself can cause failure to thrive and muscle weakness.
Growth hormone replacement therapy, which interferes with glucose metabolism and worsens ketosis. Growth hormone therapy has been associated with adenoma growth and complications in GSD I; therefore, growth hormone should only be used in individuals with documented growth hormone deficiency.
Medications that can cause rhabdomyolysis
Use the following with caution:
Hormonal (estrogen) contraceptives in women. Estrogen is known to contribute to both benign and malignant hepatocellular tumors.
Statins for control of hyperlipidemia. Use of statins requires CK monitoring because of the potential of exacerbating the muscle disease of GSD IIIa.
Beta blockers, which can cause hypoglycemia and mask the signs and symptoms associated with the adrenergic response during hypoglycemia
Diagnosis of at-risk sibs at birth allows for early dietary intervention to prevent development of hypoglycemia associated with GSD III.
If the
If the
See
Increased monitoring and support are required in pregnancy of women with GSD III. The goal during all trimesters of the pregnancy and peripartum is to maintain normoglycemia and to avoid upregulation of counterregulatory hormones, which result in lipolysis, increased mitochondrial fatty acid oxidation, and hyperketosis [
Throughout the entire pregnancy, adequate protein is necessary to provide an alternate source of glucose via gluconeogenesis. Hyperemesis may cause secondary hyperketosis and hypoglycemia. The metabolic requirements will gradually increase throughout the second and third trimesters, necessitating dietary adjustments to meet the glucose demands of the fetus.
Women with GSD III may be at risk of gestational diabetes, but oral glucose tests are contraindicated.
Ketonuria for healthy women in labor is generally accepted as a normal physiologic response [
Search
• Glucose, AST, ALT, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, international normalized ratio, albumin, bilirubin, creatinine
• Consultation w/biochemical geneticist
• Liver ultrasound to assess liver size & structure
• CK
• Developmental assessment (incl gross & fine motor assessment)
• Neuromuscular consultation, incl strength, endurance, exercise tolerance, & pain assessment
• PT consultation
• Neuromuscular assessment (e.g., muscle ultrasound, dynamometry) should be performed subsequently based on physical status, function, symptoms, or need.
• Electromyography/nerve conduction tests in those w/suspected peripheral neuropathy
• CK-MB, troponin I/T, NT-proBNP
• Electrocardiogram
• Echocardiogram
• Measure length/height, weight; BMI.
• Eval of nutritional status
• Assess & optimize dietary intake for exercise & activity levels.
• Serum calcium & 25(OH)-vitamin D
• Bone mineral density
• Orthopedic consultation as needed
• Females w/GSD III may develop polycystic ovaries from a young age.
• Avoid estrogen (may contribute to hepatocellular neoplasm).
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Emergency letters to prevent/ manage metabolic decompensation.
• As an alternative for uncooked cornstarch, Glycosade
• Skeletal muscle metabolism may be impaired during exercise in GSD III. Consumption of maltodextrin or rapidly absorbable carbohydrates can prevent hypoglycemia during physical activity. Fructose or sucrose prior to exercise may improve exercise tolerance but does not completely prevent exercise-induced damage [
• Titration of protein and cornstarch in the diet is the primary treatment for elevated cholesterol and triglyceride concentrations, which usually result from suboptimal metabolic control.
• It has been shown that high-fat diet can reduce cardiomyopathy in individuals with GSD III [
• Measure blood glucose preprandially.
• Measure blood ketones on waking using a portable blood ketone meter
• Continuous glucose monitoring can be helpful for many.
• Direct & functional neuromuscular assessment of strength & endurance
• Assessment of exercise tolerance & pain
• PT assessment in children incl gross & fine motor skills
• In adults: musculoskeletal assessment for alterations in alignment (hypermobility, ↑ width of base of support, anterior pelvic tilt, genu valgum & recurvatum, hindfoot valgus, & forefoot varus) & assessment for adaptive equipment
• Annual neuromuscular, PT, & musculoskeletal assessments in adults based on signs/symptoms
• Follow-up assessments (e.g., muscle ultrasound, dynamometry) based on physical status, function, & symptoms
• Note: Statins can worsen myopathy.
• NT-proBNP, CK-MB
• Electrocardiogram
• Echocardiogram
• Additional investigations (e.g., heart MRI) may be indicated.
• GSD IIIa: every 12-24 mos
• GSD IIIb: every 5 yrs
• Note: Exercise restriction is usually not recommended.
• Measure height, weight, & head circumference to monitor growth.
• Assess & optimize dietary intake for exercise & activity levels.
• In females at each visit, as females w/GSD III may develop polycystic ovaries from a young age
• Avoid estrogen (may contribute to hepatocellular neoplasm).
• High carbohydrate intake. Excess sugar is stored as glycogen, which cannot be broken down, resulting in hepatomegaly.
• Steroid-based drugs, which interfere with glucose metabolism and utilization. Long-term steroid usage itself can cause failure to thrive and muscle weakness.
• Growth hormone replacement therapy, which interferes with glucose metabolism and worsens ketosis. Growth hormone therapy has been associated with adenoma growth and complications in GSD I; therefore, growth hormone should only be used in individuals with documented growth hormone deficiency.
• Medications that can cause rhabdomyolysis
• Hormonal (estrogen) contraceptives in women. Estrogen is known to contribute to both benign and malignant hepatocellular tumors.
• Statins for control of hyperlipidemia. Use of statins requires CK monitoring because of the potential of exacerbating the muscle disease of GSD IIIa.
• Beta blockers, which can cause hypoglycemia and mask the signs and symptoms associated with the adrenergic response during hypoglycemia
• If the
• If the
## Evaluations Following Initial Diagnosis
Based on the 2010 ACMG practice guidelines, the investigations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Glycogen Storage Disease Type III
Glucose, AST, ALT, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, international normalized ratio, albumin, bilirubin, creatinine
Consultation w/biochemical geneticist
Liver ultrasound to assess liver size & structure
CK
Developmental assessment (incl gross & fine motor assessment)
Neuromuscular consultation, incl strength, endurance, exercise tolerance, & pain assessment
PT consultation
Neuromuscular assessment (e.g., muscle ultrasound, dynamometry) should be performed subsequently based on physical status, function, symptoms, or need.
Electromyography/nerve conduction tests in those w/suspected peripheral neuropathy
CK-MB, troponin I/T, NT-proBNP
Electrocardiogram
Echocardiogram
Measure length/height, weight; BMI.
Eval of nutritional status
Assess & optimize dietary intake for exercise & activity levels.
Serum calcium & 25(OH)-vitamin D
Bone mineral density
Orthopedic consultation as needed
Females w/GSD III may develop polycystic ovaries from a young age.
Avoid estrogen (may contribute to hepatocellular neoplasm).
Community or
Social work involvement for parental support;
Home nursing referral;
Emergency letters to prevent/ manage metabolic decompensation.
ALT = alanine transaminase; AST = aspartate aminotransferase; BMI = body mass index; BNP = B-type natriuretic peptide; CK = creatine kinase; GSD = glycogen storage disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MOI = mode of inheritance; NT = N-terminal; PT = physical therapist
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Glucose, AST, ALT, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, international normalized ratio, albumin, bilirubin, creatinine
• Consultation w/biochemical geneticist
• Liver ultrasound to assess liver size & structure
• CK
• Developmental assessment (incl gross & fine motor assessment)
• Neuromuscular consultation, incl strength, endurance, exercise tolerance, & pain assessment
• PT consultation
• Neuromuscular assessment (e.g., muscle ultrasound, dynamometry) should be performed subsequently based on physical status, function, symptoms, or need.
• Electromyography/nerve conduction tests in those w/suspected peripheral neuropathy
• CK-MB, troponin I/T, NT-proBNP
• Electrocardiogram
• Echocardiogram
• Measure length/height, weight; BMI.
• Eval of nutritional status
• Assess & optimize dietary intake for exercise & activity levels.
• Serum calcium & 25(OH)-vitamin D
• Bone mineral density
• Orthopedic consultation as needed
• Females w/GSD III may develop polycystic ovaries from a young age.
• Avoid estrogen (may contribute to hepatocellular neoplasm).
• Community or
• Social work involvement for parental support;
• Home nursing referral;
• Emergency letters to prevent/ manage metabolic decompensation.
## Treatment of Manifestations
As an alternative for uncooked cornstarch, Glycosade
Skeletal muscle metabolism may be impaired during exercise in GSD III. Consumption of maltodextrin or rapidly absorbable carbohydrates can prevent hypoglycemia during physical activity. Fructose or sucrose prior to exercise may improve exercise tolerance but does not completely prevent exercise-induced damage [
Titration of protein and cornstarch in the diet is the primary treatment for elevated cholesterol and triglyceride concentrations, which usually result from suboptimal metabolic control.
It has been shown that high-fat diet can reduce cardiomyopathy in individuals with GSD III [
• As an alternative for uncooked cornstarch, Glycosade
• Skeletal muscle metabolism may be impaired during exercise in GSD III. Consumption of maltodextrin or rapidly absorbable carbohydrates can prevent hypoglycemia during physical activity. Fructose or sucrose prior to exercise may improve exercise tolerance but does not completely prevent exercise-induced damage [
• Titration of protein and cornstarch in the diet is the primary treatment for elevated cholesterol and triglyceride concentrations, which usually result from suboptimal metabolic control.
• It has been shown that high-fat diet can reduce cardiomyopathy in individuals with GSD III [
## Surveillance
Recommended Surveillance for Individuals with Glycogen Storage Disease Type III
Measure blood glucose preprandially.
Measure blood ketones on waking using a portable blood ketone meter
Continuous glucose monitoring can be helpful for many.
Direct & functional neuromuscular assessment of strength & endurance
Assessment of exercise tolerance & pain
PT assessment in children incl gross & fine motor skills
In adults: musculoskeletal assessment for alterations in alignment (hypermobility, ↑ width of base of support, anterior pelvic tilt, genu valgum & recurvatum, hindfoot valgus, & forefoot varus) & assessment for adaptive equipment
Annual neuromuscular, PT, & musculoskeletal assessments in adults based on signs/symptoms
Follow-up assessments (e.g., muscle ultrasound, dynamometry) based on physical status, function, & symptoms
Note: Statins can worsen myopathy.
NT-proBNP, CK-MB
Electrocardiogram
Echocardiogram
Additional investigations (e.g., heart MRI) may be indicated.
GSD IIIa: every 12-24 mos
GSD IIIb: every 5 yrs
Note: Exercise restriction is usually not recommended.
Measure height, weight, & head circumference to monitor growth.
Assess & optimize dietary intake for exercise & activity levels.
In females at each visit, as females w/GSD III may develop polycystic ovaries from a young age
Avoid estrogen (may contribute to hepatocellular neoplasm).
ALT = alanine transaminase; AST = aspartate aminotransferase; B-type natriuretic peptide = BNP; CK = creatine kinase; NT = N-terminal; PT = physical therapy
Hypoglycemia is uncommon in older children and adults on waking since counterregulation can raise blood glucose concentrations; however, monitoring blood glucose concentrations preprandially can reveal periods of suboptimal control.
Elevated ketones reflect poor metabolic control, as ketones are produced when glucose is unavailable and instead fatty acid oxidation is used as a source of energy.
• Measure blood glucose preprandially.
• Measure blood ketones on waking using a portable blood ketone meter
• Continuous glucose monitoring can be helpful for many.
• Direct & functional neuromuscular assessment of strength & endurance
• Assessment of exercise tolerance & pain
• PT assessment in children incl gross & fine motor skills
• In adults: musculoskeletal assessment for alterations in alignment (hypermobility, ↑ width of base of support, anterior pelvic tilt, genu valgum & recurvatum, hindfoot valgus, & forefoot varus) & assessment for adaptive equipment
• Annual neuromuscular, PT, & musculoskeletal assessments in adults based on signs/symptoms
• Follow-up assessments (e.g., muscle ultrasound, dynamometry) based on physical status, function, & symptoms
• Note: Statins can worsen myopathy.
• NT-proBNP, CK-MB
• Electrocardiogram
• Echocardiogram
• Additional investigations (e.g., heart MRI) may be indicated.
• GSD IIIa: every 12-24 mos
• GSD IIIb: every 5 yrs
• Note: Exercise restriction is usually not recommended.
• Measure height, weight, & head circumference to monitor growth.
• Assess & optimize dietary intake for exercise & activity levels.
• In females at each visit, as females w/GSD III may develop polycystic ovaries from a young age
• Avoid estrogen (may contribute to hepatocellular neoplasm).
## Agents/Circumstances to Avoid
Avoid the following:
High carbohydrate intake. Excess sugar is stored as glycogen, which cannot be broken down, resulting in hepatomegaly.
Steroid-based drugs, which interfere with glucose metabolism and utilization. Long-term steroid usage itself can cause failure to thrive and muscle weakness.
Growth hormone replacement therapy, which interferes with glucose metabolism and worsens ketosis. Growth hormone therapy has been associated with adenoma growth and complications in GSD I; therefore, growth hormone should only be used in individuals with documented growth hormone deficiency.
Medications that can cause rhabdomyolysis
Use the following with caution:
Hormonal (estrogen) contraceptives in women. Estrogen is known to contribute to both benign and malignant hepatocellular tumors.
Statins for control of hyperlipidemia. Use of statins requires CK monitoring because of the potential of exacerbating the muscle disease of GSD IIIa.
Beta blockers, which can cause hypoglycemia and mask the signs and symptoms associated with the adrenergic response during hypoglycemia
• High carbohydrate intake. Excess sugar is stored as glycogen, which cannot be broken down, resulting in hepatomegaly.
• Steroid-based drugs, which interfere with glucose metabolism and utilization. Long-term steroid usage itself can cause failure to thrive and muscle weakness.
• Growth hormone replacement therapy, which interferes with glucose metabolism and worsens ketosis. Growth hormone therapy has been associated with adenoma growth and complications in GSD I; therefore, growth hormone should only be used in individuals with documented growth hormone deficiency.
• Medications that can cause rhabdomyolysis
• Hormonal (estrogen) contraceptives in women. Estrogen is known to contribute to both benign and malignant hepatocellular tumors.
• Statins for control of hyperlipidemia. Use of statins requires CK monitoring because of the potential of exacerbating the muscle disease of GSD IIIa.
• Beta blockers, which can cause hypoglycemia and mask the signs and symptoms associated with the adrenergic response during hypoglycemia
## Evaluation of Relatives at Risk
Diagnosis of at-risk sibs at birth allows for early dietary intervention to prevent development of hypoglycemia associated with GSD III.
If the
If the
See
• If the
• If the
## Pregnancy Management
Increased monitoring and support are required in pregnancy of women with GSD III. The goal during all trimesters of the pregnancy and peripartum is to maintain normoglycemia and to avoid upregulation of counterregulatory hormones, which result in lipolysis, increased mitochondrial fatty acid oxidation, and hyperketosis [
Throughout the entire pregnancy, adequate protein is necessary to provide an alternate source of glucose via gluconeogenesis. Hyperemesis may cause secondary hyperketosis and hypoglycemia. The metabolic requirements will gradually increase throughout the second and third trimesters, necessitating dietary adjustments to meet the glucose demands of the fetus.
Women with GSD III may be at risk of gestational diabetes, but oral glucose tests are contraindicated.
Ketonuria for healthy women in labor is generally accepted as a normal physiologic response [
## Therapies Under Investigation
Search
## Genetic Counseling
Glycogen storage disease type III (GSD III) is inherited in an autosomal recessive manner.
The parents of an affected child are usually heterozygotes (i.e., carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Clinical variability may be observed between affected sibs [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
The offspring of an individual with GSD III are obligate heterozygotes (carriers) for a pathogenic variant in
If the reproductive partner of an affected person is a carrier, the offspring are at a 50% risk of being affected. This is more likely to occur in populations with a higher prevalence of GSD III as the result of a founder effect (see
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are usually heterozygotes (i.e., carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband [
• A single- or multiexon deletion in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband [
• If both parents are known to be heterozygous for an
• Clinical variability may be observed between affected sibs [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The offspring of an individual with GSD III are obligate heterozygotes (carriers) for a pathogenic variant in
• If the reproductive partner of an affected person is a carrier, the offspring are at a 50% risk of being affected. This is more likely to occur in populations with a higher prevalence of GSD III as the result of a founder effect (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.
## Mode of Inheritance
Glycogen storage disease type III (GSD III) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are usually heterozygotes (i.e., carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Clinical variability may be observed between affected sibs [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
The offspring of an individual with GSD III are obligate heterozygotes (carriers) for a pathogenic variant in
If the reproductive partner of an affected person is a carrier, the offspring are at a 50% risk of being affected. This is more likely to occur in populations with a higher prevalence of GSD III as the result of a founder effect (see
• The parents of an affected child are usually heterozygotes (i.e., carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband [
• A single- or multiexon deletion in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A single- or multiexon deletion in the proband was not detected by sequence analysis and resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband [
• If both parents are known to be heterozygous for an
• Clinical variability may be observed between affected sibs [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The offspring of an individual with GSD III are obligate heterozygotes (carriers) for a pathogenic variant in
• If the reproductive partner of an affected person is a carrier, the offspring are at a 50% risk of being affected. This is more likely to occur in populations with a higher prevalence of GSD III as the result of a founder effect (see
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Brazil
Spain
Belgium
9 Lindop Road
Altrincham Cheshire WA15 9DZ
United Kingdom
France
Italy
Canada
United Kingdom
Germany
Netherlands
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• Brazil
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• Belgium
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• 9 Lindop Road
• Altrincham Cheshire WA15 9DZ
• United Kingdom
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• France
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• Italy
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• Canada
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## Molecular Genetics
Glycogen Storage Disease Type III: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Glycogen Storage Disease Type III (
To make glycogen, glucose molecules forming uridine diphosphate glucose are added via alpha 1,4 linkages to the matrix for glycogen, called glycogenin. This process is catalyzed by glycogen synthase. When the chain reaches a certain length, "branching enzyme" cleaves off the terminal portion of the chain and attaches it via an alpha 1,6 linkage to the parent chain. This process is repeated over and over again on all the different branches of the chain and the complex glycogen molecules are created.
When digestion of a meal is complete, insulin levels decrease and glucagon is secreted. In a process mediated by the enzyme glycogen phosphorylase, these hormones stimulate cleavage of glucose molecules from the terminal strands of glycogen as glucose-1-phosphate. This process continues until four glucose molecules remain before the alpha 1,6 bond. At this point, the human debranching enzyme with its two distinct catalytic activities comes into play. The 1,4-α-D-glucan 4-α-D-glycosyl transferase component transfers the terminal three glucose molecules to the parent chain and the amylo-1,6-glucosidase component cleaves the alpha 1,6 bond to release free glucose.
With debranching enzyme deficiency, glycogen cannot be completely degraded and as a consequence, an abnormal glycogen with branched outer points called "limit dextrin" accumulates.
Notable
Variants listed in the table have been provided by the authors.
One of the most common variants in the US (10.3%)
## Molecular Pathogenesis
To make glycogen, glucose molecules forming uridine diphosphate glucose are added via alpha 1,4 linkages to the matrix for glycogen, called glycogenin. This process is catalyzed by glycogen synthase. When the chain reaches a certain length, "branching enzyme" cleaves off the terminal portion of the chain and attaches it via an alpha 1,6 linkage to the parent chain. This process is repeated over and over again on all the different branches of the chain and the complex glycogen molecules are created.
When digestion of a meal is complete, insulin levels decrease and glucagon is secreted. In a process mediated by the enzyme glycogen phosphorylase, these hormones stimulate cleavage of glucose molecules from the terminal strands of glycogen as glucose-1-phosphate. This process continues until four glucose molecules remain before the alpha 1,6 bond. At this point, the human debranching enzyme with its two distinct catalytic activities comes into play. The 1,4-α-D-glucan 4-α-D-glycosyl transferase component transfers the terminal three glucose molecules to the parent chain and the amylo-1,6-glucosidase component cleaves the alpha 1,6 bond to release free glucose.
With debranching enzyme deficiency, glycogen cannot be completely degraded and as a consequence, an abnormal glycogen with branched outer points called "limit dextrin" accumulates.
Notable
Variants listed in the table have been provided by the authors.
One of the most common variants in the US (10.3%)
## Chapter Notes
Research priorities have been defined for liver glycogen storage disease (GSD) and also for GSD III [
We acknowledge the individuals with GSD and their families, our institutions, collaborating health care providers treating individuals with GSD, laboratory personnel and researchers, the (inter)national patient support groups, and private companies for their untiring work and collaboration.
Aditi Dagli, MD; University of Florida College of Medicine (2010-2022)Terry GJ Derks, MD, PhD (2022-present)Sarah C Grünert, MD (2022-present)Alessandro Rossi, MD (2022-present)Andrea B Schreuder, MD, PhD (2022-present)Christiaan P Sentner, MD; University Medical Center Groningen (2010-2022)David A Weinstein, MD, MMSc; University of Connecticut (2010-2022)
6 January 2022 (sw) Comprehensive update posted live
29 December 2016 (bp) Comprehensive update posted live
6 September 2012 (me) Comprehensive update posted live
15 March 2011 (cd) Revision: targeted mutation analysis no longer listed in the GeneTests Laboratory Directory as clinically available
21 October 2010 (cd) Revision: deletion/duplication analysis available for
3 March 2010 (me) Review posted live
5 November 2009 (daw) Original submission
• 6 January 2022 (sw) Comprehensive update posted live
• 29 December 2016 (bp) Comprehensive update posted live
• 6 September 2012 (me) Comprehensive update posted live
• 15 March 2011 (cd) Revision: targeted mutation analysis no longer listed in the GeneTests Laboratory Directory as clinically available
• 21 October 2010 (cd) Revision: deletion/duplication analysis available for
• 3 March 2010 (me) Review posted live
• 5 November 2009 (daw) Original submission
## Author Notes
Research priorities have been defined for liver glycogen storage disease (GSD) and also for GSD III [
## Acknowledgments
We acknowledge the individuals with GSD and their families, our institutions, collaborating health care providers treating individuals with GSD, laboratory personnel and researchers, the (inter)national patient support groups, and private companies for their untiring work and collaboration.
## Author History
Aditi Dagli, MD; University of Florida College of Medicine (2010-2022)Terry GJ Derks, MD, PhD (2022-present)Sarah C Grünert, MD (2022-present)Alessandro Rossi, MD (2022-present)Andrea B Schreuder, MD, PhD (2022-present)Christiaan P Sentner, MD; University Medical Center Groningen (2010-2022)David A Weinstein, MD, MMSc; University of Connecticut (2010-2022)
## Revision History
6 January 2022 (sw) Comprehensive update posted live
29 December 2016 (bp) Comprehensive update posted live
6 September 2012 (me) Comprehensive update posted live
15 March 2011 (cd) Revision: targeted mutation analysis no longer listed in the GeneTests Laboratory Directory as clinically available
21 October 2010 (cd) Revision: deletion/duplication analysis available for
3 March 2010 (me) Review posted live
5 November 2009 (daw) Original submission
• 6 January 2022 (sw) Comprehensive update posted live
• 29 December 2016 (bp) Comprehensive update posted live
• 6 September 2012 (me) Comprehensive update posted live
• 15 March 2011 (cd) Revision: targeted mutation analysis no longer listed in the GeneTests Laboratory Directory as clinically available
• 21 October 2010 (cd) Revision: deletion/duplication analysis available for
• 3 March 2010 (me) Review posted live
• 5 November 2009 (daw) Original submission
## References
## Literature Cited
|
[
"SL Austin, AD Proia, MJ Spencer-Manzon, J Butany, SB Wechsler, PS Kishnani. Cardiac pathology in glycogen storage disease type III.. JIMD Rep 2012;6:65-72",
"Y Bao, TL Dawson, YT Chen. Human glycogen debranching enzyme gene (AGL): complete structural organization and characterization of the 5' flanking region.. Genomics 1996;38:155-65",
"Y Bao, BZ Yang, TL Dawson, YT Chen. Isolation and nucleotide sequence of human liver glycogen debranching enzyme mRNA: identification of multiple tissue-specific isoforms.. Gene 1997;197:389-98",
"AV Bernier, CP Sentner, CE Correia, DW Theriaque, JJ Shuster, GP Smit, DA Weinstein. Hyperlipidemia in glycogen storage disease type III: effect of age and metabolic control.. J Inherit Metab Dis 2008;31:729-32",
"A Ben Chehida, S Ben Messaoud, R Ben Abdelaziz, N Ben Ali, H Boudabous, I Ben Abdelaziz, Z Ben Ameur, Y Sassi, N Kaabachi, S Abdelhak, MS Abdelmoula, M Fradj, H Azzouz, N Tebib. Neuromuscular involvement in glycogen storage disease type III in fifty Tunisian patients: phenotype and natural history in young patients.. Neuropediatrics. 2019;50:22-30",
"A Cheng, M Zhang, M Okubo, K Omichi, AR Saltiel. Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions.. Hum Mol Genet. 2009;18:2045-52",
"MK Davis, DA Weinstein. Liver transplantation in children with glycogen storage disease: controversies and evaluation of the risk/benefit of this procedure.. Pediatr Transplant 2008;12:137-45",
"E Demo, D Frush, M Gottfried, J Koepke, A Boney, D Bali, YT Chen, PS Kishnani. Glycogen storage disease type III-hepatocellular carcinoma a long-term complication?. J Hepatol 2007;46:492-8",
"TG Derks, GP Smit. Dietary management in glycogen storage disease type III: what is the evidence?. J Inherit Metab Dis. 2015;38:545-50",
"ON Elpeleg. The molecular background of glycogen metabolism disorders.. J Pediatr Endocrinol Metab 1999;12:363-79",
"M Focardi, A Bosco, V Bugelli, B Defraia, MA Donati, V Pinchi. \"On air\" diagnosis of sudden cardia death with dynamic Holter ECG in glycogen storage disease type III young female.. Minerva Pediatr. 2020;72:142-4",
"JL Goldstein, SL Austin, K Boyette, A Kanaly, A Veerapandiyan, C Rehder, PS Kishnani, DS Bali. Molecular analysis of the AGL gene: identification of 25 novel mutations and evidence of genetic heterogeneity in patients with glycogen storage disease type III.. Genet Med. 2010;12:424-30",
"MR Heiner-Fokkema, J van der Krogt, F de Boer, MJ Fokkert-Wilts, RGHJ Maatman, IJ Hoogeveen, TGJ Derks. The multiple faces of urinary glucose tetrasaccharide as biomarker for patients with hepatic glycogen storage diseases.. Genet Med. 2020;22:1915-16",
"LD Hobson-Webb, SL Austin, DS Bali, PS Kishnani. The electrodiagnostic characteristics of glycogen storage disease type III.. Genet Med. 2010;12:440-5",
"IJ Hoogeveen, F De Boer, WF Boonstra, CJ Van der Schaaf, U Steuerwald, AJ Sibeijn-Kuiper, RJK Veger, JH Van der Hoeven, MR Heiner-Fokkema, KC Clarke, PJ Cox, TGJ Derks, JAL Jeneson. Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease type IIIa are phenotypic specific: An investigator-initiated, randomized, crossover study.. J Inherit Metab Dis 2021;44:226-39",
"B Illingworth, GT Cori. Structure of glycogens and amylopectins. III. Normal and abnormal human glycogen.. J Biol Chem 1952;199:653-60",
"H. Ismail. Glycogen storage disease type III presenting with secondary diabetes and managed with insulin: a case report.. Cases J. 2009;2:6891",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"PS Kishnani, SL Austin, P Arn, DS Bali, A Boney, LE Case, WK Chung, DM Desai, A El-Gharbawy, R Haller, GP Smit, AD Smith, LD Hobson-Webb, SB Wechsler, DA Weinstein, MS Watson. ACMG. Glycogen storage disease type III diagnosis and management guidelines.. Genet Med. 2010;12:446-63",
"S Lucchiari, D Santoro, S Pagliarani, GP Comi. Clinical, biochemical and genetic features of glycogen debranching enzyme deficiency.. Acta Myol 2007;26:72-4",
"D Melis, A Rossi, R Pivonello, A Del Puente, C Pivonello, G Cangemi, M Negri, A Colao, G Andria, G Parenti. Reduced bone mineral density in glycogen storage disease type III: evidence for a possible connection between metabolic imbalance and bone homeostasis.. Bone. 2016;86:79-85",
"HR Mundy, JE Williams, PJ Lee, MS Fewtrell. Reduction in bone mineral density in glycogenosis type III may be due to a mixed muscle and bone deficit.. J Inherit Metab Dis 2008;31:418-23",
"Y Oki, M Okubo, S Tanaka, K Nakanishi, T Kobayashi, T Murase. Diabetes mellitus secondary to glycogen storage disease type III.. Diabet Med. 2000;17:810-2",
"R Parvari, S Moses, J Shen, E Hershkovitz, A Lerner, YT Chen. A single-base deletion in the 3'-coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients.. Eur J Hum Genet 1997;5:266-70",
"F Peeks, WF Boonstra, L de Baere, C Carøe, T Casswall, D Cohen, K Cowan, I Ferrecchia, A Ferriani, C Gimbert, M Landgren, NL Maldonado, J McMillan, A Nemeth, N Seidita, U Stachelhaus-Theimer, DA Weinstein, TGJ Derks. Research priorities for liver glycogen storage disease: An international priority setting partnership with the James Lind Alliance.. J Inherit Metab Dis. 2020;43:279-89",
"S Perveen, N Gupta, M Kumar, P Kaur, MR Chowdhury, M Kabra. Spectrum of amyloglucosidase mutations in Asian Indian patients with Glycogen storage disease type III.. Am J Med Genet A. 2020;182:1190-200",
"E Ponzi, V Alesi, FR Lepri, S Genovese, S Loddo, M Mucciolo, A Novelli, C Dionisi-Vici, A Maiorana. Uniparental isodisomy of chromosome 1 results in glycogen storage disease type III with profound growth retardation.. Mol Genet Genomic Med. 2019;7",
"N Preisler, P Laforêt, KL Madsen, KP Prahm, G Hedermann, CR Vissing, H Galbo, J Vissing. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III.. Neurology. 2015;84:1767-71",
"KM Ross, LM Brown, MM Corrado, T Chengsupanimit, LM Curry, IA Ferrecchia, LY Porras, JT Mathew, M Dambska, DA Weinstein. Safety and efficacy of long-term use of extended release cornstarch therapy for glycogen storage disease types 0, III, VI, and IX.. J Nutr Ther. 2015;4:137-42",
"A Rossi, IJ Hoogeveen, VB Bastek, F de Boer, C Montanari, U Meyer, A Maiorana, A Bordugo, A Dianin, C Campana, M Rigoldi, PS Kishnani, S Pendyal, P Strisciuglio, S Gasperini, G Parenti, R Parini, S Paci, D Melis, TGJ Derks. Dietary lipids in glycogen storage disease type III: A systematic literature study, case studies, and future recommendations.. J Inherit Metab Dis. 2020;43:770-7",
"I Rousseau-Nepton, M Okubo, R Grabs, J Mitchell, C Polychronakos, C Rodd. A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: a case series.. CMAJ 2015;187:E68-73",
"R Santer, M Kinner, U Steuerwald, S Kjaergaard, F Skovby, H Simonsen, WL Shaiu, YT Chen, R Schneppenheim, J Schaub. Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands.. Eur J Hum Genet 2001;9:388-91",
"CP Sentner, K Caliskan, WB Vletter, GP Smit. Heart failure due to severe hypertrophic cardiomyopathy reversed by low calorie, high protein dietary adjustments in a glycogen storage disease type IIIa patient.. JIMD Rep. 2012;5:13-6",
"CP Sentner, IJ Hoogeveen, DA Weinstein, R Santer, E Murphy, PJ McKiernan, U Steuerwald, NJ Beauchamp, J Taybert, P Laforêt, FM Petit, A Hubert, P Labrune, GP Smit, TG Derks. Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome.. J Inherit Metab Dis. 2016;39:697-704",
"WL Shaiu, PS Kishnani, J Shen, HM Liu, YT Chen. Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease.. Mol Genet Metab 2000;69:16-23",
"J Shen, Y Bao, HM Liu, P Lee, JV Leonard, YT Chen. Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle.. J Clin Invest 1996;98:352-7",
"K Spengos, H Michelakakis, A Vontzalidis, V Zouvelou, P Manta. Diabetes mellitus associated with glycogen storage disease type III.. Muscle Nerve. 2009;39:876-7",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"J Toohill, B Soong, V Flenady. Interventions for ketosis during labour.. Cochrane Database Syst Rev. 2008",
"V Valayannopoulos, F Bajolle, JB Arnoux, S Dubois, N Sannier, C Baussan, F Petit, P Labrune, D Rabier, C Ottolenghi, A Vassault, C Broissand, D Bonnet, P de Lonlay. Successful treatment of severe cardiomyopathy in glycogen storage disease type III with D,L-3-hydroxybutyrate, ketogenic and high protein diet.. Pediatr Res 2011;70:638-41",
"C Wary, A Nadaj-Pakleza, P Laforêt, KG Claeys, R Carlier, A Monnet, S Fleury, C Baligand, B Eymard, P Labrune, PG Carlier. Investigating glycogenosis type III patients with multi-parametric functional NMR imaging and spectroscopy.. Neuromuscul Disord. 2010;20:548-58",
"JI Wolfsdorf, DA Weinstein. Glycogen storage diseases.. Rev Endocr Metab Disord 2003;4:95-102",
"B Xiao, L Wang, H Liu, Y Fan, Y Xu, Y Sun, W Qiu. Uniparental isodisomy caused autosomal recessive diseases: NGS-based analysis allows the concurrent detection of homogenous variants and copy-neutral loss of heterozygosity.. Mol Genet Genomic Med. 2019;7"
] |
9/3/2010
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6/1/2022
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15/3/2011
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GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
gsd4
|
gsd4
|
[
"Andersen Disease",
"Glycogen Branching Enzyme Deficiency",
"Glycogen Storage Disease IV",
"GSD IV",
"Glycogen Storage Disease IV",
"Glycogen Branching Enzyme Deficiency",
"Andersen Disease",
"GSD IV",
"1,4-alpha-glucan-branching enzyme",
"GBE1",
"Glycogen Storage Disease Type IV"
] |
Glycogen Storage Disease Type IV
|
Pilar L Magoulas, Ayman W El-Hattab
|
Summary The clinical manifestations of glycogen storage disease type IV (GSD IV) discussed in this entry span a continuum of different subtypes with variable ages of onset, severity, and clinical features. Clinical findings vary extensively both within and between families. The The Infants with the Children with the The The diagnosis is established in a proband by the demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts or the identification of biallelic pathogenic variants in GSD IV is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Although affected sibs are expected to manifest the same subtype of GSD IV, the age of onset and presentation may differ. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible based on molecular testing if the pathogenic variants in the family have been identified. If the pathogenic variants have not been identified, GBE testing on cultured amniocytes can be performed for prenatal diagnosis.
|
## Diagnosis
The diagnosis of glycogen storage disease type IV (GSD IV) is suspected based on the clinical presentation and the finding of abnormally branched glycogen accumulation in muscle or liver tissue. The diagnosis is confirmed by the demonstration of glycogen branching enzyme (GBE) deficiency in liver, muscle, or skin fibroblasts [
Glycogen storage disease type IV (GSD IV)
Prolonged
Markedly enlarged hepatocytes that contain periodic acid-Schiff (PAS)-positive and diastase-resistant inclusions, features characteristic of the abnormally branched glycogen found in GSD IV. Widespread infiltrates of foamy histiocytes with intra-cytoplasmic deposits within the reticuloendothelial system (RES) have been reported [
On electron microscopy, fine fibrillary aggregates of electron-dense amylopectin-like material within the cytoplasm of hepatocytes in some individuals.
The diagnosis of glycogen storage disease type IV (GSD IV)
Reduced glycogen branching enzyme (GBE) activity (most commonly assayed in cultured skin fibroblasts but may also be assayed in muscle or liver tissue); OR
Biallelic pathogenic variants in
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GSD IV is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of GSD IV, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by liver dysfunction,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type IV
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Of 42 affected individuals, 37 had at least one identifiable variant detected by sequencing analysis; 28 individuals had biallelic pathogenic variants, and six had one identifiable pathogenic variant, implying that the second causative variant was not identified.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Of the 42 affected individuals, three were homozygous for exon or multiexon deletions and two were compound heterozygous for one exon or multiexon deletion and one sequence variant detectable by sequence analysis [
•
• Prolonged
• Markedly enlarged hepatocytes that contain periodic acid-Schiff (PAS)-positive and diastase-resistant inclusions, features characteristic of the abnormally branched glycogen found in GSD IV. Widespread infiltrates of foamy histiocytes with intra-cytoplasmic deposits within the reticuloendothelial system (RES) have been reported [
• On electron microscopy, fine fibrillary aggregates of electron-dense amylopectin-like material within the cytoplasm of hepatocytes in some individuals.
• Reduced glycogen branching enzyme (GBE) activity (most commonly assayed in cultured skin fibroblasts but may also be assayed in muscle or liver tissue); OR
• Biallelic pathogenic variants in
• For an introduction to multigene panels click
## Suggestive Findings
Glycogen storage disease type IV (GSD IV)
Prolonged
Markedly enlarged hepatocytes that contain periodic acid-Schiff (PAS)-positive and diastase-resistant inclusions, features characteristic of the abnormally branched glycogen found in GSD IV. Widespread infiltrates of foamy histiocytes with intra-cytoplasmic deposits within the reticuloendothelial system (RES) have been reported [
On electron microscopy, fine fibrillary aggregates of electron-dense amylopectin-like material within the cytoplasm of hepatocytes in some individuals.
•
• Prolonged
• Markedly enlarged hepatocytes that contain periodic acid-Schiff (PAS)-positive and diastase-resistant inclusions, features characteristic of the abnormally branched glycogen found in GSD IV. Widespread infiltrates of foamy histiocytes with intra-cytoplasmic deposits within the reticuloendothelial system (RES) have been reported [
• On electron microscopy, fine fibrillary aggregates of electron-dense amylopectin-like material within the cytoplasm of hepatocytes in some individuals.
## Establishing the Diagnosis
The diagnosis of glycogen storage disease type IV (GSD IV)
Reduced glycogen branching enzyme (GBE) activity (most commonly assayed in cultured skin fibroblasts but may also be assayed in muscle or liver tissue); OR
Biallelic pathogenic variants in
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GSD IV is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of GSD IV, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by liver dysfunction,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type IV
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Of 42 affected individuals, 37 had at least one identifiable variant detected by sequencing analysis; 28 individuals had biallelic pathogenic variants, and six had one identifiable pathogenic variant, implying that the second causative variant was not identified.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Of the 42 affected individuals, three were homozygous for exon or multiexon deletions and two were compound heterozygous for one exon or multiexon deletion and one sequence variant detectable by sequence analysis [
• Reduced glycogen branching enzyme (GBE) activity (most commonly assayed in cultured skin fibroblasts but may also be assayed in muscle or liver tissue); OR
• Biallelic pathogenic variants in
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of GSD IV, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by liver dysfunction,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type IV
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Of 42 affected individuals, 37 had at least one identifiable variant detected by sequencing analysis; 28 individuals had biallelic pathogenic variants, and six had one identifiable pathogenic variant, implying that the second causative variant was not identified.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Of the 42 affected individuals, three were homozygous for exon or multiexon deletions and two were compound heterozygous for one exon or multiexon deletion and one sequence variant detectable by sequence analysis [
## Clinical Characteristics
The clinical manifestations of glycogen storage disease type IV (GSD IV) span a continuum from mild to severe [
The
The
The
In the
In the less common
The
Genotype-phenotype correlations remain unclear, but are emerging [
Individuals with the perinatal and congenital subtypes tend to have two null variants, including nonsense, frameshift, and splice site variants leading to premature truncation of the protein likely resulting in complete absence of glycogen branching enzyme (GBE) activity;
Individuals with the classic hepatic subtype tend to be compound heterozygotes for a null and a missense variant.
These generalizations notwithstanding, considerable overlap exists both between and within the subtypes of GSD IV [
Glycogen storage disease type IV was referred to as glycogenosis IV in early publications.
Glycogen storage disease type IV is rare, accounting for approximately 3% of the glycogen storage diseases [
To date, more than 50 individuals with molecularly confirmed GSD IV have been reported [
• In the
• In the less common
• Individuals with the perinatal and congenital subtypes tend to have two null variants, including nonsense, frameshift, and splice site variants leading to premature truncation of the protein likely resulting in complete absence of glycogen branching enzyme (GBE) activity;
• Individuals with the classic hepatic subtype tend to be compound heterozygotes for a null and a missense variant.
## Clinical Description
The clinical manifestations of glycogen storage disease type IV (GSD IV) span a continuum from mild to severe [
The
The
The
In the
In the less common
The
• In the
• In the less common
## Genotype-Phenotype Correlations
Genotype-phenotype correlations remain unclear, but are emerging [
Individuals with the perinatal and congenital subtypes tend to have two null variants, including nonsense, frameshift, and splice site variants leading to premature truncation of the protein likely resulting in complete absence of glycogen branching enzyme (GBE) activity;
Individuals with the classic hepatic subtype tend to be compound heterozygotes for a null and a missense variant.
These generalizations notwithstanding, considerable overlap exists both between and within the subtypes of GSD IV [
• Individuals with the perinatal and congenital subtypes tend to have two null variants, including nonsense, frameshift, and splice site variants leading to premature truncation of the protein likely resulting in complete absence of glycogen branching enzyme (GBE) activity;
• Individuals with the classic hepatic subtype tend to be compound heterozygotes for a null and a missense variant.
## Nomenclature
Glycogen storage disease type IV was referred to as glycogenosis IV in early publications.
## Prevalence
Glycogen storage disease type IV is rare, accounting for approximately 3% of the glycogen storage diseases [
To date, more than 50 individuals with molecularly confirmed GSD IV have been reported [
## Genetically Related (Allelic) Disorders
Adult-onset polyglucosan body disease (APBD) is the only other phenotype known to be associated with mutation of
## Differential Diagnosis
The differential diagnosis of the perinatal and congenital neuromuscular subtypes of GSD IV includes the disorders summarized in
Other Genes of Interest in the Differential Diagnosis of Perinatal and Congenital Neuromuscular Subtypes of GSD IV
↓ fetal movement
Arthrogryposis
Severe congenital hypotonia
Cardiopulmonary compromise
Tongue fasciculations
↓ or absent deep tendon reflexes
Profound hypotonia
Respiratory distress
Profound hypotonia
Respiratory distress
Hypotonia
Liver disease
Cardiomyopathy
Seizures
Stroke-like episodes
AR = autosomal recessive; GSD = glycogen storage disease; MOI = mode of inheritance; XL = X-linked
See
See OMIM Phenotypic Series:
The differential diagnosis of the classic hepatic subtype of GSD IV includes other glycogen storage disorders and mitochondrial DNA depletion syndromes. Examples of these categories of disorders are described in
Other Genes of Interest in the Differential Diagnosis of the Classic Hepatic Subtype of GSD IV
Hepatomegaly
Liver disease
Myopathy
Hypoglycemia
Hyperlipidemia
Severe hypotonia
Liver disease
Nystagmus
Lactic acidosis
Developmental regression
Liver disease
Hepatomegaly
Hypotonia
Vomiting
Diarrhea
Failure to thrive
AR = autosomal recessive; GSD = glycogen storage disease; MOI = mode of inheritance; mtDNA = mitochondrial DNA
The differential diagnosis of the childhood neuromuscular subtype of GSD IV includes
Other Genes of Interest in the Differential Diagnosis of the Childhood Neuromuscular Subtype of GSD IV
Dilated cardiomyopathy
Myopathy
Calf pseudohypertrophy
Abnormal dystrophin staining on muscle biopsy
Myopathy
Cardiomyopathy (in some)
Muscle weakness or exercise intolerance
Heart failure
Dementia
Movement disorders
Stroke-like episodes
Deafness
Blindness
Vomiting
Seizures
AD = autosomal dominant; AR = autosomal recessive; GSD = glycogen storage disease; Mat = maternal; MOI = mode of inheritance; XL = X-linked
See
• ↓ fetal movement
• Arthrogryposis
• Severe congenital hypotonia
• Cardiopulmonary compromise
• Tongue fasciculations
• ↓ or absent deep tendon reflexes
• Profound hypotonia
• Respiratory distress
• Profound hypotonia
• Respiratory distress
• Hypotonia
• Liver disease
• Cardiomyopathy
• Seizures
• Stroke-like episodes
• Hepatomegaly
• Liver disease
• Myopathy
• Hypoglycemia
• Hyperlipidemia
• Severe hypotonia
• Liver disease
• Nystagmus
• Lactic acidosis
• Developmental regression
• Liver disease
• Hepatomegaly
• Hypotonia
• Vomiting
• Diarrhea
• Failure to thrive
• Dilated cardiomyopathy
• Myopathy
• Calf pseudohypertrophy
• Abnormal dystrophin staining on muscle biopsy
• Myopathy
• Cardiomyopathy (in some)
• Muscle weakness or exercise intolerance
• Heart failure
• Dementia
• Movement disorders
• Stroke-like episodes
• Deafness
• Blindness
• Vomiting
• Seizures
## Perinatal and Congenital Neuromuscular Subtypes of GSD IV
The differential diagnosis of the perinatal and congenital neuromuscular subtypes of GSD IV includes the disorders summarized in
Other Genes of Interest in the Differential Diagnosis of Perinatal and Congenital Neuromuscular Subtypes of GSD IV
↓ fetal movement
Arthrogryposis
Severe congenital hypotonia
Cardiopulmonary compromise
Tongue fasciculations
↓ or absent deep tendon reflexes
Profound hypotonia
Respiratory distress
Profound hypotonia
Respiratory distress
Hypotonia
Liver disease
Cardiomyopathy
Seizures
Stroke-like episodes
AR = autosomal recessive; GSD = glycogen storage disease; MOI = mode of inheritance; XL = X-linked
See
See OMIM Phenotypic Series:
• ↓ fetal movement
• Arthrogryposis
• Severe congenital hypotonia
• Cardiopulmonary compromise
• Tongue fasciculations
• ↓ or absent deep tendon reflexes
• Profound hypotonia
• Respiratory distress
• Profound hypotonia
• Respiratory distress
• Hypotonia
• Liver disease
• Cardiomyopathy
• Seizures
• Stroke-like episodes
## Classic Hepatic Subtype of GSD IV
The differential diagnosis of the classic hepatic subtype of GSD IV includes other glycogen storage disorders and mitochondrial DNA depletion syndromes. Examples of these categories of disorders are described in
Other Genes of Interest in the Differential Diagnosis of the Classic Hepatic Subtype of GSD IV
Hepatomegaly
Liver disease
Myopathy
Hypoglycemia
Hyperlipidemia
Severe hypotonia
Liver disease
Nystagmus
Lactic acidosis
Developmental regression
Liver disease
Hepatomegaly
Hypotonia
Vomiting
Diarrhea
Failure to thrive
AR = autosomal recessive; GSD = glycogen storage disease; MOI = mode of inheritance; mtDNA = mitochondrial DNA
• Hepatomegaly
• Liver disease
• Myopathy
• Hypoglycemia
• Hyperlipidemia
• Severe hypotonia
• Liver disease
• Nystagmus
• Lactic acidosis
• Developmental regression
• Liver disease
• Hepatomegaly
• Hypotonia
• Vomiting
• Diarrhea
• Failure to thrive
## Childhood Neuromuscular Subtype of GSD IV
The differential diagnosis of the childhood neuromuscular subtype of GSD IV includes
Other Genes of Interest in the Differential Diagnosis of the Childhood Neuromuscular Subtype of GSD IV
Dilated cardiomyopathy
Myopathy
Calf pseudohypertrophy
Abnormal dystrophin staining on muscle biopsy
Myopathy
Cardiomyopathy (in some)
Muscle weakness or exercise intolerance
Heart failure
Dementia
Movement disorders
Stroke-like episodes
Deafness
Blindness
Vomiting
Seizures
AD = autosomal dominant; AR = autosomal recessive; GSD = glycogen storage disease; Mat = maternal; MOI = mode of inheritance; XL = X-linked
See
• Dilated cardiomyopathy
• Myopathy
• Calf pseudohypertrophy
• Abnormal dystrophin staining on muscle biopsy
• Myopathy
• Cardiomyopathy (in some)
• Muscle weakness or exercise intolerance
• Heart failure
• Dementia
• Movement disorders
• Stroke-like episodes
• Deafness
• Blindness
• Vomiting
• Seizures
## Management
To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type IV (GSD IV), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Glycogen Storage Disease Type IV
Management should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, medical or biochemical genetics, and child development.
Liver transplantation is the only treatment option for individuals with the progressive hepatic subtype of GSD IV who develop liver failure. Of the 20 individuals with GSD IV who have received a liver transplant to date, two required a second liver transplant and six died: four from sepsis, one from hepatic artery thrombosis, and one from cardiomyopathy. The prognosis in persons with GSD IV who undergo liver transplantation is poor because of the significant risk for morbidity and mortality, which is in part attributed to the extrahepatic manifestations of GSD type IV, especially cardiomyopathy [
Selecting appropriate candidates for liver transplantation can be complex. Histologic, molecular, or clinical predictors of disease progression are likely to be useful in stratifying patients prior to liver transplantation [
Children with skeletal myopathy and/or hypotonia who experience motor developmental delay warrant developmental evaluation and physical therapy as needed.
For those with cardiomyopathy, care by a cardiologist is warranted. Individuals with severe cardiomyopathy secondary to glycogenosis may be candidates for cardiac transplantation [
Nutritional deficiencies (e.g., of fat-soluble vitamins) can be prevented by ensuring adequate dietary intake based on frequent assessments by and recommendations of a dietitian experienced in managing children with liver disease.
Bleeding due to coagulopathy can occur especially with surgical procedures; therefore, it is recommended that a coagulation profile be assessed before surgical procedures and fresh frozen plasma be given preoperatively as needed.
No clinical guidelines for surveillance are available.
Recommended Surveillance for Individuals with Glycogen Storage Disease Type IV
Liver function tests incl liver transaminases, albumin, & coagulation profile (PT & PTT)
Abdominal ultrasound examination
If the
See
Search
• Liver function tests incl liver transaminases, albumin, & coagulation profile (PT & PTT)
• Abdominal ultrasound examination
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type IV (GSD IV), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Glycogen Storage Disease Type IV
## Treatment of Manifestations
Management should involve a multidisciplinary team including specialists in hepatology, neurology, nutrition, medical or biochemical genetics, and child development.
Liver transplantation is the only treatment option for individuals with the progressive hepatic subtype of GSD IV who develop liver failure. Of the 20 individuals with GSD IV who have received a liver transplant to date, two required a second liver transplant and six died: four from sepsis, one from hepatic artery thrombosis, and one from cardiomyopathy. The prognosis in persons with GSD IV who undergo liver transplantation is poor because of the significant risk for morbidity and mortality, which is in part attributed to the extrahepatic manifestations of GSD type IV, especially cardiomyopathy [
Selecting appropriate candidates for liver transplantation can be complex. Histologic, molecular, or clinical predictors of disease progression are likely to be useful in stratifying patients prior to liver transplantation [
Children with skeletal myopathy and/or hypotonia who experience motor developmental delay warrant developmental evaluation and physical therapy as needed.
For those with cardiomyopathy, care by a cardiologist is warranted. Individuals with severe cardiomyopathy secondary to glycogenosis may be candidates for cardiac transplantation [
## Hepatic Manifestations
Liver transplantation is the only treatment option for individuals with the progressive hepatic subtype of GSD IV who develop liver failure. Of the 20 individuals with GSD IV who have received a liver transplant to date, two required a second liver transplant and six died: four from sepsis, one from hepatic artery thrombosis, and one from cardiomyopathy. The prognosis in persons with GSD IV who undergo liver transplantation is poor because of the significant risk for morbidity and mortality, which is in part attributed to the extrahepatic manifestations of GSD type IV, especially cardiomyopathy [
Selecting appropriate candidates for liver transplantation can be complex. Histologic, molecular, or clinical predictors of disease progression are likely to be useful in stratifying patients prior to liver transplantation [
## Neurologic Manifestations
Children with skeletal myopathy and/or hypotonia who experience motor developmental delay warrant developmental evaluation and physical therapy as needed.
## Cardiac Manifestations
For those with cardiomyopathy, care by a cardiologist is warranted. Individuals with severe cardiomyopathy secondary to glycogenosis may be candidates for cardiac transplantation [
## Prevention of Secondary Complications
Nutritional deficiencies (e.g., of fat-soluble vitamins) can be prevented by ensuring adequate dietary intake based on frequent assessments by and recommendations of a dietitian experienced in managing children with liver disease.
Bleeding due to coagulopathy can occur especially with surgical procedures; therefore, it is recommended that a coagulation profile be assessed before surgical procedures and fresh frozen plasma be given preoperatively as needed.
## Surveillance
No clinical guidelines for surveillance are available.
Recommended Surveillance for Individuals with Glycogen Storage Disease Type IV
Liver function tests incl liver transaminases, albumin, & coagulation profile (PT & PTT)
Abdominal ultrasound examination
• Liver function tests incl liver transaminases, albumin, & coagulation profile (PT & PTT)
• Abdominal ultrasound examination
## Evaluation of Relatives at Risk
If the
See
## Therapies Under Investigation
Search
## Genetic Counseling
Glycogen storage disease type IV (GSD IV) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Affected sibs are expected to manifest the same subtype of GSD IV; however, age of onset and presentation may differ.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Affected sibs are expected to manifest the same subtype of GSD IV; however, age of onset and presentation may differ.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Glycogen storage disease type IV (GSD IV) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Affected sibs are expected to manifest the same subtype of GSD IV; however, age of onset and presentation may differ.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Affected sibs are expected to manifest the same subtype of GSD IV; however, age of onset and presentation may differ.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
## Resources
9 Lindop Road
Altrincham Cheshire WA15 9DZ
United Kingdom
United Kingdom
Spain
•
•
•
• 9 Lindop Road
• Altrincham Cheshire WA15 9DZ
• United Kingdom
•
•
•
•
•
•
• United Kingdom
•
•
• Spain
•
## Molecular Genetics
Glycogen Storage Disease Type IV: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Glycogen Storage Disease Type IV (
Glycogen branching enzyme (GBE), a 702-amino acid protein, catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, reduce the osmotic pressure within cells [
The underlying molecular defects in
Notable
APBD =
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Glycogen branching enzyme (GBE), a 702-amino acid protein, catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, reduce the osmotic pressure within cells [
The underlying molecular defects in
Notable
APBD =
Variants listed in the table have been provided by the authors.
## References
## Literature Cited
## Chapter Notes
1 August 2019 (sw) Comprehensive update posted live
3 January 2013 (me) Review posted live
17 September 2012 (aeh) Original submission
• 1 August 2019 (sw) Comprehensive update posted live
• 3 January 2013 (me) Review posted live
• 17 September 2012 (aeh) Original submission
## Revision History
1 August 2019 (sw) Comprehensive update posted live
3 January 2013 (me) Review posted live
17 September 2012 (aeh) Original submission
• 1 August 2019 (sw) Comprehensive update posted live
• 3 January 2013 (me) Review posted live
• 17 September 2012 (aeh) Original submission
|
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"F Mochel, R Schiffmann, ME Steenweg, HO Akman, M Wallace, F Sedel, P Laforêt, R Levy, JM Powers, S Demeret, T Maisonobe, R Froissart, BB Da Nobrega, BL Fogel, MR Natowicz, C Lubetzki, A Durr, A Brice, H Rosenmann, V Barash, O Kakhlon, JM Gomori, MS van der Knaap, A Lossos. Adult polyglucosan body disease: natural history and key magnetic resonance imaging findings.. Ann Neurol. 2012;72:433-41",
"SW Moses, R Parvari. The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies.. Curr Mol Med. 2002;2:177-88",
"C Paradas, HO Akman, C Ionete, H Lau, PN Riskind, DE Jones, TW Smith, M Hirano, S Dimauro. Branching enzyme deficiency: expanding the clinical spectrum.. JAMA Neurol. 2014;71:41-7",
"G Ravenscroft, EM Thompson, EJ Todd, KS Yau, N Kresoje, P Sivadorai, K Friend, K Riley, ND Manton, P Blumbergs, M Fietz, RM Duff, MR Davis, RJ Allcock, NG Laing. Whole exome sequencing in foetal akinesia expands the genotype-phenotype spectrum of GBE1 glycogen storage disease mutations.. Neuromuscul Disord. 2013;23:165-9",
"E Reusche, F Aksu, HH Goebel, YS Shin, T Yokota, H Reichmann. A mild juvenile variant of type IV glycogenosis.. Brain Dev. 1992;14:36-43",
"P Rosenthal, L Podesta, R Grier, JW Said, L Sher, J Cocjin, F Watanabe, E Vasiliauskas, R van de Velde, L Makowka. Failure of liver transplantation to diminish cardiac deposits of amylopectin and leukocyte inclusions in type IV glycogen storage disease.. Liver Transpl Surg. 1995;1:373-6",
"SM Said, MI Murphree, T Mounajjed, M El-Youssef, L Zhang. A novel GBE1 gene variant in a child with glycogen storage disease type IV.. Hum Pathol. 2016;54:152-6",
"S Sampaolo, T Esposito, F Gianfrancesco, F Napolitano, L Lombardi, R Lucà, F Roperto, G. Di Iorio. A novel GBE1 mutation and features of polyglucosan bodies autophagy in adult polyglucosan body disease.. Neuromuscul Disord. 2015;25:247-52",
"JM Schröder, R May, YS Shin, M Sigmund, S Nase-Hüppmeier. Juvenile hereditary polyglucosan body disease with complete branching enzyme deficiency (type IV glycogenosis).. Acta Neuropathol. 1993;85:419-30",
"EM Sokal, F Van Hoof, D Alberti, J de Ville de Goyet, T de Barsy, JB Otte. Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis.. Eur J Pediatr. 1992;151:200-3",
"SK Tay, HO Akman, WK Chung, MG Pike, F Muntoni, AP Hays, S Shanske, SJ Valberg, JR Mickelson, K Tanji, S DiMauro. Fatal infantile neuromuscular presentation of glycogen storage disease type IV.. Neuromuscul Disord. 2004;14:253-60",
"VJ Thon, M Khalil, JF Cannon. Isolation of human glycogen branching enzyme cDNAs by screening complementation in yeast.. J Biol Chem. 1993;268:7509-13",
"RI Troisi, YM Elsheikh, MA Shagrani, D Broering. First fully laparoscopic donor hepatectomy for pediatric liver transplantation using the indocyanine green near-infrared fluorescence imaging in the Middle East: a case report.. Ann Saudi Med. 2014;34:354-7",
"F Ziemssen, E Sindern, JM Schröder, YS Shin, J Zange, MW Kilimann, JP Malin, M Vorgerd. Novel missense mutations in the glycogen-branching enzyme gene in adult polyglucosan body disease.. Ann Neurol. 2000;47:536-40"
] |
3/1/2013
|
1/8/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
gsd5
|
gsd5
|
[
"Glycogenosis Type V",
"GSDV",
"McArdle Disease",
"Muscle Glycogen Phosphorylase Deficiency",
"Myophosphorylase Deficiency",
"PYGM Deficiency",
"Glycogenosis Type V",
"GSDV",
"McArdle Disease",
"Muscle Glycogen Phosphorylase Deficiency",
"Myophosphorylase Deficiency",
"PYGM Deficiency",
"Glycogen phosphorylase, muscle form",
"PYGM",
"Glycogen Storage Disease Type V"
] |
Glycogen Storage Disease Type V
|
Miguel A Martín, Alejandro Lucia, Joaquin Arenas, Antonio L Andreu
|
Summary Glycogen storage disease type V (GSDV, McArdle disease) is a metabolic myopathy characterized by exercise intolerance manifested by rapid fatigue, myalgia, and cramps in exercising muscles. Symptoms are usually precipitated by isometric exercise or sustained aerobic exercise. Most individuals improve their exercise tolerance by exploiting the "second-wind" phenomenon with relief of myalgia and fatigue after a few minutes of rest. Age of onset is frequently in the first decade of life but can vary; however, diagnosis is typically delayed as myalgia and fatigability are dismissed/overlooked. Fixed muscle weakness occurs in approximately 25% of affected individuals, is more likely to involve proximal muscles, and is more common in individuals of advanced age. Approximately 50% of affected individuals have recurrent episodes of myoglobinuria that can – on occasion – eventually result in acute renal failure. The diagnosis of GSDV is established in a proband with suggestive findings and by identification of biallelic GSDV is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes are asymptomatic. Once the pathogenic variants in the family are known, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
|
## Diagnosis
Glycogen storage disease type V
Childhood onset of exercise-induced muscle contractures and pain, especially during the first approximately ten minutes of exercise. Although symptoms are frequently noted in physical education classes or on the school playground, their significance is not usually recognized, and diagnosis is delayed until most affected individuals are older.
Second-wind phenomenon, i.e., improvement in exercise-induced muscle cramps and/or pain after a brief rest period when exercise intensity is reduced, or after the first (~) ten minutes of continuous exercise at the same constant, moderate intensity (see
Episodes of rhabdomyolysis (which can result in myoglobinuria) triggered by persistent skeletal muscle activity despite symptoms (i.e., before getting into the second-wind phenomenon), intense exertion, anaerobic activity (e.g., sprinting to catch a bus), lifting heavy weights, isometric contraction (e.g., carrying weights), and sustained muscle contraction [
Unusual clinical presentations such as difficulty with mastication, dysphagia, and oral motor function appear to be more common in younger individuals. Other rare presentations are spontaneous compartment syndrome [
Some affected individuals have minimal symptoms (i.e., only during strenuous exercise) with essentially no limitations in activities of daily living [
Physical activity habits may explain variability in phenotypic manifestations of GSDV: individuals who are physically active at work or during their leisure time are less affected [
The cycle test is positive when the first ~10 minutes of cycling elicits a marked increase in heart rate (>30-40 beats/min) at a moderate, constant load (~40 watts for most adults*) and frequent muscle symptoms (myalgia and contractures), followed by a decrease in both heart rate (from ~150 to ~120 beats/min) and muscle symptoms [
* Corresponding to a heart rate of 60%-70% of the predicted maximum heart rate (i.e., 220 beats/min minus age in years)
The walking test can be performed in less specialized clinical settings [
The diagnosis of glycogen storage disease type V is established in a proband with suggestive findings and biallelic
When the phenotypic and laboratory findings suggest the diagnosis of glycogen storage disease type V, options can include
For an introduction to multigene panels click
When the diagnosis of glycogen storage disease type V is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type V
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
A 1,094-bp deletion variant, c.1969+214_2177+369del, extends from intron 16 to intron 17 [
A clinical utility card regarding genetic test usage for
• Childhood onset of exercise-induced muscle contractures and pain, especially during the first approximately ten minutes of exercise. Although symptoms are frequently noted in physical education classes or on the school playground, their significance is not usually recognized, and diagnosis is delayed until most affected individuals are older.
• Second-wind phenomenon, i.e., improvement in exercise-induced muscle cramps and/or pain after a brief rest period when exercise intensity is reduced, or after the first (~) ten minutes of continuous exercise at the same constant, moderate intensity (see
• Episodes of rhabdomyolysis (which can result in myoglobinuria) triggered by persistent skeletal muscle activity despite symptoms (i.e., before getting into the second-wind phenomenon), intense exertion, anaerobic activity (e.g., sprinting to catch a bus), lifting heavy weights, isometric contraction (e.g., carrying weights), and sustained muscle contraction [
• Unusual clinical presentations such as difficulty with mastication, dysphagia, and oral motor function appear to be more common in younger individuals. Other rare presentations are spontaneous compartment syndrome [
• Some affected individuals have minimal symptoms (i.e., only during strenuous exercise) with essentially no limitations in activities of daily living [
• Physical activity habits may explain variability in phenotypic manifestations of GSDV: individuals who are physically active at work or during their leisure time are less affected [
• The cycle test is positive when the first ~10 minutes of cycling elicits a marked increase in heart rate (>30-40 beats/min) at a moderate, constant load (~40 watts for most adults*) and frequent muscle symptoms (myalgia and contractures), followed by a decrease in both heart rate (from ~150 to ~120 beats/min) and muscle symptoms [
• * Corresponding to a heart rate of 60%-70% of the predicted maximum heart rate (i.e., 220 beats/min minus age in years)
• The walking test can be performed in less specialized clinical settings [
• For an introduction to multigene panels click
## Suggestive Findings
Glycogen storage disease type V
Childhood onset of exercise-induced muscle contractures and pain, especially during the first approximately ten minutes of exercise. Although symptoms are frequently noted in physical education classes or on the school playground, their significance is not usually recognized, and diagnosis is delayed until most affected individuals are older.
Second-wind phenomenon, i.e., improvement in exercise-induced muscle cramps and/or pain after a brief rest period when exercise intensity is reduced, or after the first (~) ten minutes of continuous exercise at the same constant, moderate intensity (see
Episodes of rhabdomyolysis (which can result in myoglobinuria) triggered by persistent skeletal muscle activity despite symptoms (i.e., before getting into the second-wind phenomenon), intense exertion, anaerobic activity (e.g., sprinting to catch a bus), lifting heavy weights, isometric contraction (e.g., carrying weights), and sustained muscle contraction [
Unusual clinical presentations such as difficulty with mastication, dysphagia, and oral motor function appear to be more common in younger individuals. Other rare presentations are spontaneous compartment syndrome [
Some affected individuals have minimal symptoms (i.e., only during strenuous exercise) with essentially no limitations in activities of daily living [
Physical activity habits may explain variability in phenotypic manifestations of GSDV: individuals who are physically active at work or during their leisure time are less affected [
The cycle test is positive when the first ~10 minutes of cycling elicits a marked increase in heart rate (>30-40 beats/min) at a moderate, constant load (~40 watts for most adults*) and frequent muscle symptoms (myalgia and contractures), followed by a decrease in both heart rate (from ~150 to ~120 beats/min) and muscle symptoms [
* Corresponding to a heart rate of 60%-70% of the predicted maximum heart rate (i.e., 220 beats/min minus age in years)
The walking test can be performed in less specialized clinical settings [
• Childhood onset of exercise-induced muscle contractures and pain, especially during the first approximately ten minutes of exercise. Although symptoms are frequently noted in physical education classes or on the school playground, their significance is not usually recognized, and diagnosis is delayed until most affected individuals are older.
• Second-wind phenomenon, i.e., improvement in exercise-induced muscle cramps and/or pain after a brief rest period when exercise intensity is reduced, or after the first (~) ten minutes of continuous exercise at the same constant, moderate intensity (see
• Episodes of rhabdomyolysis (which can result in myoglobinuria) triggered by persistent skeletal muscle activity despite symptoms (i.e., before getting into the second-wind phenomenon), intense exertion, anaerobic activity (e.g., sprinting to catch a bus), lifting heavy weights, isometric contraction (e.g., carrying weights), and sustained muscle contraction [
• Unusual clinical presentations such as difficulty with mastication, dysphagia, and oral motor function appear to be more common in younger individuals. Other rare presentations are spontaneous compartment syndrome [
• Some affected individuals have minimal symptoms (i.e., only during strenuous exercise) with essentially no limitations in activities of daily living [
• Physical activity habits may explain variability in phenotypic manifestations of GSDV: individuals who are physically active at work or during their leisure time are less affected [
• The cycle test is positive when the first ~10 minutes of cycling elicits a marked increase in heart rate (>30-40 beats/min) at a moderate, constant load (~40 watts for most adults*) and frequent muscle symptoms (myalgia and contractures), followed by a decrease in both heart rate (from ~150 to ~120 beats/min) and muscle symptoms [
• * Corresponding to a heart rate of 60%-70% of the predicted maximum heart rate (i.e., 220 beats/min minus age in years)
• The walking test can be performed in less specialized clinical settings [
## Establishing the Diagnosis
The diagnosis of glycogen storage disease type V is established in a proband with suggestive findings and biallelic
When the phenotypic and laboratory findings suggest the diagnosis of glycogen storage disease type V, options can include
For an introduction to multigene panels click
When the diagnosis of glycogen storage disease type V is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type V
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
A 1,094-bp deletion variant, c.1969+214_2177+369del, extends from intron 16 to intron 17 [
A clinical utility card regarding genetic test usage for
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of glycogen storage disease type V, options can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of glycogen storage disease type V is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type V
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
A 1,094-bp deletion variant, c.1969+214_2177+369del, extends from intron 16 to intron 17 [
A clinical utility card regarding genetic test usage for
## Clinical Characteristics
Glycogen storage disease type V (GSDV) is a metabolic myopathy with onset frequently in the first decade of life. Clinical heterogeneity exists; about 10% of all affected individuals have mild manifestations (e.g., fatigue or poor stamina without contractures) and remain virtually asymptomatic during daily activities of living [
The usual presentation of GSDV is exercise intolerance (including contractures, stiffness, and/or weakness of the muscles in use), myalgia, and fatigue in the first few minutes of exercise. These symptoms are usually precipitated by isometric exercise (e.g., carrying weights) or sustained vigorous "aerobic" exercise (e.g., stair climbing, jogging), and typically are relieved by rest. Any skeletal muscle can be affected. Recurrent episodes of myoglobinuria as a consequence of such exercise are observed in about 50% of affected individuals [
Atypical presentations have been also described, such as difficulty with mastication, dysphagia, and oral motor function (which appear to be more common in younger individuals) [
While most affected individuals remember painful symptoms from early childhood, the disorder is rarely diagnosed before adulthood (i.e., usually after age 20 years, median age 33 years) [
Most individuals learn to improve their exercise tolerance by exploiting the second-wind phenomenon, a unique feature of GSDV, which is relief of myalgia and rapid fatigue after a few minutes of rest. The metabolic events underlying the second wind are the increased supply of blood-borne glucose and free fatty acids as exercise progresses, leading to an increase in the rate of metabolism of these fuels inside working muscle fibers. The ability to develop a second wind is greatly increased in those who stay physically fit with regular aerobic exercise, such as walking.
In contrast, continuing to exercise in the presence of severe pain might result in muscle damage (rhabdomyolysis) and myoglobinuria. Myoglobinuria due to rhabdomyolysis following intense exercise occurs in approximately 50% of individuals; despite the risk of acute renal failure, very few develop it. While kidney failure is almost always reversible, emergency treatment is required [
Other presentations of GSDV:
Severe paraspinal wasting and weakness [
Incidental finding of severe obstructive hypertrophic cardiomyopathy [
Acute renal failure in the absence of exertion
HyperCKemia (asymptomatic elevations of serum CK activity) up to 17,000 IU/L in the infantile myopathy and preadolescents.
Aerobic exercise includes walking, gentle swimming, jogging, and cycling. During aerobic exercise, the fuel used by skeletal muscle depends on several factors including the following: type, intensity, and duration of exercise; physical condition; and dietary regimen. Because aerobic exercise favors the utilization of blood-borne substrates, such as fatty acids, it is better tolerated by individuals with GSDV and thus beneficial as a therapeutic regimen.
"Anaerobic" exercise is intense and cannot be sustained (e.g., weight lifting or 100-meter dash). Normally, during anaerobic exercise, myophosphorylase converts glycogen to glucose, which enters the glycolytic pathway and produces ATP "anaerobically" (or with no need for oxygen).
The first few minutes of any exercise have an anaerobic component. Depending on intensity and duration of the exercise, muscle uses different fuel sources such as anaerobic glycolysis, blood glucose, muscle glycogen, and aerobic glycolysis, followed by fatty acid oxidation.
Several studies in European populations have not found an association between severity of clinical findings and
The prevalence of GSDV in the Dallas-Fort Worth, Texas, area was estimated at 1:100,000.
The Spanish McArdle Disease patient registry reported a minimum prevalence in Spain of nearly 1:170,000 [
• Severe paraspinal wasting and weakness [
• Incidental finding of severe obstructive hypertrophic cardiomyopathy [
• Acute renal failure in the absence of exertion
• HyperCKemia (asymptomatic elevations of serum CK activity) up to 17,000 IU/L in the infantile myopathy and preadolescents.
• Aerobic exercise includes walking, gentle swimming, jogging, and cycling. During aerobic exercise, the fuel used by skeletal muscle depends on several factors including the following: type, intensity, and duration of exercise; physical condition; and dietary regimen. Because aerobic exercise favors the utilization of blood-borne substrates, such as fatty acids, it is better tolerated by individuals with GSDV and thus beneficial as a therapeutic regimen.
• "Anaerobic" exercise is intense and cannot be sustained (e.g., weight lifting or 100-meter dash). Normally, during anaerobic exercise, myophosphorylase converts glycogen to glucose, which enters the glycolytic pathway and produces ATP "anaerobically" (or with no need for oxygen).
## Clinical Description
Glycogen storage disease type V (GSDV) is a metabolic myopathy with onset frequently in the first decade of life. Clinical heterogeneity exists; about 10% of all affected individuals have mild manifestations (e.g., fatigue or poor stamina without contractures) and remain virtually asymptomatic during daily activities of living [
The usual presentation of GSDV is exercise intolerance (including contractures, stiffness, and/or weakness of the muscles in use), myalgia, and fatigue in the first few minutes of exercise. These symptoms are usually precipitated by isometric exercise (e.g., carrying weights) or sustained vigorous "aerobic" exercise (e.g., stair climbing, jogging), and typically are relieved by rest. Any skeletal muscle can be affected. Recurrent episodes of myoglobinuria as a consequence of such exercise are observed in about 50% of affected individuals [
Atypical presentations have been also described, such as difficulty with mastication, dysphagia, and oral motor function (which appear to be more common in younger individuals) [
While most affected individuals remember painful symptoms from early childhood, the disorder is rarely diagnosed before adulthood (i.e., usually after age 20 years, median age 33 years) [
Most individuals learn to improve their exercise tolerance by exploiting the second-wind phenomenon, a unique feature of GSDV, which is relief of myalgia and rapid fatigue after a few minutes of rest. The metabolic events underlying the second wind are the increased supply of blood-borne glucose and free fatty acids as exercise progresses, leading to an increase in the rate of metabolism of these fuels inside working muscle fibers. The ability to develop a second wind is greatly increased in those who stay physically fit with regular aerobic exercise, such as walking.
In contrast, continuing to exercise in the presence of severe pain might result in muscle damage (rhabdomyolysis) and myoglobinuria. Myoglobinuria due to rhabdomyolysis following intense exercise occurs in approximately 50% of individuals; despite the risk of acute renal failure, very few develop it. While kidney failure is almost always reversible, emergency treatment is required [
Other presentations of GSDV:
Severe paraspinal wasting and weakness [
Incidental finding of severe obstructive hypertrophic cardiomyopathy [
Acute renal failure in the absence of exertion
HyperCKemia (asymptomatic elevations of serum CK activity) up to 17,000 IU/L in the infantile myopathy and preadolescents.
Aerobic exercise includes walking, gentle swimming, jogging, and cycling. During aerobic exercise, the fuel used by skeletal muscle depends on several factors including the following: type, intensity, and duration of exercise; physical condition; and dietary regimen. Because aerobic exercise favors the utilization of blood-borne substrates, such as fatty acids, it is better tolerated by individuals with GSDV and thus beneficial as a therapeutic regimen.
"Anaerobic" exercise is intense and cannot be sustained (e.g., weight lifting or 100-meter dash). Normally, during anaerobic exercise, myophosphorylase converts glycogen to glucose, which enters the glycolytic pathway and produces ATP "anaerobically" (or with no need for oxygen).
The first few minutes of any exercise have an anaerobic component. Depending on intensity and duration of the exercise, muscle uses different fuel sources such as anaerobic glycolysis, blood glucose, muscle glycogen, and aerobic glycolysis, followed by fatty acid oxidation.
• Severe paraspinal wasting and weakness [
• Incidental finding of severe obstructive hypertrophic cardiomyopathy [
• Acute renal failure in the absence of exertion
• HyperCKemia (asymptomatic elevations of serum CK activity) up to 17,000 IU/L in the infantile myopathy and preadolescents.
• Aerobic exercise includes walking, gentle swimming, jogging, and cycling. During aerobic exercise, the fuel used by skeletal muscle depends on several factors including the following: type, intensity, and duration of exercise; physical condition; and dietary regimen. Because aerobic exercise favors the utilization of blood-borne substrates, such as fatty acids, it is better tolerated by individuals with GSDV and thus beneficial as a therapeutic regimen.
• "Anaerobic" exercise is intense and cannot be sustained (e.g., weight lifting or 100-meter dash). Normally, during anaerobic exercise, myophosphorylase converts glycogen to glucose, which enters the glycolytic pathway and produces ATP "anaerobically" (or with no need for oxygen).
## Genotype-Phenotype Correlations
Several studies in European populations have not found an association between severity of clinical findings and
## Prevalence
The prevalence of GSDV in the Dallas-Fort Worth, Texas, area was estimated at 1:100,000.
The Spanish McArdle Disease patient registry reported a minimum prevalence in Spain of nearly 1:170,000 [
## Genetically Related (Allelic) Disorders
Late-onset limb-girdle myopathy, ptosis, and camptocormia (i.e., flexion of the torso during walking or standing caused by weakness of the spinal extensors; resolves in the supine position), with no history of exercise intolerance, was reported in two unrelated individuals over age 75 years, both of whom were homozygous for the same novel
## Differential Diagnosis
The differential diagnosis of glycogen storage disease type V (GSDV) includes mitochondrial myopathy (mitochondrial myopathy is genetically heterogeneous [see
Other Genes of Interest in the Differential Diagnosis of Glycogen Storage Disease Type V (GSDV)
Exercise intolerance
Intermittent rhabdomyolysis
Precipitants: prolonged exercise, fasting, cold, fever
Normal basal CK
No clinical findings of muscle disease
Normal lactate exercise testing
Myoglobinuria
Cramps, premature fatigue
Precipitants: after prolonged exercise, fasting, fever
Basal CK (inter-episodic) normal
↑ lactate & pyruvate on exercise testing
Uterine muscle may be stiff during pregnancy.
Exercise intolerance cramps & myglobinuria
No ↑ of lactate on exercise test
Compensated hemolysis
Hyperuricemia
Myoglobinuria, intolerance for strenuous exercise
Basal serum CK ↑
Muscle cramps w/exercise
Rhabdomyolysis
Hemolytic anemia
CNS involvement
Exercise intolerance
Myalgia, cramps
Myoglobinuria
Progressive muscle weakness
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; CNS = central nervous system; DiffDx = differential diagnosis; GSD = glycogen storage disease; MOI = mode of inheritance; VLCAD = very long-chain acyl-CoA dehydrogenase; XL = X-linked
Genes are in alphabetic order.
Also referred to as "creatine phosphokinase, elevated serum"
Lactate dehydrogenase deficiency
Phosphofructokinase deficiency
Phosphoglycerate mutase deficiency
• Exercise intolerance
• Intermittent rhabdomyolysis
• Precipitants: prolonged exercise, fasting, cold, fever
• Normal basal CK
• No clinical findings of muscle disease
• Normal lactate exercise testing
• Myoglobinuria
• Cramps, premature fatigue
• Precipitants: after prolonged exercise, fasting, fever
• Basal CK (inter-episodic) normal
• ↑ lactate & pyruvate on exercise testing
• Uterine muscle may be stiff during pregnancy.
• Exercise intolerance cramps & myglobinuria
• No ↑ of lactate on exercise test
• Compensated hemolysis
• Hyperuricemia
• Myoglobinuria, intolerance for strenuous exercise
• Basal serum CK ↑
• Muscle cramps w/exercise
• Rhabdomyolysis
• Hemolytic anemia
• CNS involvement
• Exercise intolerance
• Myalgia, cramps
• Myoglobinuria
• Progressive muscle weakness
## Management
To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type V (GSDV), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Physical examination with emphasis on muscle strength/weakness
Basal serum CK activity
Consultation with a clinical geneticist and/or genetic counselor
Currently, simple healthy lifestyle interventions (i.e., following a diet rich in complex carbohydrates and regular exercise practice), the most effective means of preventing and managing exercise intolerance in GSDV, require a proactive attitude of clinicians, exercise professionals, and patient advocates [
The benefits of a professionally supervised exercise program are safety and ease of implementation. Patients with GSDV generally adapt well to regular exercise; training should be designed to ensure gradual progression of exercise intensity, especially in the more severely affected patients. For children, it is important to provide parents, caregivers, and educators (especially physical education teachers) with appropriate information to ensure their best possible management. Patients who commit to a supervised, gradual exercise program are able to improve their fitness levels almost as effectively as healthy individuals. Indeed, affected individuals may become virtually asymptomatic during activities of daily living. It should also be noted that physical activity in general has been associated with improvements in peak oxygen uptake (VO2peak, or "cardiorespiratory fitness" [CRF]), an important health indicator. For more details on exercise recommendations and pre-exercise nutrition schedules see
A systematic review of physical training for GSDV published in the Cochrane Database found no randomized or quasi-randomized controlled trials of aerobic training in people with GSDV; however, three studies using small numbers of participants provided some evidence that aerobic training improves CRF without adverse events and called for larger controlled trials of aerobic training in patients with GSDV [
Historically, patients with GSDV have been advised to avoid resistance (strength) exercises and other forms of physical activity involving high mechanical loads such as prolonged isometric contraction. However, a recent study of seven adults (5 female) showed improved muscle strength and mass (clinically as well as objectively using dual-energy x-ray absorptiometry) following a four-month-long resistance training program (i.e., weight lifting with qualified instruction and supervision and a two-month detraining period [
A revised and updated systematic review in the Cochrane Database of nutritional and pharmacologic trials for GSDV [Quinlivan et al 2014 (updated from 2008)] indicate that high-dose oral ribose, fat-rich diet, glucagon, verapamil, vitamin B
The study concluded that: (1) consuming a sugary drink before planned strenuous exercise can improve performance but is not practical for day-to-day living; (2) a diet rich in complex carbohydrates may be superior to a diet rich in protein; however, because of the small number of participants, evidence was insufficiently strong to indicate a significant clinical benefit; (3) ramipril 2.5 mg orally daily showed some subjective improvement in participants with the DD-ACE polymorphism, which is thought to have a modulating effect on the condition; however, there was no improvement in objective measures of exercise performance; and (4) low-dose creatine supplementation demonstrated a statistically significant (albeit modest) benefit in the tolerance to ischemic exercise in a small number of individuals [
Details of interventions with pre-exercise nutrition and physical exercise recommendations are set forth in
Because of the rarity of GSDV, multicenter collaboration and standardized assessment protocols are needed for future treatment trials.
See
Appropriate surveillance includes the following:
Annual routine physical examination
Annual review of diet
Static muscle contractions (e.g., handgrip exercises)
Static muscle contractions or heavy loads on low muscle mass (e.g., weight lifting), unless performed under programmed supervision of clinicians and exercise/fitness specialists [
Dynamic exercises at a high-intensity level (e.g., competitive ball games)
Exercises with a high involvement of eccentric (lengthening) muscle contractions (e.g., jumps)
Very intense dynamic aerobic exercise (e.g., running, strenuous swimming, or cycling) except in very fit individuals who are also well trained for the specific activity
It is appropriate to clarify the clinical/genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual as early diagnosis of GSDV may improve long-term outcome by heightening awareness of the need to avoid repetitive episodes of muscle damage that may lead to rhabdomyolysis and fixed weakness.
Molecular genetic testing can be used for evaluation of relatives at risk if the
If the family-specific
See
GSDV does not appear to adversely affect pregnancy or childbirth [
Search
• Physical examination with emphasis on muscle strength/weakness
• Basal serum CK activity
• Consultation with a clinical geneticist and/or genetic counselor
• Annual routine physical examination
• Annual review of diet
• Static muscle contractions (e.g., handgrip exercises)
• Static muscle contractions or heavy loads on low muscle mass (e.g., weight lifting), unless performed under programmed supervision of clinicians and exercise/fitness specialists [
• Dynamic exercises at a high-intensity level (e.g., competitive ball games)
• Exercises with a high involvement of eccentric (lengthening) muscle contractions (e.g., jumps)
• Very intense dynamic aerobic exercise (e.g., running, strenuous swimming, or cycling) except in very fit individuals who are also well trained for the specific activity
• Molecular genetic testing can be used for evaluation of relatives at risk if the
• If the family-specific
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type V (GSDV), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Physical examination with emphasis on muscle strength/weakness
Basal serum CK activity
Consultation with a clinical geneticist and/or genetic counselor
• Physical examination with emphasis on muscle strength/weakness
• Basal serum CK activity
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Currently, simple healthy lifestyle interventions (i.e., following a diet rich in complex carbohydrates and regular exercise practice), the most effective means of preventing and managing exercise intolerance in GSDV, require a proactive attitude of clinicians, exercise professionals, and patient advocates [
The benefits of a professionally supervised exercise program are safety and ease of implementation. Patients with GSDV generally adapt well to regular exercise; training should be designed to ensure gradual progression of exercise intensity, especially in the more severely affected patients. For children, it is important to provide parents, caregivers, and educators (especially physical education teachers) with appropriate information to ensure their best possible management. Patients who commit to a supervised, gradual exercise program are able to improve their fitness levels almost as effectively as healthy individuals. Indeed, affected individuals may become virtually asymptomatic during activities of daily living. It should also be noted that physical activity in general has been associated with improvements in peak oxygen uptake (VO2peak, or "cardiorespiratory fitness" [CRF]), an important health indicator. For more details on exercise recommendations and pre-exercise nutrition schedules see
A systematic review of physical training for GSDV published in the Cochrane Database found no randomized or quasi-randomized controlled trials of aerobic training in people with GSDV; however, three studies using small numbers of participants provided some evidence that aerobic training improves CRF without adverse events and called for larger controlled trials of aerobic training in patients with GSDV [
Historically, patients with GSDV have been advised to avoid resistance (strength) exercises and other forms of physical activity involving high mechanical loads such as prolonged isometric contraction. However, a recent study of seven adults (5 female) showed improved muscle strength and mass (clinically as well as objectively using dual-energy x-ray absorptiometry) following a four-month-long resistance training program (i.e., weight lifting with qualified instruction and supervision and a two-month detraining period [
A revised and updated systematic review in the Cochrane Database of nutritional and pharmacologic trials for GSDV [Quinlivan et al 2014 (updated from 2008)] indicate that high-dose oral ribose, fat-rich diet, glucagon, verapamil, vitamin B
The study concluded that: (1) consuming a sugary drink before planned strenuous exercise can improve performance but is not practical for day-to-day living; (2) a diet rich in complex carbohydrates may be superior to a diet rich in protein; however, because of the small number of participants, evidence was insufficiently strong to indicate a significant clinical benefit; (3) ramipril 2.5 mg orally daily showed some subjective improvement in participants with the DD-ACE polymorphism, which is thought to have a modulating effect on the condition; however, there was no improvement in objective measures of exercise performance; and (4) low-dose creatine supplementation demonstrated a statistically significant (albeit modest) benefit in the tolerance to ischemic exercise in a small number of individuals [
Details of interventions with pre-exercise nutrition and physical exercise recommendations are set forth in
Because of the rarity of GSDV, multicenter collaboration and standardized assessment protocols are needed for future treatment trials.
## Pharmacologic and Nutritional Treatments
A revised and updated systematic review in the Cochrane Database of nutritional and pharmacologic trials for GSDV [Quinlivan et al 2014 (updated from 2008)] indicate that high-dose oral ribose, fat-rich diet, glucagon, verapamil, vitamin B
The study concluded that: (1) consuming a sugary drink before planned strenuous exercise can improve performance but is not practical for day-to-day living; (2) a diet rich in complex carbohydrates may be superior to a diet rich in protein; however, because of the small number of participants, evidence was insufficiently strong to indicate a significant clinical benefit; (3) ramipril 2.5 mg orally daily showed some subjective improvement in participants with the DD-ACE polymorphism, which is thought to have a modulating effect on the condition; however, there was no improvement in objective measures of exercise performance; and (4) low-dose creatine supplementation demonstrated a statistically significant (albeit modest) benefit in the tolerance to ischemic exercise in a small number of individuals [
Details of interventions with pre-exercise nutrition and physical exercise recommendations are set forth in
Because of the rarity of GSDV, multicenter collaboration and standardized assessment protocols are needed for future treatment trials.
## Prevention of Primary Manifestations
See
## Surveillance
Appropriate surveillance includes the following:
Annual routine physical examination
Annual review of diet
• Annual routine physical examination
• Annual review of diet
## Agents/Circumstances to Avoid
Static muscle contractions (e.g., handgrip exercises)
Static muscle contractions or heavy loads on low muscle mass (e.g., weight lifting), unless performed under programmed supervision of clinicians and exercise/fitness specialists [
Dynamic exercises at a high-intensity level (e.g., competitive ball games)
Exercises with a high involvement of eccentric (lengthening) muscle contractions (e.g., jumps)
Very intense dynamic aerobic exercise (e.g., running, strenuous swimming, or cycling) except in very fit individuals who are also well trained for the specific activity
• Static muscle contractions (e.g., handgrip exercises)
• Static muscle contractions or heavy loads on low muscle mass (e.g., weight lifting), unless performed under programmed supervision of clinicians and exercise/fitness specialists [
• Dynamic exercises at a high-intensity level (e.g., competitive ball games)
• Exercises with a high involvement of eccentric (lengthening) muscle contractions (e.g., jumps)
• Very intense dynamic aerobic exercise (e.g., running, strenuous swimming, or cycling) except in very fit individuals who are also well trained for the specific activity
## Evaluation of Relatives at Risk
It is appropriate to clarify the clinical/genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual as early diagnosis of GSDV may improve long-term outcome by heightening awareness of the need to avoid repetitive episodes of muscle damage that may lead to rhabdomyolysis and fixed weakness.
Molecular genetic testing can be used for evaluation of relatives at risk if the
If the family-specific
See
• Molecular genetic testing can be used for evaluation of relatives at risk if the
• If the family-specific
## Pregnancy Management
GSDV does not appear to adversely affect pregnancy or childbirth [
## Therapies Under Investigation
Search
## Genetic Counseling
Glycogen storage disease type V (GSDV) is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Although some heterozygotes (carriers) may manifest mild exercise-related muscle symptoms, heterozygotes are not at risk of developing GSDV and are typically asymptomatic (see
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are typically asymptomatic (see
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Note: Although manifesting heterozygotes (i.e., carriers of only 1
In a study of 26 individuals – eight with GSDV, seven heterozygotes, and 11 controls – the heterozygotes and controls had identical values of exercise capacity indicators (maximal oxidative capacity and peak lactate response), suggesting that heterozygotes are not prone to developing symptoms of GSDV [
In a more recent study of 81 relatives of individuals with GSDV (50
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Although some heterozygotes (carriers) may manifest mild exercise-related muscle symptoms, heterozygotes are not at risk of developing GSDV and are typically asymptomatic (see
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are typically asymptomatic (see
• In a study of 26 individuals – eight with GSDV, seven heterozygotes, and 11 controls – the heterozygotes and controls had identical values of exercise capacity indicators (maximal oxidative capacity and peak lactate response), suggesting that heterozygotes are not prone to developing symptoms of GSDV [
• In a more recent study of 81 relatives of individuals with GSDV (50
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Glycogen storage disease type V (GSDV) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Although some heterozygotes (carriers) may manifest mild exercise-related muscle symptoms, heterozygotes are not at risk of developing GSDV and are typically asymptomatic (see
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are typically asymptomatic (see
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Although some heterozygotes (carriers) may manifest mild exercise-related muscle symptoms, heterozygotes are not at risk of developing GSDV and are typically asymptomatic (see
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are typically asymptomatic (see
## Carrier Detection
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Note: Although manifesting heterozygotes (i.e., carriers of only 1
In a study of 26 individuals – eight with GSDV, seven heterozygotes, and 11 controls – the heterozygotes and controls had identical values of exercise capacity indicators (maximal oxidative capacity and peak lactate response), suggesting that heterozygotes are not prone to developing symptoms of GSDV [
In a more recent study of 81 relatives of individuals with GSDV (50
• In a study of 26 individuals – eight with GSDV, seven heterozygotes, and 11 controls – the heterozygotes and controls had identical values of exercise capacity indicators (maximal oxidative capacity and peak lactate response), suggesting that heterozygotes are not prone to developing symptoms of GSDV [
• In a more recent study of 81 relatives of individuals with GSDV (50
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Spain
United Kingdom
United Kingdom
Spain
•
• Spain
•
•
• United Kingdom
•
•
•
•
• United Kingdom
•
•
•
•
• Spain
•
## Molecular Genetics
Glycogen Storage Disease Type V: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Glycogen Storage Disease Type V (
Genetic alterations in
Notable Recurrent
Variants listed in the table have been provided by the authors.
See the review by
The variant p.Arg50Ter (previously p.Arg49Ter) is the most common pathogenic variant in individuals of European and US descent. Frequency (among all variants) of p.Arg50Ter observed by population: 81% (English), 63% (North American), 56% (German), 56% (French), 55% (Spanish); p.Arg50Ter has never been found in individuals of Japanese descent [
## Molecular Pathogenesis
Genetic alterations in
Notable Recurrent
Variants listed in the table have been provided by the authors.
See the review by
The variant p.Arg50Ter (previously p.Arg49Ter) is the most common pathogenic variant in individuals of European and US descent. Frequency (among all variants) of p.Arg50Ter observed by population: 81% (English), 63% (North American), 56% (German), 56% (French), 55% (Spanish); p.Arg50Ter has never been found in individuals of Japanese descent [
## Chapter Notes
Supported by grants from the Spanish Instituto de Salud Carlos III, Madrid (PI15/00431, PI17/02052, and PI15/00558), Comunidad de Madrid (B2017-BMD-3721), and Centro de Investigación Biomedica en Red de Enfermedades Raras (CIBERER).
20 June 2019 (bp) Comprehensive update posted live
26 June 2014 (me) Comprehensive update posted live
12 May 2009 (me) Comprehensive update posted live
8 May 2006 (cd) Revision: sequence analysis of
19 April 2006 (me) Review posted live
26 August 2005 (ja) Original submission
• 20 June 2019 (bp) Comprehensive update posted live
• 26 June 2014 (me) Comprehensive update posted live
• 12 May 2009 (me) Comprehensive update posted live
• 8 May 2006 (cd) Revision: sequence analysis of
• 19 April 2006 (me) Review posted live
• 26 August 2005 (ja) Original submission
## Acknowledgments
Supported by grants from the Spanish Instituto de Salud Carlos III, Madrid (PI15/00431, PI17/02052, and PI15/00558), Comunidad de Madrid (B2017-BMD-3721), and Centro de Investigación Biomedica en Red de Enfermedades Raras (CIBERER).
## Revision History
20 June 2019 (bp) Comprehensive update posted live
26 June 2014 (me) Comprehensive update posted live
12 May 2009 (me) Comprehensive update posted live
8 May 2006 (cd) Revision: sequence analysis of
19 April 2006 (me) Review posted live
26 August 2005 (ja) Original submission
• 20 June 2019 (bp) Comprehensive update posted live
• 26 June 2014 (me) Comprehensive update posted live
• 12 May 2009 (me) Comprehensive update posted live
• 8 May 2006 (cd) Revision: sequence analysis of
• 19 April 2006 (me) Review posted live
• 26 August 2005 (ja) Original submission
## References
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"G Bollig. McArdle's disease (glycogen storage disease type V) and anesthesia--a case report and review of the literature.. Paediatr Anaesth 2013;23:817-23",
"JP Buckley, RM Quinlivan, J Sim, RG Eston, DS Short. Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease.. J Sports Sci. 2014;32:1561-9",
"C Chéraud, R Froissart, B Lannes, A Echaniz-Laguna. Novel variant in the PYGM gene causing late-onset limb-girdle myopathy, ptosis, and camptocormia.. Muscle Nerve. 2018;57:157-160",
"N de Luna, A Brull, JM Guiu, A Lucia, MA Martin, J Arenas, R Martí, AL Andreu, T Pinós. Sodium valproate increases the brain isoform of glycogen phosphorylase: looking for a compensation mechanism in McArdle disease using a mouse primary skeletal-muscle culture in vitro.. Dis Model Mech. 2015;8:467-72",
"I García-Consuegra, A Blázquez, JC Rubio, J Arenas, A Ballester-Lopez, A González-Quintana, AL Andreu, T Pinós, J Coll-Cantí, A Lucia, G Nogales-Gadea, MA Martín. Taking advantage of an old concept, \"illegitimate transcription,\" for a proposed novel method of genetic diagnosis of McArdle disease.. Genet Med. 2016;18:1128-35",
"I García-Consuegra, JC Rubio, G Nogales-Gadea, J Bautista, S Jiménez, A Cabello, A Lucía, AL Andreu, J Arenas, MA Martin. Novel mutations in patients with McArdle disease by analysis of skeletal muscle mRNA.. J Med Genet 2009;46:198-202",
"JY Hogrel, F van den Bogaart, I Ledoux, G Ollivier, F Petit, N Koujah, A Béhin, T Stojkovic, B Eymard, N Voermans, P Laforêt. Diagnostic power of the non-ischaemic forearm exercise test in detecting glycogenosis type V.. Eur J Neurol. 2015;22:933-40",
"JM Howell, E Dunton, KE Creed, R Quinlivan, C Sewry. Investigating sodium valproate as a treatment for McArdle disease in sheep.. Neuromuscul Disord. 2015;25:111-9",
"SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97",
"CV Kouwenberg, NC Voermans, R Quinlivan, L Van Den Engel-Hoek. Mastication and oral motor function in McArdle disease: patient reported complaints.. J Neuromuscul Dis. 2018;5:353-7",
"A Lucia, G Nogales-Gadea, M Pérez, MA Martín, AL Andreu, J Arenas. McArdle disease: what do neurologists need to know?. Nat Clin Pract Neurol 2008;4:568-77",
"A Lucia, JR Ruiz, A Santalla, G Nogales-Gadea, JC Rubio, I García-Consuegra, A Cabello, M Pérez, S Teijeira, I Vieitez, C Navarro, J Arenas, MA Martin, AL Andreu. Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry.. J Neurol Neurosurg Psychiatry 2012;83:322-8",
"JM Martinez-Thompson, SJ Pittock, M Milone. PRES leading to the diagnosis of McArdle disease.. J Clin Neurosci. 2017;46:62-4",
"S Moustafa, DJ Patton, MS Connelly. Unforeseen cardiac involvement in McArdle's disease.. Heart Lung Circ. 2013;22:769-71",
"AB Mull, JI Wagner, TM Myckatyn, AF Kells. Recurrent compartment syndrome leading to the diagnosis of McArdle disease: case report.. J Hand Surg Am. 2015;40:2377-9",
"G Nogales-Gadea, A Brull, A Santalla, AL Andreu, J Arenas, MA Martín, A Lucia, N de Luna, T Pinós. McArdle disease: update of reported mutations and polymorphisms in the PYGM gene.. Hum Mutat. 2015;36:669-78",
"G Nogales-Gadea, A Santalla, A Ballester-Lopez, J Arenas, MA Martín, R Godfrey, T Pinós, G Pintos-Morell, J Coll-Cantí, A Lucia. Exercise and preexercise nutrition as treatment for McArdle disease.. Med Sci Sports Exerc. 2016;48:673-9",
"J Núñez-Manchón, A Ballester-Lopez, E Koehorst, I Linares-Pardo, D Coenen, I Ara, C Rodriguez-Lopez, A Ramos-Fransi, A Martínez-Piñeiro, G Lucente, M Almendrote, J Coll-Cantí, G Pintos-Morell, A Santos-Lozano, J Arenas, MA Martín, M de Castro, A Lucia, A Santalla, G Nogales-Gadea. Manifesting heterozygotes in McArdle disease: a myth or a reality-role of statins.. J Inherit Metab Dis. 2018;41:1027-35",
"SE Olpin, E Murphy, RJ Kirk, RW Taylor, R Quinlivan. The investigation and management of metabolic myopathies.. J Clin Pathol. 2015;68:410-7",
"R Quinlivan, J Vissing, D Hilton-Jones, J. Buckley. Physical training for McArdle disease.. Cochrane Database Syst Rev. 2011;12",
"A Pietrusz, RS Scalco, R Quinlivan. Resistance exercise training in McArdle disease: myth or reality?. Case Rep Neurol Med. 2018;2018",
"T Pinós, A Lucia, J Arenas, A Brull, AL Andreu, MA Martin, G Nogales-Gadea. Minimal symptoms in McArdle disease: a real PYGM genotype effect?. Muscle Nerve. 2015;52:1136-7",
"A Santalla, D Munguía-Izquierdo, L Brea-Alejo, I Pagola-Aldazábal, J Díez-Bermejo, SJ Fleck, I Ara, A Lucia. Feasibility of resistance training in adult McArdle patients: clinical outcomes and muscle strength and mass benefits.. Front Aging Neurosci. 2014;6:334",
"A Santalla, G Nogales-Gadea, AB Encinar, I Vieitez, A González-Quintana, P Serrano-Lorenzo, IG Consuegra, S Asensio, A Ballester-Lopez, G Pintos-Morell, J Coll-Cantí, H Pareja-Galeano, J Díez-Bermejo, M Pérez, AL Andreu, T Pinós, J Arenas, MA Martín, A Lucia. Genotypic and phenotypic features of all Spanish patients with McArdle disease: a 2016 update.. BMC Genomics. 2017;18:819",
"RS Scalco, S Chatfield, MH Junejo, S Booth, J Pattni, R Godfrey, R Quinlivan. McArdle disease misdiagnosed as meningitis.. Am J Case Rep. 2016;17:905-8",
"RS Scalco, AR Gardiner, RD Pitceathly, E Zanoteli, J Becker, JL Holton, H Houlden, H Jungbluth, R Quinlivan. Rhabdomyolysis: a genetic perspective.. Orphanet J Rare Dis. 2015;10:51",
"RS Scalco, JM Morrow, S Booth, S Chatfield, R Godfrey, R Quinlivan. Misdiagnosis is an important factor for diagnostic delay in McArdle disease.. Neuromuscul Disord. 2017;27:852-5",
"T Stopp, M Feichtinger, W Eppel, TM Stulnig, P Husslein, C Göbl. Pre- and peripartal management of a woman with McArdle disease: a case report.. Gynecol Endocrinol. 2018;34:736-9",
"RL Taylor, M Davis, E Turner, A Brull, T Pinos, M Cabrera, KJ Nowak. Clinical utility gene card for McArdle disease.. Eur J Hum Genet. 2018;26:758-64",
"JJ Triplet, DA Goss, B Taylor. Spontaneous compartment syndrome in a patient with McArdle disease.. JBJS Case Connect. 2017;7",
"WD Walters, AD Garnica, GB Schaefer. McArdle disease presenting with muscle pain in a teenage girl: the role of whole-exome sequencing in neurogenetic disorders.. Semin Pediatr Neurol. 2018;26:50-1",
"N Witting, M Duno, M Piraud, J Vissing. Severe axial myopathy in McArdle disease.. JAMA Neurol 2014;71:88-90"
] |
19/4/2006
|
20/6/2019
|
8/5/2006
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
gsd6
|
gsd6
|
[
"GSD VI",
"GSD VI",
"Glycogen phosphorylase, liver form",
"PYGL",
"Glycogen Storage Disease Type VI"
] |
Glycogen Storage Disease Type VI
|
Emma Labrador, David A Weinstein
|
Summary Glycogen storage disease type VI (GSD VI) is a disorder of glycogenolysis caused by deficiency of hepatic glycogen phosphorylase. This critical enzyme catalyzes the rate-limiting step in glycogen degradation, and deficiency of the enzyme in the untreated child is characterized by hepatomegaly, poor growth, ketotic hypoglycemia, elevated hepatic transaminases, hyperlipidemia, and low prealbumin level. GSD VI is usually a relatively mild disorder that presents in infancy and childhood; rare cases of more severe disease manifesting with recurrent hypoglycemia and marked hepatomegaly have been described. More common complications in the setting of suboptimal metabolic control include short stature, delayed puberty, osteopenia, and osteoporosis. Hepatic fibrosis commonly develops in GSD VI, but cirrhosis and hypertrophic cardiomyopathy are rare. Clinical and biochemical abnormalities may decrease with age, but ketosis and hypoglycemia can continue to occur. The diagnosis of GSD VI is established in a proband with typical clinical findings and/or biallelic pathogenic variants in GSD VI is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.
|
## Diagnosis
Glycogen storage disease type VI (formerly known as Hers disease) is a disorder affecting hepatic glycogenolysis due to a deficiency of glycogen phosphorylase. This critical enzyme catalyzes the rate-limiting step in glycogen degradation.
Glycogen storage disease type VI (GSD VI)
Hepatomegaly
Poor growth
Ketotic hypoglycemia
Elevated hepatic transaminases
Hyperlipidemia
Low prealbumin level
Abdominal ultrasound showing hepatomegaly with diffuse echogenicity
The diagnosis of GSD VI
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
A liver biopsy is reserved for those in whom the diagnosis cannot be confirmed by molecular genetic techniques [
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GSD VI is fairly broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of GSD VI, molecular genetic testing approaches can include
Targeted analysis for the founder pathogenic variant,
A
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by glycogen storage disorder,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type VI
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from personal experience and the subscription-based professional view of the Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Hepatomegaly
• Poor growth
• Ketotic hypoglycemia
• Elevated hepatic transaminases
• Hyperlipidemia
• Low prealbumin level
• Abdominal ultrasound showing hepatomegaly with diffuse echogenicity
• Targeted analysis for the founder pathogenic variant,
• A
• For an introduction to multigene panels click
## Suggestive Findings
Glycogen storage disease type VI (GSD VI)
Hepatomegaly
Poor growth
Ketotic hypoglycemia
Elevated hepatic transaminases
Hyperlipidemia
Low prealbumin level
Abdominal ultrasound showing hepatomegaly with diffuse echogenicity
• Hepatomegaly
• Poor growth
• Ketotic hypoglycemia
• Elevated hepatic transaminases
• Hyperlipidemia
• Low prealbumin level
• Abdominal ultrasound showing hepatomegaly with diffuse echogenicity
## Establishing the Diagnosis
The diagnosis of GSD VI
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
A liver biopsy is reserved for those in whom the diagnosis cannot be confirmed by molecular genetic techniques [
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GSD VI is fairly broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of GSD VI, molecular genetic testing approaches can include
Targeted analysis for the founder pathogenic variant,
A
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by glycogen storage disorder,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type VI
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from personal experience and the subscription-based professional view of the Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Targeted analysis for the founder pathogenic variant,
• A
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of GSD VI, molecular genetic testing approaches can include
Targeted analysis for the founder pathogenic variant,
A
For an introduction to multigene panels click
• Targeted analysis for the founder pathogenic variant,
• A
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by glycogen storage disorder,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Glycogen Storage Disease Type VI
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from personal experience and the subscription-based professional view of the Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Growth normalizes;
Final height is usually appropriate for genetic potential.
Osteopenia and osteoporosis are common in untreated individuals.
Bone mineral density can normalize with treatment [
Due to the overstorage of glycogen and high protein diet, the consensus guidelines recommend screening for kidney disease.
Renal abnormalities including proteinuria, however, are rarely seen in GSD VI [
No clear genotype-phenotype correlation exists.
The Mennonite pathogenic variant,
GSD VI (Hers disease) was first reported by
GSD VI now refers to liver glycogen phosphorylase deficiency.
Liver glycogen phosphorylase deficiency affects approximately 1:65,000-85,000 live births; however, many people with this condition are undiagnosed. GSD VI is equally prevalent in males and females. The Mennonite population is at increased risk for GSD VI, with a prevalence of 1:1,000 resulting from the founder variant
•
• Growth normalizes;
• Final height is usually appropriate for genetic potential.
• Growth normalizes;
• Final height is usually appropriate for genetic potential.
• Growth normalizes;
• Final height is usually appropriate for genetic potential.
• Osteopenia and osteoporosis are common in untreated individuals.
• Bone mineral density can normalize with treatment [
• Due to the overstorage of glycogen and high protein diet, the consensus guidelines recommend screening for kidney disease.
• Renal abnormalities including proteinuria, however, are rarely seen in GSD VI [
## Clinical Description
Growth normalizes;
Final height is usually appropriate for genetic potential.
Osteopenia and osteoporosis are common in untreated individuals.
Bone mineral density can normalize with treatment [
Due to the overstorage of glycogen and high protein diet, the consensus guidelines recommend screening for kidney disease.
Renal abnormalities including proteinuria, however, are rarely seen in GSD VI [
•
• Growth normalizes;
• Final height is usually appropriate for genetic potential.
• Growth normalizes;
• Final height is usually appropriate for genetic potential.
• Growth normalizes;
• Final height is usually appropriate for genetic potential.
• Osteopenia and osteoporosis are common in untreated individuals.
• Bone mineral density can normalize with treatment [
• Due to the overstorage of glycogen and high protein diet, the consensus guidelines recommend screening for kidney disease.
• Renal abnormalities including proteinuria, however, are rarely seen in GSD VI [
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlation exists.
The Mennonite pathogenic variant,
## Nomenclature
GSD VI (Hers disease) was first reported by
GSD VI now refers to liver glycogen phosphorylase deficiency.
## Prevalence
Liver glycogen phosphorylase deficiency affects approximately 1:65,000-85,000 live births; however, many people with this condition are undiagnosed. GSD VI is equally prevalent in males and females. The Mennonite population is at increased risk for GSD VI, with a prevalence of 1:1,000 resulting from the founder variant
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of Glycogen Storage Disease Type VI
Hepatomegaly
Fasting ketosis
Hypoglycemia
↑ AST/ALT
↑ lipids
Male predominance
AST & ALT commonly more severely ↑
Fasting hypoglycemia
Ketosis
Absence of hepatomegaly
Postprandial hyperglycemia & hyperlactatemia
Hepatomegaly
Fasting hypoglycemia
↑ AST/ALT
Hyperlipidemia
Severe fasting lactic acidosis
Hyperuricemia
Marked hyperlipidemia
Hepatomegaly
Fasting hypoglycemia
↑ AST/ALT
Hyperlipidemia
Neutropenia
Crohn disease
Hyperuricemia
Hepatomegaly
Fasting hypoglycemia
↑ AST/ALT
Hyperlipidemia
Low prealbumin
AST & ALT usually markedly ↑
Muscle involvement w/↑ CK
Hepatomegaly
↑ AST/ALT
↓ prealbumin
Hepatomegaly
Fasting hypoglycemia
Fasting ketosis
↑ AST/ALT
Low prealbumin
Postprandial hyperglycemia
Chronic diarrhea
Hypophosphatemic rickets
Fanconi nephropathy
Hepatomegaly
Fasting hypoglycemia
↑ AST/ALT
Hepatomegaly
↑ AST/ALT
Nonlysosomal glycogen accumulation primarily in skeletal & cardiac muscle
Ventricular pre-excitation & mild-to-severe cardiac hypertrophy
No hypoglycemia
Hepatomegaly
Growth failure
Hyperlipidemia
No fasting hypoglycemia
Significant splenomegaly
Bone & pulmonary involvement
Adapted from
AD = autosomal dominant; AR = autosomal recessive; ASM = acid sphingomyelinase; GSD = glycogen storage disease; MOI = mode of inheritance; XL = X-linked
Fructose-1,6-bisphosphatase deficiency is one example of a disorder of gluconeogenesis; other should also be considered.
Alpha-1 antitrypsin deficiency-related hepatitis is one example of a primary liver disease; other primary liver diseases should also be considered.
Niemann-Pick disease type B and Gaucher disease are examples of metabolic storage disorders; other metabolic storage disorders should also be considered.
• Hepatomegaly
• Fasting ketosis
• Hypoglycemia
• ↑ AST/ALT
• ↑ lipids
• Male predominance
• AST & ALT commonly more severely ↑
• Fasting hypoglycemia
• Ketosis
• Absence of hepatomegaly
• Postprandial hyperglycemia & hyperlactatemia
• Hepatomegaly
• Fasting hypoglycemia
• ↑ AST/ALT
• Hyperlipidemia
• Severe fasting lactic acidosis
• Hyperuricemia
• Marked hyperlipidemia
• Hepatomegaly
• Fasting hypoglycemia
• ↑ AST/ALT
• Hyperlipidemia
• Neutropenia
• Crohn disease
• Hyperuricemia
• Hepatomegaly
• Fasting hypoglycemia
• ↑ AST/ALT
• Hyperlipidemia
• Low prealbumin
• AST & ALT usually markedly ↑
• Muscle involvement w/↑ CK
• Hepatomegaly
• ↑ AST/ALT
• ↓ prealbumin
• Hepatomegaly
• Fasting hypoglycemia
• Fasting ketosis
• ↑ AST/ALT
• Low prealbumin
• Postprandial hyperglycemia
• Chronic diarrhea
• Hypophosphatemic rickets
• Fanconi nephropathy
• Hepatomegaly
• Fasting hypoglycemia
• ↑ AST/ALT
• Hepatomegaly
• ↑ AST/ALT
• Nonlysosomal glycogen accumulation primarily in skeletal & cardiac muscle
• Ventricular pre-excitation & mild-to-severe cardiac hypertrophy
• No hypoglycemia
• Hepatomegaly
• Growth failure
• Hyperlipidemia
• No fasting hypoglycemia
• Significant splenomegaly
• Bone & pulmonary involvement
## Management
To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type VI (GSD VI), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with GSD VI
Assessment of liver size
Abdominal ultrasound
Note: Some individuals with GSD VI may not require any treatment, but most have better growth and stamina with therapy.
Treatment of Manifestations in individuals with GSD VI
Frequent small meals
Uncooked cornstarch (1-1.5 g/kg) 1-4x/day
Protein 2-3 g/kg body weight per day
Glycosade
Restricted intake of simple sugars (<5 g)
Restricted intake of total carbohydrates (15-30 g per meal)
Growth normalizes w/treatment
Growth hormone contraindicated
Cornstarch & protein supplementation
Calcium & Vitamin D
Extended-release cornstarch
[
Diet should be high in protein and provide 2-3 g protein/kg body weight or 20%-25% of total calories.
Protein intake should be distributed throughout the day.
Protein should be consumed at each meal and snack, before bedtime, and before physical activities.
Carbohydrates should provide 45%-50% of total calories.
Complex carbohydrates should be consumed with each meal to provide a sustained source.
Overtreatment with cornstarch can be detrimental.
Small amounts of dairy and fruits are allowed in the diet.
Simple sugars should be limited to 5 g.
Fats should provide 25%-30%of total calories.
Diet should include good sources of poly-and mono-unsaturated fatty acids.
Saturated fats should provide <10% of total calories.
Cholesterol should be restricted to <300 mg/day.
Recommended Surveillance for Individuals with GSDVI
Glucose and ketone levels should also be measured during times of stress including illness, intense activity, periods of rapid growth, or any time at which intake of food is reduced and before and after changes are made to the amount of cornstarch or protein intake. Monitoring recommendations should be tailored to individual needs.
Avoid the following:
Excessive amounts of simple sugars to prevent excessive hepatic glycogen deposition
Glucagon administration as a rescue therapy for hypoglycemia because blood glucose concentrations will not increase
Growth hormone for short stature because it usually exacerbates ketosis and may increase the risk of complications
Contact sports when hepatomegaly is present (or use appropriate cautions)
It is appropriate to evaluate apparently asymptomatic at-risk sibs to identify as early as possible those who would benefit from prompt initiation of treatment and avoidance of factors that exacerbate disease.
Molecular genetic testing is indicated if the pathogenic variants in the family are known.
See
A pregnant woman with GSD VI must be vigilant in monitoring for hypoglycemia and ketosis during pregnancy. Cornstarch and protein supplementation (2-4x/day) are needed during pregnancy to prevent ketosis and premature labor. The goal is to maintain euglycemia throughout pregnancy to prevent morbidity and mortality to the fetus due to activation of counterregulatory hormones resulting in lipolysis and ketosis. Increasing protein intake may be necessary to provide an alternate source of glucose via gluconeogenesis.
An extended-release cornstarch preparation is presently being tested as part of the Clinical Trials
There is also an ongoing trial looking for a biomarker for glycogen storage disease (
Search
• Assessment of liver size
• Abdominal ultrasound
• Frequent small meals
• Uncooked cornstarch (1-1.5 g/kg) 1-4x/day
• Protein 2-3 g/kg body weight per day
• Glycosade
• Restricted intake of simple sugars (<5 g)
• Restricted intake of total carbohydrates (15-30 g per meal)
• Growth normalizes w/treatment
• Growth hormone contraindicated
• Cornstarch & protein supplementation
• Calcium & Vitamin D
• Diet should be high in protein and provide 2-3 g protein/kg body weight or 20%-25% of total calories.
• Protein intake should be distributed throughout the day.
• Protein should be consumed at each meal and snack, before bedtime, and before physical activities.
• Carbohydrates should provide 45%-50% of total calories.
• Complex carbohydrates should be consumed with each meal to provide a sustained source.
• Overtreatment with cornstarch can be detrimental.
• Small amounts of dairy and fruits are allowed in the diet.
• Simple sugars should be limited to 5 g.
• Fats should provide 25%-30%of total calories.
• Diet should include good sources of poly-and mono-unsaturated fatty acids.
• Saturated fats should provide <10% of total calories.
• Cholesterol should be restricted to <300 mg/day.
• Excessive amounts of simple sugars to prevent excessive hepatic glycogen deposition
• Glucagon administration as a rescue therapy for hypoglycemia because blood glucose concentrations will not increase
• Growth hormone for short stature because it usually exacerbates ketosis and may increase the risk of complications
• Contact sports when hepatomegaly is present (or use appropriate cautions)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type VI (GSD VI), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with GSD VI
Assessment of liver size
Abdominal ultrasound
• Assessment of liver size
• Abdominal ultrasound
## Treatment of Manifestations
Note: Some individuals with GSD VI may not require any treatment, but most have better growth and stamina with therapy.
Treatment of Manifestations in individuals with GSD VI
Frequent small meals
Uncooked cornstarch (1-1.5 g/kg) 1-4x/day
Protein 2-3 g/kg body weight per day
Glycosade
Restricted intake of simple sugars (<5 g)
Restricted intake of total carbohydrates (15-30 g per meal)
Growth normalizes w/treatment
Growth hormone contraindicated
Cornstarch & protein supplementation
Calcium & Vitamin D
Extended-release cornstarch
[
Diet should be high in protein and provide 2-3 g protein/kg body weight or 20%-25% of total calories.
Protein intake should be distributed throughout the day.
Protein should be consumed at each meal and snack, before bedtime, and before physical activities.
Carbohydrates should provide 45%-50% of total calories.
Complex carbohydrates should be consumed with each meal to provide a sustained source.
Overtreatment with cornstarch can be detrimental.
Small amounts of dairy and fruits are allowed in the diet.
Simple sugars should be limited to 5 g.
Fats should provide 25%-30%of total calories.
Diet should include good sources of poly-and mono-unsaturated fatty acids.
Saturated fats should provide <10% of total calories.
Cholesterol should be restricted to <300 mg/day.
• Frequent small meals
• Uncooked cornstarch (1-1.5 g/kg) 1-4x/day
• Protein 2-3 g/kg body weight per day
• Glycosade
• Restricted intake of simple sugars (<5 g)
• Restricted intake of total carbohydrates (15-30 g per meal)
• Growth normalizes w/treatment
• Growth hormone contraindicated
• Cornstarch & protein supplementation
• Calcium & Vitamin D
• Diet should be high in protein and provide 2-3 g protein/kg body weight or 20%-25% of total calories.
• Protein intake should be distributed throughout the day.
• Protein should be consumed at each meal and snack, before bedtime, and before physical activities.
• Carbohydrates should provide 45%-50% of total calories.
• Complex carbohydrates should be consumed with each meal to provide a sustained source.
• Overtreatment with cornstarch can be detrimental.
• Small amounts of dairy and fruits are allowed in the diet.
• Simple sugars should be limited to 5 g.
• Fats should provide 25%-30%of total calories.
• Diet should include good sources of poly-and mono-unsaturated fatty acids.
• Saturated fats should provide <10% of total calories.
• Cholesterol should be restricted to <300 mg/day.
## General Nutrition Recommendations
[
Diet should be high in protein and provide 2-3 g protein/kg body weight or 20%-25% of total calories.
Protein intake should be distributed throughout the day.
Protein should be consumed at each meal and snack, before bedtime, and before physical activities.
Carbohydrates should provide 45%-50% of total calories.
Complex carbohydrates should be consumed with each meal to provide a sustained source.
Overtreatment with cornstarch can be detrimental.
Small amounts of dairy and fruits are allowed in the diet.
Simple sugars should be limited to 5 g.
Fats should provide 25%-30%of total calories.
Diet should include good sources of poly-and mono-unsaturated fatty acids.
Saturated fats should provide <10% of total calories.
Cholesterol should be restricted to <300 mg/day.
• Diet should be high in protein and provide 2-3 g protein/kg body weight or 20%-25% of total calories.
• Protein intake should be distributed throughout the day.
• Protein should be consumed at each meal and snack, before bedtime, and before physical activities.
• Carbohydrates should provide 45%-50% of total calories.
• Complex carbohydrates should be consumed with each meal to provide a sustained source.
• Overtreatment with cornstarch can be detrimental.
• Small amounts of dairy and fruits are allowed in the diet.
• Simple sugars should be limited to 5 g.
• Fats should provide 25%-30%of total calories.
• Diet should include good sources of poly-and mono-unsaturated fatty acids.
• Saturated fats should provide <10% of total calories.
• Cholesterol should be restricted to <300 mg/day.
## Surveillance
Recommended Surveillance for Individuals with GSDVI
Glucose and ketone levels should also be measured during times of stress including illness, intense activity, periods of rapid growth, or any time at which intake of food is reduced and before and after changes are made to the amount of cornstarch or protein intake. Monitoring recommendations should be tailored to individual needs.
## Agents/Circumstances to Avoid
Avoid the following:
Excessive amounts of simple sugars to prevent excessive hepatic glycogen deposition
Glucagon administration as a rescue therapy for hypoglycemia because blood glucose concentrations will not increase
Growth hormone for short stature because it usually exacerbates ketosis and may increase the risk of complications
Contact sports when hepatomegaly is present (or use appropriate cautions)
• Excessive amounts of simple sugars to prevent excessive hepatic glycogen deposition
• Glucagon administration as a rescue therapy for hypoglycemia because blood glucose concentrations will not increase
• Growth hormone for short stature because it usually exacerbates ketosis and may increase the risk of complications
• Contact sports when hepatomegaly is present (or use appropriate cautions)
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic at-risk sibs to identify as early as possible those who would benefit from prompt initiation of treatment and avoidance of factors that exacerbate disease.
Molecular genetic testing is indicated if the pathogenic variants in the family are known.
See
## Pregnancy Management
A pregnant woman with GSD VI must be vigilant in monitoring for hypoglycemia and ketosis during pregnancy. Cornstarch and protein supplementation (2-4x/day) are needed during pregnancy to prevent ketosis and premature labor. The goal is to maintain euglycemia throughout pregnancy to prevent morbidity and mortality to the fetus due to activation of counterregulatory hormones resulting in lipolysis and ketosis. Increasing protein intake may be necessary to provide an alternate source of glucose via gluconeogenesis.
## Therapies Under Investigation
An extended-release cornstarch preparation is presently being tested as part of the Clinical Trials
There is also an ongoing trial looking for a biomarker for glycogen storage disease (
Search
## Genetic Counseling
Glycogen storage disease type VI (GSD VI) is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
The offspring of an individual with GSD VI are obligate heterozygotes (carriers) for a pathogenic variant in
A higher carrier rate for GSD VI exists in the Mennonite population (see
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The offspring of an individual with GSD VI are obligate heterozygotes (carriers) for a pathogenic variant in
• A higher carrier rate for GSD VI exists in the Mennonite population (see
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Glycogen storage disease type VI (GSD VI) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
The offspring of an individual with GSD VI are obligate heterozygotes (carriers) for a pathogenic variant in
A higher carrier rate for GSD VI exists in the Mennonite population (see
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The offspring of an individual with GSD VI are obligate heterozygotes (carriers) for a pathogenic variant in
• A higher carrier rate for GSD VI exists in the Mennonite population (see
## Carrier Detection
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
## Resources
9 Lindop Road
Altrincham Cheshire WA15 9DZ
United Kingdom
United Kingdom
•
•
•
• 9 Lindop Road
• Altrincham Cheshire WA15 9DZ
• United Kingdom
•
•
•
•
• United Kingdom
•
•
## Molecular Genetics
Glycogen Storage Disease Type VI: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Glycogen Storage Disease Type VI (
Glycogen phosphorylase, which requires pyridoxal phosphate as a cofactor, cleaves the α(1→4) glycosidic bonds between the glycosyl residues at the periphery of the glycogen molecule to release glucose-1-phosphate. This enzymatic reaction is the rating-limiting process in glycogenolysis, and it is repeated until the proximal four residues before the branch point of that particular glycogen chain are reached. The three isoforms of glycogen phosphorylase – muscle, liver, and brain – are encoded by different genes.
Liver glycogen phosphorylase, encoded by
Contains the phosphorylation peptide and the AMP binding site;
Interacts with the phosphorylase kinase, allosteric effectors, and phosphatase.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
•
• Contains the phosphorylation peptide and the AMP binding site;
• Interacts with the phosphorylase kinase, allosteric effectors, and phosphatase.
• Contains the phosphorylation peptide and the AMP binding site;
• Interacts with the phosphorylase kinase, allosteric effectors, and phosphatase.
• Contains the phosphorylation peptide and the AMP binding site;
• Interacts with the phosphorylase kinase, allosteric effectors, and phosphatase.
## Molecular Pathogenesis
Glycogen phosphorylase, which requires pyridoxal phosphate as a cofactor, cleaves the α(1→4) glycosidic bonds between the glycosyl residues at the periphery of the glycogen molecule to release glucose-1-phosphate. This enzymatic reaction is the rating-limiting process in glycogenolysis, and it is repeated until the proximal four residues before the branch point of that particular glycogen chain are reached. The three isoforms of glycogen phosphorylase – muscle, liver, and brain – are encoded by different genes.
Liver glycogen phosphorylase, encoded by
Contains the phosphorylation peptide and the AMP binding site;
Interacts with the phosphorylase kinase, allosteric effectors, and phosphatase.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
•
• Contains the phosphorylation peptide and the AMP binding site;
• Interacts with the phosphorylase kinase, allosteric effectors, and phosphatase.
• Contains the phosphorylation peptide and the AMP binding site;
• Interacts with the phosphorylase kinase, allosteric effectors, and phosphatase.
• Contains the phosphorylation peptide and the AMP binding site;
• Interacts with the phosphorylase kinase, allosteric effectors, and phosphatase.
## Chapter Notes
The authors also wish to thank Drs Holmes Morton and Kevin Strauss for sharing their experience with the Mennonite population.
Aditi I Dagli, MD; University of Florida (2009-2019)Emma Labrador, RN (2019-present)David A Weinstein, MD, MMSc (2009-present)
27 November 2019 (ha) Comprehensive update posted live
17 May 2011 (me) Comprehensive update posted live
23 April 2009 (et) Review posted live
4 February 2009 (ad) Original submission
• 27 November 2019 (ha) Comprehensive update posted live
• 17 May 2011 (me) Comprehensive update posted live
• 23 April 2009 (et) Review posted live
• 4 February 2009 (ad) Original submission
## Acknowledgments
The authors also wish to thank Drs Holmes Morton and Kevin Strauss for sharing their experience with the Mennonite population.
## Author History
Aditi I Dagli, MD; University of Florida (2009-2019)Emma Labrador, RN (2019-present)David A Weinstein, MD, MMSc (2009-present)
## Revision History
27 November 2019 (ha) Comprehensive update posted live
17 May 2011 (me) Comprehensive update posted live
23 April 2009 (et) Review posted live
4 February 2009 (ad) Original submission
• 27 November 2019 (ha) Comprehensive update posted live
• 17 May 2011 (me) Comprehensive update posted live
• 23 April 2009 (et) Review posted live
• 4 February 2009 (ad) Original submission
## References
## Literature Cited
|
[] |
23/4/2009
|
27/11/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
gsd9
|
gsd9
|
[
"Glycogen Storage Disease Type IX",
"GSDIX",
"PhK Deficiency",
"Phosphorylase b Kinase Deficiency",
"GSDIX",
"Phosphorylase b Kinase Deficiency",
"PhK Deficiency",
"Glycogen Storage Disease Type IX",
"Muscle Phosphorylase Kinase Deficiency",
"Liver Phosphorylase Kinase Deficiency",
"Phosphorylase b kinase gamma catalytic chain, liver/testis isoform",
"Phosphorylase b kinase regulatory subunit alpha, liver isoform",
"Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform",
"Phosphorylase b kinase regulatory subunit beta",
"PHKA1",
"PHKA2",
"PHKB",
"PHKG2",
"Phosphorylase Kinase Deficiency"
] |
Phosphorylase Kinase Deficiency
|
Mrudu Herbert, Jennifer L Goldstein, Catherine Rehder, Stephanie Austin, Priya S Kishnani, Deeksha S Bali
|
Summary Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are The enzyme PhK comprises four copies each of four subunits (α, β, γ, and δ). Pathogenic variants in: The diagnosis of PhK deficiency is established in a proband with the characteristic clinical findings, a family history of suspected storage disease, and/or a hemizygous pathogenic variant in Carrier testing for at-risk relatives, prenatal testing for pregnancies at risk, and preimplantation genetic testing are possible if the pathogenic variant(s) in the family have been identified.
|
Liver phosphorylase kinase deficiency
Muscle phosphorylase kinase deficiency
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• Liver phosphorylase kinase deficiency
• Muscle phosphorylase kinase deficiency
## Diagnosis
Phosphorylase kinase deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase (PhK), an enzyme with a key regulatory role in the breakdown of glycogen. Deficiency of this enzyme, which is composed of four copies each of four subunits (α, β, γ, and δ), results in considerable clinical variability [
For the purposes of this review, phosphorylase kinase (PhK) deficiency has been divided into liver PhK deficiency and muscle PhK deficiency (see
Muscle PhK deficiency in this review refers to
The delta subunit of PhK, calmodulin, is encoded by three different genes:
Liver or muscle phosphorylase kinase (PhK) deficiency resulting in glycogen storage disease type IX (GSD IX)
PhK Deficiency: Suggestive Phenotypic Findings
Hepatomegaly
Growth restriction in many (not all)
Fasting ketosis & hypoglycemia – mild to severe
↑ liver transaminases
↑ triglycerides & cholesterol [
Normal uric acid & lactic acid concentrations
Exercise intolerance
Myalgia
Muscle cramps
Myoglobinuria
Progressive muscle weakness
Serum concentration of creatine kinase > upper limits of normal in some cases
Electromyography usually normal
Lactic acid levels may be elevated postprandially [
There is considerable variability in the clinical presentation. Some individuals may be virtually asymptomatic.
Note: Normal ranges tend to be laboratory specific.
The diagnosis of PhK deficiency
Note: (1) While
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PhK deficiency is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of PhK deficiency, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
For liver PhK deficiency, perform sequence analysis of
For muscle PhK deficiency, perform sequence analysis of
In a male with a maternal family history of similarly affected males, it is appropriate to perform sequence analysis of
When the phenotype is indistinguishable from many other inherited disorders characterized by hepatomegaly and/or muscle weakness, or if an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Phosphorylase Kinase Deficiency
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Histology usually shows distended hepatocytes as a result of excess glycogen accumulation. Bridging portal fibrosis, steatosis, and low-grade inflammatory changes may also be seen [
Remarkably elevated glycogen content with normal glycogen structure is found on biochemical testing of snap-frozen liver biopsy tissue.
Normal PhK activity in erythrocytes is 1.0 μmol/min/g hemoglobin, and in liver it is 0.1 μmol/min/mg protein.
Abnormal range is <10% of normal level in the tissue being tested.
Note: (1) PhK is a labile enzyme that is highly sensitive to handling conditions and temperature exposure; thus, it is recommended that test blood samples be accompanied by a control blood sample drawn at the same time from an unrelated individual. Samples need to be kept cold (4
Excessive amounts of subsarcolemmal glycogen accumulation are found on histology.
Elevated glycogen content with normal glycogen structure is found on biochemical testing of muscle.
PhK enzyme activity is markedly reduced in muscle but normal in liver, blood cells, and fibroblasts.
Because PhK enzyme activates the enzyme glycogen phosphorylase in muscle and liver, the activity of glycogen myophosphorylase (phosphorylase-a) may be reduced in muscle in individuals with muscle PhK deficiency.
• Hepatomegaly
• Growth restriction in many (not all)
• Fasting ketosis & hypoglycemia – mild to severe
• ↑ liver transaminases
• ↑ triglycerides & cholesterol [
• Normal uric acid & lactic acid concentrations
• Exercise intolerance
• Myalgia
• Muscle cramps
• Myoglobinuria
• Progressive muscle weakness
• Serum concentration of creatine kinase > upper limits of normal in some cases
• Electromyography usually normal
• For liver PhK deficiency, perform sequence analysis of
• For muscle PhK deficiency, perform sequence analysis of
• In a male with a maternal family history of similarly affected males, it is appropriate to perform sequence analysis of
• Histology usually shows distended hepatocytes as a result of excess glycogen accumulation. Bridging portal fibrosis, steatosis, and low-grade inflammatory changes may also be seen [
• Remarkably elevated glycogen content with normal glycogen structure is found on biochemical testing of snap-frozen liver biopsy tissue.
• Normal PhK activity in erythrocytes is 1.0 μmol/min/g hemoglobin, and in liver it is 0.1 μmol/min/mg protein.
• Abnormal range is <10% of normal level in the tissue being tested.
• Excessive amounts of subsarcolemmal glycogen accumulation are found on histology.
• Elevated glycogen content with normal glycogen structure is found on biochemical testing of muscle.
• PhK enzyme activity is markedly reduced in muscle but normal in liver, blood cells, and fibroblasts.
• Because PhK enzyme activates the enzyme glycogen phosphorylase in muscle and liver, the activity of glycogen myophosphorylase (phosphorylase-a) may be reduced in muscle in individuals with muscle PhK deficiency.
## Suggestive Findings
Liver or muscle phosphorylase kinase (PhK) deficiency resulting in glycogen storage disease type IX (GSD IX)
PhK Deficiency: Suggestive Phenotypic Findings
Hepatomegaly
Growth restriction in many (not all)
Fasting ketosis & hypoglycemia – mild to severe
↑ liver transaminases
↑ triglycerides & cholesterol [
Normal uric acid & lactic acid concentrations
Exercise intolerance
Myalgia
Muscle cramps
Myoglobinuria
Progressive muscle weakness
Serum concentration of creatine kinase > upper limits of normal in some cases
Electromyography usually normal
Lactic acid levels may be elevated postprandially [
There is considerable variability in the clinical presentation. Some individuals may be virtually asymptomatic.
Note: Normal ranges tend to be laboratory specific.
• Hepatomegaly
• Growth restriction in many (not all)
• Fasting ketosis & hypoglycemia – mild to severe
• ↑ liver transaminases
• ↑ triglycerides & cholesterol [
• Normal uric acid & lactic acid concentrations
• Exercise intolerance
• Myalgia
• Muscle cramps
• Myoglobinuria
• Progressive muscle weakness
• Serum concentration of creatine kinase > upper limits of normal in some cases
• Electromyography usually normal
## Establishing the Diagnosis
The diagnosis of PhK deficiency
Note: (1) While
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PhK deficiency is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of PhK deficiency, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
For liver PhK deficiency, perform sequence analysis of
For muscle PhK deficiency, perform sequence analysis of
In a male with a maternal family history of similarly affected males, it is appropriate to perform sequence analysis of
When the phenotype is indistinguishable from many other inherited disorders characterized by hepatomegaly and/or muscle weakness, or if an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Phosphorylase Kinase Deficiency
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Histology usually shows distended hepatocytes as a result of excess glycogen accumulation. Bridging portal fibrosis, steatosis, and low-grade inflammatory changes may also be seen [
Remarkably elevated glycogen content with normal glycogen structure is found on biochemical testing of snap-frozen liver biopsy tissue.
Normal PhK activity in erythrocytes is 1.0 μmol/min/g hemoglobin, and in liver it is 0.1 μmol/min/mg protein.
Abnormal range is <10% of normal level in the tissue being tested.
Note: (1) PhK is a labile enzyme that is highly sensitive to handling conditions and temperature exposure; thus, it is recommended that test blood samples be accompanied by a control blood sample drawn at the same time from an unrelated individual. Samples need to be kept cold (4
Excessive amounts of subsarcolemmal glycogen accumulation are found on histology.
Elevated glycogen content with normal glycogen structure is found on biochemical testing of muscle.
PhK enzyme activity is markedly reduced in muscle but normal in liver, blood cells, and fibroblasts.
Because PhK enzyme activates the enzyme glycogen phosphorylase in muscle and liver, the activity of glycogen myophosphorylase (phosphorylase-a) may be reduced in muscle in individuals with muscle PhK deficiency.
• For liver PhK deficiency, perform sequence analysis of
• For muscle PhK deficiency, perform sequence analysis of
• In a male with a maternal family history of similarly affected males, it is appropriate to perform sequence analysis of
• Histology usually shows distended hepatocytes as a result of excess glycogen accumulation. Bridging portal fibrosis, steatosis, and low-grade inflammatory changes may also be seen [
• Remarkably elevated glycogen content with normal glycogen structure is found on biochemical testing of snap-frozen liver biopsy tissue.
• Normal PhK activity in erythrocytes is 1.0 μmol/min/g hemoglobin, and in liver it is 0.1 μmol/min/mg protein.
• Abnormal range is <10% of normal level in the tissue being tested.
• Excessive amounts of subsarcolemmal glycogen accumulation are found on histology.
• Elevated glycogen content with normal glycogen structure is found on biochemical testing of muscle.
• PhK enzyme activity is markedly reduced in muscle but normal in liver, blood cells, and fibroblasts.
• Because PhK enzyme activates the enzyme glycogen phosphorylase in muscle and liver, the activity of glycogen myophosphorylase (phosphorylase-a) may be reduced in muscle in individuals with muscle PhK deficiency.
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of PhK deficiency, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
For liver PhK deficiency, perform sequence analysis of
For muscle PhK deficiency, perform sequence analysis of
In a male with a maternal family history of similarly affected males, it is appropriate to perform sequence analysis of
• For liver PhK deficiency, perform sequence analysis of
• For muscle PhK deficiency, perform sequence analysis of
• In a male with a maternal family history of similarly affected males, it is appropriate to perform sequence analysis of
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by hepatomegaly and/or muscle weakness, or if an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Phosphorylase Kinase Deficiency
AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Liver Biopsy
Histology usually shows distended hepatocytes as a result of excess glycogen accumulation. Bridging portal fibrosis, steatosis, and low-grade inflammatory changes may also be seen [
Remarkably elevated glycogen content with normal glycogen structure is found on biochemical testing of snap-frozen liver biopsy tissue.
Normal PhK activity in erythrocytes is 1.0 μmol/min/g hemoglobin, and in liver it is 0.1 μmol/min/mg protein.
Abnormal range is <10% of normal level in the tissue being tested.
Note: (1) PhK is a labile enzyme that is highly sensitive to handling conditions and temperature exposure; thus, it is recommended that test blood samples be accompanied by a control blood sample drawn at the same time from an unrelated individual. Samples need to be kept cold (4
• Histology usually shows distended hepatocytes as a result of excess glycogen accumulation. Bridging portal fibrosis, steatosis, and low-grade inflammatory changes may also be seen [
• Remarkably elevated glycogen content with normal glycogen structure is found on biochemical testing of snap-frozen liver biopsy tissue.
• Normal PhK activity in erythrocytes is 1.0 μmol/min/g hemoglobin, and in liver it is 0.1 μmol/min/mg protein.
• Abnormal range is <10% of normal level in the tissue being tested.
## Muscle Biopsy
Excessive amounts of subsarcolemmal glycogen accumulation are found on histology.
Elevated glycogen content with normal glycogen structure is found on biochemical testing of muscle.
PhK enzyme activity is markedly reduced in muscle but normal in liver, blood cells, and fibroblasts.
Because PhK enzyme activates the enzyme glycogen phosphorylase in muscle and liver, the activity of glycogen myophosphorylase (phosphorylase-a) may be reduced in muscle in individuals with muscle PhK deficiency.
• Excessive amounts of subsarcolemmal glycogen accumulation are found on histology.
• Elevated glycogen content with normal glycogen structure is found on biochemical testing of muscle.
• PhK enzyme activity is markedly reduced in muscle but normal in liver, blood cells, and fibroblasts.
• Because PhK enzyme activates the enzyme glycogen phosphorylase in muscle and liver, the activity of glycogen myophosphorylase (phosphorylase-a) may be reduced in muscle in individuals with muscle PhK deficiency.
## Clinical Characteristics
Glycogen storage disease type IX (GSD IX) is caused by PhK deficiency affecting primarily liver or muscle.
While liver PhK deficiency has been considered a mild condition, more severe involvement has been documented [
Hepatomegaly is one of the most common presentations of liver PhK deficiency. The extent of liver enlargement is variable, ranging from mild to massive [
Liver fibrosis can occur and in some instances progress to cirrhosis, especially in liver PhK deficiency caused by pathogenic variants in
Liver adenoma has been reported but appears to be very rare and mostly associated with the
Hepatomegaly usually decreases with age. Decrease in liver size and normalization of liver enzymes following treatment with cornstarch and high-protein diet is reported [
However, as affected individuals live longer and the natural history and long-term complications are better understood, it is becoming clear that individuals can progress to liver cirrhosis after a period of quiescence and what appears to be normalization.
Ketotic hypoglycemia varies from occasional to recurrent in some cases [
Chronic ketosis indicates poor metabolic control and can affect growth and overall health.
Mild delays in gross motor development are often seen in early childhood.
Cardiac manifestations are rare; however, asymptomatic interventricular septal hypertrophy was reported in an individual with
Polycystic ovaries have been noted in females with liver PhK deficiency [
Renal tubular acidosis has been reported in some individuals [
Reports of liver cirrhosis and hepatocellular carcinoma show that long-term monitoring is needed in individuals with liver PhK deficiency [
Muscle-specific phosphorylase kinase deficiency is caused by the
Minor muscle involvement has been reported in some affected individuals, particularly associated with
Interventricular septal hypertrophy has been reported in an individual with pathogenic variants in
Exercise-induced cramps, muscle pain, and fatigue [
Proximal limb-girdle weakness, especially of the pelvic girdle [
Progressive muscle weakness leading to muscular atrophy [
Rhabdomyolysis [
Asymptomatic elevation of plasma CK in some individuals
Liver involvement
Liver involvement has not been reported in GSD IX caused by pathogenic variants in
Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
Interventricular septal hypertrophy has been reported in an individual with a
One adult male with asymptomatic myopathy and cognitive impairment has been reported, suggesting wide variability in the clinical findings associated with pathogenic variants in
Pathogenic variants in
There is no consistent genotype-phenotype correlation for pathogenic variants in any of the four genes. Pathogenic variants in
Note: (1) Deficiency of the enzyme glycogen phosphorylase that causes GSD V (muscle specific) or GSD VI (liver specific) is distinct from deficiency of the enzyme PhK that causes GSD IX. However, confusion may have arisen in the past reclassification of these types of GSD: because the enzyme PhK activates the enzyme glycogen phosphorylase, PhK deficiency can also result in phosphorylase deficiency. (2) The classification GSD VIII no longer exists: in the past GSD VIII was used to describe some cases of PhK deficiency.
Liver PhK deficiency has been further subclassified into:
GSD IXa, now known as
GSD IXb, now known as
GSD IXc, now known as
Liver PhK deficiency is thought to account for about 25% of all GSDs with an estimated prevalence of 1:100,000 [
Muscle PhK deficiency appears to be rare, but could be underdiagnosed because of the milder and more variable muscle symptoms.
No populations are known to have an increased prevalence of PhK deficiency.
• Hepatomegaly is one of the most common presentations of liver PhK deficiency. The extent of liver enlargement is variable, ranging from mild to massive [
• Liver fibrosis can occur and in some instances progress to cirrhosis, especially in liver PhK deficiency caused by pathogenic variants in
• Liver adenoma has been reported but appears to be very rare and mostly associated with the
• Hepatomegaly usually decreases with age. Decrease in liver size and normalization of liver enzymes following treatment with cornstarch and high-protein diet is reported [
• However, as affected individuals live longer and the natural history and long-term complications are better understood, it is becoming clear that individuals can progress to liver cirrhosis after a period of quiescence and what appears to be normalization.
• Ketotic hypoglycemia varies from occasional to recurrent in some cases [
• Chronic ketosis indicates poor metabolic control and can affect growth and overall health.
• Mild delays in gross motor development are often seen in early childhood.
• Cardiac manifestations are rare; however, asymptomatic interventricular septal hypertrophy was reported in an individual with
• Polycystic ovaries have been noted in females with liver PhK deficiency [
• Renal tubular acidosis has been reported in some individuals [
• Minor muscle involvement has been reported in some affected individuals, particularly associated with
• Interventricular septal hypertrophy has been reported in an individual with pathogenic variants in
• Exercise-induced cramps, muscle pain, and fatigue [
• Proximal limb-girdle weakness, especially of the pelvic girdle [
• Progressive muscle weakness leading to muscular atrophy [
• Rhabdomyolysis [
• Asymptomatic elevation of plasma CK in some individuals
• Liver involvement
• Liver involvement has not been reported in GSD IX caused by pathogenic variants in
• Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
• Liver involvement has not been reported in GSD IX caused by pathogenic variants in
• Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
• Interventricular septal hypertrophy has been reported in an individual with a
• One adult male with asymptomatic myopathy and cognitive impairment has been reported, suggesting wide variability in the clinical findings associated with pathogenic variants in
• Liver involvement has not been reported in GSD IX caused by pathogenic variants in
• Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
• GSD IXa, now known as
• GSD IXb, now known as
• GSD IXc, now known as
## Clinical Description
Glycogen storage disease type IX (GSD IX) is caused by PhK deficiency affecting primarily liver or muscle.
While liver PhK deficiency has been considered a mild condition, more severe involvement has been documented [
Hepatomegaly is one of the most common presentations of liver PhK deficiency. The extent of liver enlargement is variable, ranging from mild to massive [
Liver fibrosis can occur and in some instances progress to cirrhosis, especially in liver PhK deficiency caused by pathogenic variants in
Liver adenoma has been reported but appears to be very rare and mostly associated with the
Hepatomegaly usually decreases with age. Decrease in liver size and normalization of liver enzymes following treatment with cornstarch and high-protein diet is reported [
However, as affected individuals live longer and the natural history and long-term complications are better understood, it is becoming clear that individuals can progress to liver cirrhosis after a period of quiescence and what appears to be normalization.
Ketotic hypoglycemia varies from occasional to recurrent in some cases [
Chronic ketosis indicates poor metabolic control and can affect growth and overall health.
Mild delays in gross motor development are often seen in early childhood.
Cardiac manifestations are rare; however, asymptomatic interventricular septal hypertrophy was reported in an individual with
Polycystic ovaries have been noted in females with liver PhK deficiency [
Renal tubular acidosis has been reported in some individuals [
Reports of liver cirrhosis and hepatocellular carcinoma show that long-term monitoring is needed in individuals with liver PhK deficiency [
Muscle-specific phosphorylase kinase deficiency is caused by the
Minor muscle involvement has been reported in some affected individuals, particularly associated with
Interventricular septal hypertrophy has been reported in an individual with pathogenic variants in
Exercise-induced cramps, muscle pain, and fatigue [
Proximal limb-girdle weakness, especially of the pelvic girdle [
Progressive muscle weakness leading to muscular atrophy [
Rhabdomyolysis [
Asymptomatic elevation of plasma CK in some individuals
Liver involvement
Liver involvement has not been reported in GSD IX caused by pathogenic variants in
Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
Interventricular septal hypertrophy has been reported in an individual with a
One adult male with asymptomatic myopathy and cognitive impairment has been reported, suggesting wide variability in the clinical findings associated with pathogenic variants in
• Hepatomegaly is one of the most common presentations of liver PhK deficiency. The extent of liver enlargement is variable, ranging from mild to massive [
• Liver fibrosis can occur and in some instances progress to cirrhosis, especially in liver PhK deficiency caused by pathogenic variants in
• Liver adenoma has been reported but appears to be very rare and mostly associated with the
• Hepatomegaly usually decreases with age. Decrease in liver size and normalization of liver enzymes following treatment with cornstarch and high-protein diet is reported [
• However, as affected individuals live longer and the natural history and long-term complications are better understood, it is becoming clear that individuals can progress to liver cirrhosis after a period of quiescence and what appears to be normalization.
• Ketotic hypoglycemia varies from occasional to recurrent in some cases [
• Chronic ketosis indicates poor metabolic control and can affect growth and overall health.
• Mild delays in gross motor development are often seen in early childhood.
• Cardiac manifestations are rare; however, asymptomatic interventricular septal hypertrophy was reported in an individual with
• Polycystic ovaries have been noted in females with liver PhK deficiency [
• Renal tubular acidosis has been reported in some individuals [
• Minor muscle involvement has been reported in some affected individuals, particularly associated with
• Interventricular septal hypertrophy has been reported in an individual with pathogenic variants in
• Exercise-induced cramps, muscle pain, and fatigue [
• Proximal limb-girdle weakness, especially of the pelvic girdle [
• Progressive muscle weakness leading to muscular atrophy [
• Rhabdomyolysis [
• Asymptomatic elevation of plasma CK in some individuals
• Liver involvement
• Liver involvement has not been reported in GSD IX caused by pathogenic variants in
• Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
• Liver involvement has not been reported in GSD IX caused by pathogenic variants in
• Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
• Interventricular septal hypertrophy has been reported in an individual with a
• One adult male with asymptomatic myopathy and cognitive impairment has been reported, suggesting wide variability in the clinical findings associated with pathogenic variants in
• Liver involvement has not been reported in GSD IX caused by pathogenic variants in
• Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
## Liver PhK Deficiency
While liver PhK deficiency has been considered a mild condition, more severe involvement has been documented [
Hepatomegaly is one of the most common presentations of liver PhK deficiency. The extent of liver enlargement is variable, ranging from mild to massive [
Liver fibrosis can occur and in some instances progress to cirrhosis, especially in liver PhK deficiency caused by pathogenic variants in
Liver adenoma has been reported but appears to be very rare and mostly associated with the
Hepatomegaly usually decreases with age. Decrease in liver size and normalization of liver enzymes following treatment with cornstarch and high-protein diet is reported [
However, as affected individuals live longer and the natural history and long-term complications are better understood, it is becoming clear that individuals can progress to liver cirrhosis after a period of quiescence and what appears to be normalization.
Ketotic hypoglycemia varies from occasional to recurrent in some cases [
Chronic ketosis indicates poor metabolic control and can affect growth and overall health.
Mild delays in gross motor development are often seen in early childhood.
Cardiac manifestations are rare; however, asymptomatic interventricular septal hypertrophy was reported in an individual with
Polycystic ovaries have been noted in females with liver PhK deficiency [
Renal tubular acidosis has been reported in some individuals [
Reports of liver cirrhosis and hepatocellular carcinoma show that long-term monitoring is needed in individuals with liver PhK deficiency [
• Hepatomegaly is one of the most common presentations of liver PhK deficiency. The extent of liver enlargement is variable, ranging from mild to massive [
• Liver fibrosis can occur and in some instances progress to cirrhosis, especially in liver PhK deficiency caused by pathogenic variants in
• Liver adenoma has been reported but appears to be very rare and mostly associated with the
• Hepatomegaly usually decreases with age. Decrease in liver size and normalization of liver enzymes following treatment with cornstarch and high-protein diet is reported [
• However, as affected individuals live longer and the natural history and long-term complications are better understood, it is becoming clear that individuals can progress to liver cirrhosis after a period of quiescence and what appears to be normalization.
• Ketotic hypoglycemia varies from occasional to recurrent in some cases [
• Chronic ketosis indicates poor metabolic control and can affect growth and overall health.
• Mild delays in gross motor development are often seen in early childhood.
• Cardiac manifestations are rare; however, asymptomatic interventricular septal hypertrophy was reported in an individual with
• Polycystic ovaries have been noted in females with liver PhK deficiency [
• Renal tubular acidosis has been reported in some individuals [
## Muscle PhK Deficiency
Muscle-specific phosphorylase kinase deficiency is caused by the
Minor muscle involvement has been reported in some affected individuals, particularly associated with
Interventricular septal hypertrophy has been reported in an individual with pathogenic variants in
Exercise-induced cramps, muscle pain, and fatigue [
Proximal limb-girdle weakness, especially of the pelvic girdle [
Progressive muscle weakness leading to muscular atrophy [
Rhabdomyolysis [
Asymptomatic elevation of plasma CK in some individuals
Liver involvement
Liver involvement has not been reported in GSD IX caused by pathogenic variants in
Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
Interventricular septal hypertrophy has been reported in an individual with a
One adult male with asymptomatic myopathy and cognitive impairment has been reported, suggesting wide variability in the clinical findings associated with pathogenic variants in
• Minor muscle involvement has been reported in some affected individuals, particularly associated with
• Interventricular septal hypertrophy has been reported in an individual with pathogenic variants in
• Exercise-induced cramps, muscle pain, and fatigue [
• Proximal limb-girdle weakness, especially of the pelvic girdle [
• Progressive muscle weakness leading to muscular atrophy [
• Rhabdomyolysis [
• Asymptomatic elevation of plasma CK in some individuals
• Liver involvement
• Liver involvement has not been reported in GSD IX caused by pathogenic variants in
• Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
• Liver involvement has not been reported in GSD IX caused by pathogenic variants in
• Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
• Interventricular septal hypertrophy has been reported in an individual with a
• One adult male with asymptomatic myopathy and cognitive impairment has been reported, suggesting wide variability in the clinical findings associated with pathogenic variants in
• Liver involvement has not been reported in GSD IX caused by pathogenic variants in
• Hepatomegaly and hypoglycemia are present in some individuals with pathogenic variants in
## Genotype-Phenotype Correlations
Pathogenic variants in
There is no consistent genotype-phenotype correlation for pathogenic variants in any of the four genes. Pathogenic variants in
## Nomenclature
Note: (1) Deficiency of the enzyme glycogen phosphorylase that causes GSD V (muscle specific) or GSD VI (liver specific) is distinct from deficiency of the enzyme PhK that causes GSD IX. However, confusion may have arisen in the past reclassification of these types of GSD: because the enzyme PhK activates the enzyme glycogen phosphorylase, PhK deficiency can also result in phosphorylase deficiency. (2) The classification GSD VIII no longer exists: in the past GSD VIII was used to describe some cases of PhK deficiency.
Liver PhK deficiency has been further subclassified into:
GSD IXa, now known as
GSD IXb, now known as
GSD IXc, now known as
• GSD IXa, now known as
• GSD IXb, now known as
• GSD IXc, now known as
## Prevalence
Liver PhK deficiency is thought to account for about 25% of all GSDs with an estimated prevalence of 1:100,000 [
Muscle PhK deficiency appears to be rare, but could be underdiagnosed because of the milder and more variable muscle symptoms.
No populations are known to have an increased prevalence of PhK deficiency.
## Genetically Related (Allelic) Disorders
No other phenotypes are known to be associated with pathogenic variants in
## Differential Diagnosis
Genetic Disorders to Consider in the Differential Diagnosis of Phosphorylase Kinase (PhK) Deficiency
Hepatomegaly
Hypoglycemia
Severe fasting lactic acidosis
Hyperuricemia
Significant hyperlipidemia
Neutropenia
Glucose-6-phosphatase
Glucose-6-phosphate exchanger SLC37A4
Hepatomegaly
Hyperlipidemia
Hypoglycemia & ketosis
Hepatomegaly
Liver cirrhosis
Liver dysfunction
Hypoglycemia & ketosis not typically seen
No hypoglycemia in initial stages
Accumulation of an abnormal glycogen (amylopectin) in liver & other tissues
↑ uric acid, AST, ALT
Fasting hypoglycemia & hyperlacticacidemia
Hepatomegaly
↑ AST, ALT
Hepatomegaly
Hepatomegaly
Hypoglycemia
Neurologic abnormalities
Lactic acidosis
Ataxia
Lactic acidosis
Ketoacidosis
Extremely elevated glycerol
Growth restriction
Hepatomegaly
Hyperlipidemia
Lack of fasting hypoglycemia
Significant splenomegaly
Storage cells characteristic of disease
Other features incl bone & pulmonary involvement
Lack of fasting hypoglycemia
Significant splenomegaly
Storage cells characteristic of the disease
Other features incl bone involvement
Early-onset thrombocytopenia
Hepatomegaly
Hypoglycemia
Cardiomyopathy
Peripheral neuropathy
Retinopathy
Hepatomegaly
Hypoglycemia
Splenomegaly
Rickets
Renal tubular dysfunction
Hyperphosphatemia
Exercise intolerance
Hepatomegaly
Hypoglycemia
Hypotonia
Muscle cramps
Muscle pain
Hypoketosis
Cardiomyopathy
Pericardial effusion
Cramps
Exercise intolerance
Fatigue
Muscle weakness
Myalgia
Myoglobinuria
Poor endurance
Exercise intolerance
Fatigue
Muscle cramps
Compensated hemolysis
Hyperuricemia
Hypoglycemia
Muscle weakness
Exercise intolerance
Ragged red fibers
Multisystem involvement incl: abnormal eye movements, ptosis, optic neuropathy; epilepsy; sensorineural hearing loss; lactic acidemia
↑ hepatic transaminases
Hepatomegaly
Hypoglycemia
Myalgia
Myoglobinuria
Hypoketosis
Cardiomyopathy
Arrhythmia
Cramping, particularly w/exercise
Exercise-induced myalgia
Pain
Progressive weakness
Rhabdomyolysis &/or ↑ serum CK
Hemolytic anemia
Intellectual disability
↑ rhabdomyolysis &/or ↑ serum CK
Exercise-induced myalgia
Myoglobinuria
Exercise-induced myalgia
Exercise intolerance
Fatigue
Muscle cramps
Rhabdomyolysis
AD = autosomal dominant, AR = autosomal recessive, MOI = mode of inheritance, XL = X-linked
Liver glycogen phosphorylase is activated by liver phosphorylase b kinase (PhK).
Disorders of gluconeogenesis include: fructose-1,6-bisphosphatase deficiency,
Other causes of non-genetic primary liver disease (e.g., hepatitis) can also be considered.
Other storage (metabolic) diseases can also be considered.
LCHAD may also be referred to as mitochondrial trifunctional protein deficiency.
Glycogen storage disease type V may also be referred to as McArdle disease.
Glycogen storage disease type VII may also be referred to as Tarui disease or phosphofructokinase deficiency.
See
• Hepatomegaly
• Hypoglycemia
• Severe fasting lactic acidosis
• Hyperuricemia
• Significant hyperlipidemia
• Neutropenia
• Glucose-6-phosphatase
• Glucose-6-phosphate exchanger SLC37A4
• Hepatomegaly
• Hyperlipidemia
• Hypoglycemia & ketosis
• Hepatomegaly
• Liver cirrhosis
• Liver dysfunction
• Hypoglycemia & ketosis not typically seen
• No hypoglycemia in initial stages
• Accumulation of an abnormal glycogen (amylopectin) in liver & other tissues
• ↑ uric acid, AST, ALT
• Fasting hypoglycemia & hyperlacticacidemia
• Hepatomegaly
• ↑ AST, ALT
• Hepatomegaly
• Hepatomegaly
• Hypoglycemia
• Neurologic abnormalities
• Lactic acidosis
• Ataxia
• Lactic acidosis
• Ketoacidosis
• Extremely elevated glycerol
• Growth restriction
• Hepatomegaly
• Hyperlipidemia
• Lack of fasting hypoglycemia
• Significant splenomegaly
• Storage cells characteristic of disease
• Other features incl bone & pulmonary involvement
• Lack of fasting hypoglycemia
• Significant splenomegaly
• Storage cells characteristic of the disease
• Other features incl bone involvement
• Early-onset thrombocytopenia
• Hepatomegaly
• Hypoglycemia
• Cardiomyopathy
• Peripheral neuropathy
• Retinopathy
• Hepatomegaly
• Hypoglycemia
• Splenomegaly
• Rickets
• Renal tubular dysfunction
• Hyperphosphatemia
• Exercise intolerance
• Hepatomegaly
• Hypoglycemia
• Hypotonia
• Muscle cramps
• Muscle pain
• Hypoketosis
• Cardiomyopathy
• Pericardial effusion
• Cramps
• Exercise intolerance
• Fatigue
• Muscle weakness
• Myalgia
• Myoglobinuria
• Poor endurance
• Exercise intolerance
• Fatigue
• Muscle cramps
• Compensated hemolysis
• Hyperuricemia
• Hypoglycemia
• Muscle weakness
• Exercise intolerance
• Ragged red fibers
• Multisystem involvement incl: abnormal eye movements, ptosis, optic neuropathy; epilepsy; sensorineural hearing loss; lactic acidemia
• ↑ hepatic transaminases
• Hepatomegaly
• Hypoglycemia
• Myalgia
• Myoglobinuria
• Hypoketosis
• Cardiomyopathy
• Arrhythmia
• Cramping, particularly w/exercise
• Exercise-induced myalgia
• Pain
• Progressive weakness
• Rhabdomyolysis &/or ↑ serum CK
• Hemolytic anemia
• Intellectual disability
• ↑ rhabdomyolysis &/or ↑ serum CK
• Exercise-induced myalgia
• Myoglobinuria
• Exercise-induced myalgia
• Exercise intolerance
• Fatigue
• Muscle cramps
• Rhabdomyolysis
## Management
To establish the extent of disease and needs of an individual diagnosed with
Measurement of blood glucose concentration (normal >70 mg/dL) for two to three days:
Upon waking in the morning;
Prior to meals and nighttime supplementation with oral cornstarch; and
After activity
Measurement of blood ketone levels for two to three days:
Upon waking in the morning;
Prior to meals and nighttime supplementation with oral cornstarch; and
After activity.
Elevated blood ketones (beta-hydroxybutyrate >1.0 mmol/L) could be an indicator of suboptimal metabolic control and pending hypoglycemia.
Liver imaging, if not performed in the past year. The type of liver imaging (ultrasound, MRI, or CT) is determined by factors such as age and underlying liver status (e.g., liver cirrhosis).
Basic metabolic panel including liver enzymes (AST, ALT, and alkaline phosphatase)
Prothrombin time
Lipid panel (cholesterol and triglyceride concentrations)
Serum creatine kinase measurement (Some individuals with liver PhK deficiency have muscle involvement.)
Baseline echocardiogram (Baseline echocardiogram may be done as a precaution as interventricular septal hypertrophy was found in an individual with GSD IX caused by pathogenic variants in
To establish the extent of disease and needs of an individual diagnosed with
Physical therapy evaluation
Serum creatine kinase measurement
Consultation with a clinical geneticist and/or genetic counselor is recommended for
Goal of treatment is to keep blood glucose between 70 and 100 mg/dL. The target range for blood βOHB is 0.0-0.2 mmol/L.
The dose of cornstarch can range from 0.6 to 2.5 g/kg every six hours based on clinical symptoms. A waxy maize extended-release cornstarch, Glycosade
Protein should be given as 15% to 25% of total calories, 2-3 g protein/kg body weight/day (tailored to the individual's age) as long as renal function is normal. Protein provides an alternative source of glucose via intact gluconeogenesis.
Fats should provide ~30% of total calories. Saturated fats should be restricted to <10% of total calories and cholesterol to <300 mg/day.
Overtreatment with cornstarch should be avoided as it can cause diarrhea, weight gain, and insulin resistance.
When intravenous dextrose support is required, a concentration of 10% dextrose should be used at a rate that is 1-1.25x the maintenance rate with appropriate electrolytes. The rate can be increased based on blood glucose levels. Fluids with less concentrated dextrose (i.e., 5% dextrose) could result in fluid overload at the rate required to maintain blood glucose above 70 mg/dL and prevent ketosis.
Symptomatic management of liver manifestations such as cirrhosis, liver failure, and portal hypertension is appropriate.
Signs and symptoms should be managed as with other muscle GSDs, such as
Physical therapy evaluation and intervention based on physical status and function
Coordination with a metabolic nutritionist regarding monitoring and optimizing of blood glucose concentrations based on levels of exercise and activity
Perioperative care for elective procedures should include IV dextrose infusion preoperatively, which should start as soon as the individual is made NPO with a goal of maintaining blood glucose levels >70 mg/dL and to prevent ketosis. A concentration of 10% dextrose should be used at 1.25-1.5x the maintenance rate. Using a lower concentration of dextrose such as 5% dextrose can result in fluid overload. Blood glucose and βOHB levels should be measured upon arrival and hourly. Continue with intraoperative and postoperative IV dextrose infusion to prevent hypoglycemia. IV dextrose should be tapered off gradually over two to three hours as the individual tolerates the usual diet. Abrupt discontinuation of fluids could result in hypoglycemia.
In individuals with liver fibrosis or cirrhosis, anesthetic agents with hepatic side effects should be avoided.
If general anesthesia is required,
Lipid-lowering drugs (e.g., statins) that can worsen or unmask myopathy should be used cautiously due to the risk of rhabdomyolysis.
If general anesthesia is required,
During childhood,
Regular evaluation by a
Regular monitoring of blood glucose concentration and ketones, as recommended by a metabolic physician and nutritionist. Blood glucose concentrations and ketones should also be measured during times of stress including illness, intense activity, rapid growth, puberty, and pregnancy; and at any time in which intake of food is reduced, or meal and/or cornstarch dose or scheduling is altered.
Note: It is possible that blood glucose concentrations may be normal when moderate to large ketosis in liver PhK deficiency results from increased fatty acid oxidation and upregulated gluconeogenesis. The role of ketone monitoring in this setting as a marker of metabolic control requires further systematic investigation.
Regular evaluation by a
Regular evaluation by a
Large amounts of simple sugars, as they will increase liver storage of glycogen and may result in rapid fluctuations in levels of blood glucose and insulin
Prolonged fasting
High-impact contact sports if significant (moderate to massive) hepatomegaly is present. The final decision is based on clinician judgment.
Drugs known to:
Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)
Mask symptoms of hypoglycemia, such as beta-blockers
Alcohol, as this may predispose to hypoglycemia
Glucagon, as glycogenolysis is defective
Augmentin
Growth hormone therapy unless there is proven growth hormone deficiency, as it can promote ketosis and development of liver adenomas
Hypoglycemic events in adults with liver PhK deficiency are relatively uncommon; however, caution should be used with drugs causing potential hypoglycemia, particularly in persons with impaired liver function.
Vigorous exercise
Medications that can cause rhabdomyolysis (e.g., succinylcholine)
Statins (to be used with caution, as they can cause rhabdomyolysis)
Molecular genetic testing (if the family-specific variant[s] are known) and/or evaluation by a metabolic physician during the first year of life (if the family-specific variant[s] are not known) allows for early diagnosis and treatment for sibs at increased risk for GSD IX.
See
Females with GSD IX should be evaluated for symptoms for polycystic ovary syndrome.
Ideally, females with PhK deficiency should consult with their health care team and maintain optimal metabolic control before conception.
It is extremely important that euglycemia be maintained throughout pregnancy to avoid upregulation of counter-regulatory hormones, which would result in lipolysis and ketosis, with risk of fetal demise. The appropriate diet during pregnancy is unique to each individual. For some, this may only require following a regular healthy diet, but for many it may mean increasing snacks to include more complex carbohydrates and protein and/or adding or increasing the amount of cornstarch. Blood glucose concentrations and ketones should also be measured during pregnancy on a regular basis to ensure euglycemia. Adequate amounts of protein are necessary to provide an alternate source of glucose via gluconeogenesis.
Search
• Measurement of blood glucose concentration (normal >70 mg/dL) for two to three days:
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity
• Measurement of blood ketone levels for two to three days:
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity.
• Elevated blood ketones (beta-hydroxybutyrate >1.0 mmol/L) could be an indicator of suboptimal metabolic control and pending hypoglycemia.
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity.
• Liver imaging, if not performed in the past year. The type of liver imaging (ultrasound, MRI, or CT) is determined by factors such as age and underlying liver status (e.g., liver cirrhosis).
• Basic metabolic panel including liver enzymes (AST, ALT, and alkaline phosphatase)
• Prothrombin time
• Lipid panel (cholesterol and triglyceride concentrations)
• Serum creatine kinase measurement (Some individuals with liver PhK deficiency have muscle involvement.)
• Baseline echocardiogram (Baseline echocardiogram may be done as a precaution as interventricular septal hypertrophy was found in an individual with GSD IX caused by pathogenic variants in
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity.
• Physical therapy evaluation
• Serum creatine kinase measurement
• The dose of cornstarch can range from 0.6 to 2.5 g/kg every six hours based on clinical symptoms. A waxy maize extended-release cornstarch, Glycosade
• Protein should be given as 15% to 25% of total calories, 2-3 g protein/kg body weight/day (tailored to the individual's age) as long as renal function is normal. Protein provides an alternative source of glucose via intact gluconeogenesis.
• Fats should provide ~30% of total calories. Saturated fats should be restricted to <10% of total calories and cholesterol to <300 mg/day.
• Overtreatment with cornstarch should be avoided as it can cause diarrhea, weight gain, and insulin resistance.
• Physical therapy evaluation and intervention based on physical status and function
• Coordination with a metabolic nutritionist regarding monitoring and optimizing of blood glucose concentrations based on levels of exercise and activity
• Regular evaluation by a
• Regular monitoring of blood glucose concentration and ketones, as recommended by a metabolic physician and nutritionist. Blood glucose concentrations and ketones should also be measured during times of stress including illness, intense activity, rapid growth, puberty, and pregnancy; and at any time in which intake of food is reduced, or meal and/or cornstarch dose or scheduling is altered.
• Note: It is possible that blood glucose concentrations may be normal when moderate to large ketosis in liver PhK deficiency results from increased fatty acid oxidation and upregulated gluconeogenesis. The role of ketone monitoring in this setting as a marker of metabolic control requires further systematic investigation.
• Regular evaluation by a
• Regular evaluation by a
• Large amounts of simple sugars, as they will increase liver storage of glycogen and may result in rapid fluctuations in levels of blood glucose and insulin
• Prolonged fasting
• High-impact contact sports if significant (moderate to massive) hepatomegaly is present. The final decision is based on clinician judgment.
• Drugs known to:
• Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)
• Mask symptoms of hypoglycemia, such as beta-blockers
• Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)
• Mask symptoms of hypoglycemia, such as beta-blockers
• Alcohol, as this may predispose to hypoglycemia
• Glucagon, as glycogenolysis is defective
• Augmentin
• Growth hormone therapy unless there is proven growth hormone deficiency, as it can promote ketosis and development of liver adenomas
• Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)
• Mask symptoms of hypoglycemia, such as beta-blockers
• Vigorous exercise
• Medications that can cause rhabdomyolysis (e.g., succinylcholine)
• Statins (to be used with caution, as they can cause rhabdomyolysis)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with
Measurement of blood glucose concentration (normal >70 mg/dL) for two to three days:
Upon waking in the morning;
Prior to meals and nighttime supplementation with oral cornstarch; and
After activity
Measurement of blood ketone levels for two to three days:
Upon waking in the morning;
Prior to meals and nighttime supplementation with oral cornstarch; and
After activity.
Elevated blood ketones (beta-hydroxybutyrate >1.0 mmol/L) could be an indicator of suboptimal metabolic control and pending hypoglycemia.
Liver imaging, if not performed in the past year. The type of liver imaging (ultrasound, MRI, or CT) is determined by factors such as age and underlying liver status (e.g., liver cirrhosis).
Basic metabolic panel including liver enzymes (AST, ALT, and alkaline phosphatase)
Prothrombin time
Lipid panel (cholesterol and triglyceride concentrations)
Serum creatine kinase measurement (Some individuals with liver PhK deficiency have muscle involvement.)
Baseline echocardiogram (Baseline echocardiogram may be done as a precaution as interventricular septal hypertrophy was found in an individual with GSD IX caused by pathogenic variants in
To establish the extent of disease and needs of an individual diagnosed with
Physical therapy evaluation
Serum creatine kinase measurement
Consultation with a clinical geneticist and/or genetic counselor is recommended for
• Measurement of blood glucose concentration (normal >70 mg/dL) for two to three days:
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity
• Measurement of blood ketone levels for two to three days:
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity.
• Elevated blood ketones (beta-hydroxybutyrate >1.0 mmol/L) could be an indicator of suboptimal metabolic control and pending hypoglycemia.
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity.
• Liver imaging, if not performed in the past year. The type of liver imaging (ultrasound, MRI, or CT) is determined by factors such as age and underlying liver status (e.g., liver cirrhosis).
• Basic metabolic panel including liver enzymes (AST, ALT, and alkaline phosphatase)
• Prothrombin time
• Lipid panel (cholesterol and triglyceride concentrations)
• Serum creatine kinase measurement (Some individuals with liver PhK deficiency have muscle involvement.)
• Baseline echocardiogram (Baseline echocardiogram may be done as a precaution as interventricular septal hypertrophy was found in an individual with GSD IX caused by pathogenic variants in
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity
• Upon waking in the morning;
• Prior to meals and nighttime supplementation with oral cornstarch; and
• After activity.
• Physical therapy evaluation
• Serum creatine kinase measurement
## Treatment of Manifestations
Goal of treatment is to keep blood glucose between 70 and 100 mg/dL. The target range for blood βOHB is 0.0-0.2 mmol/L.
The dose of cornstarch can range from 0.6 to 2.5 g/kg every six hours based on clinical symptoms. A waxy maize extended-release cornstarch, Glycosade
Protein should be given as 15% to 25% of total calories, 2-3 g protein/kg body weight/day (tailored to the individual's age) as long as renal function is normal. Protein provides an alternative source of glucose via intact gluconeogenesis.
Fats should provide ~30% of total calories. Saturated fats should be restricted to <10% of total calories and cholesterol to <300 mg/day.
Overtreatment with cornstarch should be avoided as it can cause diarrhea, weight gain, and insulin resistance.
When intravenous dextrose support is required, a concentration of 10% dextrose should be used at a rate that is 1-1.25x the maintenance rate with appropriate electrolytes. The rate can be increased based on blood glucose levels. Fluids with less concentrated dextrose (i.e., 5% dextrose) could result in fluid overload at the rate required to maintain blood glucose above 70 mg/dL and prevent ketosis.
Symptomatic management of liver manifestations such as cirrhosis, liver failure, and portal hypertension is appropriate.
Signs and symptoms should be managed as with other muscle GSDs, such as
Physical therapy evaluation and intervention based on physical status and function
Coordination with a metabolic nutritionist regarding monitoring and optimizing of blood glucose concentrations based on levels of exercise and activity
• The dose of cornstarch can range from 0.6 to 2.5 g/kg every six hours based on clinical symptoms. A waxy maize extended-release cornstarch, Glycosade
• Protein should be given as 15% to 25% of total calories, 2-3 g protein/kg body weight/day (tailored to the individual's age) as long as renal function is normal. Protein provides an alternative source of glucose via intact gluconeogenesis.
• Fats should provide ~30% of total calories. Saturated fats should be restricted to <10% of total calories and cholesterol to <300 mg/day.
• Overtreatment with cornstarch should be avoided as it can cause diarrhea, weight gain, and insulin resistance.
• Physical therapy evaluation and intervention based on physical status and function
• Coordination with a metabolic nutritionist regarding monitoring and optimizing of blood glucose concentrations based on levels of exercise and activity
## Liver PhK Deficiency
Goal of treatment is to keep blood glucose between 70 and 100 mg/dL. The target range for blood βOHB is 0.0-0.2 mmol/L.
The dose of cornstarch can range from 0.6 to 2.5 g/kg every six hours based on clinical symptoms. A waxy maize extended-release cornstarch, Glycosade
Protein should be given as 15% to 25% of total calories, 2-3 g protein/kg body weight/day (tailored to the individual's age) as long as renal function is normal. Protein provides an alternative source of glucose via intact gluconeogenesis.
Fats should provide ~30% of total calories. Saturated fats should be restricted to <10% of total calories and cholesterol to <300 mg/day.
Overtreatment with cornstarch should be avoided as it can cause diarrhea, weight gain, and insulin resistance.
When intravenous dextrose support is required, a concentration of 10% dextrose should be used at a rate that is 1-1.25x the maintenance rate with appropriate electrolytes. The rate can be increased based on blood glucose levels. Fluids with less concentrated dextrose (i.e., 5% dextrose) could result in fluid overload at the rate required to maintain blood glucose above 70 mg/dL and prevent ketosis.
Symptomatic management of liver manifestations such as cirrhosis, liver failure, and portal hypertension is appropriate.
• The dose of cornstarch can range from 0.6 to 2.5 g/kg every six hours based on clinical symptoms. A waxy maize extended-release cornstarch, Glycosade
• Protein should be given as 15% to 25% of total calories, 2-3 g protein/kg body weight/day (tailored to the individual's age) as long as renal function is normal. Protein provides an alternative source of glucose via intact gluconeogenesis.
• Fats should provide ~30% of total calories. Saturated fats should be restricted to <10% of total calories and cholesterol to <300 mg/day.
• Overtreatment with cornstarch should be avoided as it can cause diarrhea, weight gain, and insulin resistance.
## Muscle PhK Deficiency
Signs and symptoms should be managed as with other muscle GSDs, such as
Physical therapy evaluation and intervention based on physical status and function
Coordination with a metabolic nutritionist regarding monitoring and optimizing of blood glucose concentrations based on levels of exercise and activity
• Physical therapy evaluation and intervention based on physical status and function
• Coordination with a metabolic nutritionist regarding monitoring and optimizing of blood glucose concentrations based on levels of exercise and activity
## Prevention of Secondary Complications
Perioperative care for elective procedures should include IV dextrose infusion preoperatively, which should start as soon as the individual is made NPO with a goal of maintaining blood glucose levels >70 mg/dL and to prevent ketosis. A concentration of 10% dextrose should be used at 1.25-1.5x the maintenance rate. Using a lower concentration of dextrose such as 5% dextrose can result in fluid overload. Blood glucose and βOHB levels should be measured upon arrival and hourly. Continue with intraoperative and postoperative IV dextrose infusion to prevent hypoglycemia. IV dextrose should be tapered off gradually over two to three hours as the individual tolerates the usual diet. Abrupt discontinuation of fluids could result in hypoglycemia.
In individuals with liver fibrosis or cirrhosis, anesthetic agents with hepatic side effects should be avoided.
If general anesthesia is required,
Lipid-lowering drugs (e.g., statins) that can worsen or unmask myopathy should be used cautiously due to the risk of rhabdomyolysis.
If general anesthesia is required,
During childhood,
## Liver PhK Deficiency
Perioperative care for elective procedures should include IV dextrose infusion preoperatively, which should start as soon as the individual is made NPO with a goal of maintaining blood glucose levels >70 mg/dL and to prevent ketosis. A concentration of 10% dextrose should be used at 1.25-1.5x the maintenance rate. Using a lower concentration of dextrose such as 5% dextrose can result in fluid overload. Blood glucose and βOHB levels should be measured upon arrival and hourly. Continue with intraoperative and postoperative IV dextrose infusion to prevent hypoglycemia. IV dextrose should be tapered off gradually over two to three hours as the individual tolerates the usual diet. Abrupt discontinuation of fluids could result in hypoglycemia.
In individuals with liver fibrosis or cirrhosis, anesthetic agents with hepatic side effects should be avoided.
If general anesthesia is required,
## Muscle PhK Deficiency
Lipid-lowering drugs (e.g., statins) that can worsen or unmask myopathy should be used cautiously due to the risk of rhabdomyolysis.
If general anesthesia is required,
During childhood,
## Surveillance
Regular evaluation by a
Regular monitoring of blood glucose concentration and ketones, as recommended by a metabolic physician and nutritionist. Blood glucose concentrations and ketones should also be measured during times of stress including illness, intense activity, rapid growth, puberty, and pregnancy; and at any time in which intake of food is reduced, or meal and/or cornstarch dose or scheduling is altered.
Note: It is possible that blood glucose concentrations may be normal when moderate to large ketosis in liver PhK deficiency results from increased fatty acid oxidation and upregulated gluconeogenesis. The role of ketone monitoring in this setting as a marker of metabolic control requires further systematic investigation.
Regular evaluation by a
Regular evaluation by a
• Regular evaluation by a
• Regular monitoring of blood glucose concentration and ketones, as recommended by a metabolic physician and nutritionist. Blood glucose concentrations and ketones should also be measured during times of stress including illness, intense activity, rapid growth, puberty, and pregnancy; and at any time in which intake of food is reduced, or meal and/or cornstarch dose or scheduling is altered.
• Note: It is possible that blood glucose concentrations may be normal when moderate to large ketosis in liver PhK deficiency results from increased fatty acid oxidation and upregulated gluconeogenesis. The role of ketone monitoring in this setting as a marker of metabolic control requires further systematic investigation.
• Regular evaluation by a
• Regular evaluation by a
## Agents/Circumstances to Avoid
Large amounts of simple sugars, as they will increase liver storage of glycogen and may result in rapid fluctuations in levels of blood glucose and insulin
Prolonged fasting
High-impact contact sports if significant (moderate to massive) hepatomegaly is present. The final decision is based on clinician judgment.
Drugs known to:
Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)
Mask symptoms of hypoglycemia, such as beta-blockers
Alcohol, as this may predispose to hypoglycemia
Glucagon, as glycogenolysis is defective
Augmentin
Growth hormone therapy unless there is proven growth hormone deficiency, as it can promote ketosis and development of liver adenomas
Hypoglycemic events in adults with liver PhK deficiency are relatively uncommon; however, caution should be used with drugs causing potential hypoglycemia, particularly in persons with impaired liver function.
Vigorous exercise
Medications that can cause rhabdomyolysis (e.g., succinylcholine)
Statins (to be used with caution, as they can cause rhabdomyolysis)
• Large amounts of simple sugars, as they will increase liver storage of glycogen and may result in rapid fluctuations in levels of blood glucose and insulin
• Prolonged fasting
• High-impact contact sports if significant (moderate to massive) hepatomegaly is present. The final decision is based on clinician judgment.
• Drugs known to:
• Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)
• Mask symptoms of hypoglycemia, such as beta-blockers
• Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)
• Mask symptoms of hypoglycemia, such as beta-blockers
• Alcohol, as this may predispose to hypoglycemia
• Glucagon, as glycogenolysis is defective
• Augmentin
• Growth hormone therapy unless there is proven growth hormone deficiency, as it can promote ketosis and development of liver adenomas
• Cause hypoglycemia, such as insulin and insulin secretagogues (the sulfonylureas)
• Mask symptoms of hypoglycemia, such as beta-blockers
• Vigorous exercise
• Medications that can cause rhabdomyolysis (e.g., succinylcholine)
• Statins (to be used with caution, as they can cause rhabdomyolysis)
## Evaluation of Relatives at Risk
Molecular genetic testing (if the family-specific variant[s] are known) and/or evaluation by a metabolic physician during the first year of life (if the family-specific variant[s] are not known) allows for early diagnosis and treatment for sibs at increased risk for GSD IX.
See
## Obstetric/Gynecologic Care
Females with GSD IX should be evaluated for symptoms for polycystic ovary syndrome.
## Pregnancy Management
Ideally, females with PhK deficiency should consult with their health care team and maintain optimal metabolic control before conception.
It is extremely important that euglycemia be maintained throughout pregnancy to avoid upregulation of counter-regulatory hormones, which would result in lipolysis and ketosis, with risk of fetal demise. The appropriate diet during pregnancy is unique to each individual. For some, this may only require following a regular healthy diet, but for many it may mean increasing snacks to include more complex carbohydrates and protein and/or adding or increasing the amount of cornstarch. Blood glucose concentrations and ketones should also be measured during pregnancy on a regular basis to ensure euglycemia. Adequate amounts of protein are necessary to provide an alternate source of glucose via gluconeogenesis.
## Therapies under Investigation
Search
## Genetic Counseling
The father of an affected male will not have the disorder nor will he be hemizygous for a
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). If a woman has more than one affected child and no other affected relatives, and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), or the affected male may have a
If the mother of the proband has a
If the affected male represents a simplex case (i.e., a single occurrence in a family) and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
Note: (1) Identification of female carriers requires either (a) prior identification of the
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing PhK deficiency.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing PhK deficiency.
Enzyme-based carrier testing is not recommended for determining carrier status.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers or of being affected.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder nor will he be hemizygous for a
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). If a woman has more than one affected child and no other affected relatives, and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), or the affected male may have a
• If the mother of the proband has a
• If the affected male represents a simplex case (i.e., a single occurrence in a family) and if the
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing PhK deficiency.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing PhK deficiency.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers or of being affected.
## Mode of Inheritance
## X-Linked Inheritance – Risk To Family Members
The father of an affected male will not have the disorder nor will he be hemizygous for a
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). If a woman has more than one affected child and no other affected relatives, and if the
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), or the affected male may have a
If the mother of the proband has a
If the affected male represents a simplex case (i.e., a single occurrence in a family) and if the
Note: Molecular genetic testing may be able to identify the family member in whom a
Note: (1) Identification of female carriers requires either (a) prior identification of the
• The father of an affected male will not have the disorder nor will he be hemizygous for a
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). If a woman has more than one affected child and no other affected relatives, and if the
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), or the affected male may have a
• If the mother of the proband has a
• If the affected male represents a simplex case (i.e., a single occurrence in a family) and if the
## Autosomal Recessive Inheritance – Risk To Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing PhK deficiency.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing PhK deficiency.
Enzyme-based carrier testing is not recommended for determining carrier status.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing PhK deficiency.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing PhK deficiency.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers or of being affected.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers or of being affected.
## Prenatal Testing and Preimplantation Genetic Testing
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
Phosphorylase Kinase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Phosphorylase Kinase Deficiency (
The enzyme phosphorylase kinase (PhK) activates liver glycogen phosphorylase and muscle glycogen phosphorylase in response to neuronal and hormonal stimuli and thus is a key regulatory enzyme in glycogen breakdown. In liver PhK deficiency, the inability to break down glycogen results in risk for hypoglycemia and glycogen accumulation in the liver, which in turn causes hepatomegaly and liver damage.
PhK is a multi-subunit enzyme composed of four copies each of four subunits (α, β, γ, and δ). The gamma (γ) subunit contains the catalytic activity and is regulated by the alpha (α), beta (β), and delta (δ) subunits. The inhibitory effect of the alpha and beta subunits is modulated by phosphorylation (phosphorylation removes the inhibitory effect); calcium levels modulate the regulatory effect of the delta subunit (calmodulin).
Each PhK subunit is encoded by at least one gene:
Of these eight genes, four are known to contain pathogenic variants that cause PhK enzyme deficiency (
The two X-linked genes are:
The two autosomal genes are:
Muscle PhK activity is normal in individuals with pathogenic variants in either
A frameshift variant in mouse ortholog
Two alternatively spliced transcript variants encoding different isoforms have been identified [
The degree of phosphorylation of the alpha subunit regulates the activity of PhK; the greater the phosphorylation, the less the inhibitory effect.
Complete lack of PHKA1 protein is predicted to affect formation or stability of PhK holoenzyme. Production of an altered PHKA1 protein, resulting from missense variants, may affect its ability to interact with other subunits or to activate PhK activity.
Variants listed in the table have been provided by the authors.
XLG1, the more common form, in which in vitro PhK activity is deficient in peripheral blood cells and liver
XLG2, in which in vitro PhK activity in peripheral blood cells is normal or even elevated and activity in liver is variable
While not yet fully understood, there are various theories as to how different pathogenic variants in
Regarding correlation between genotype and biochemical phenotype,
These subtle changes may allow normal amounts of PhK to be made but affect enzyme function [
Further studies are needed to determine the molecular basis of the XLG1 and XLG2 biochemical subtypes. Of note, the same
Two processed pseudogenes have been identified:
Variants listed in the table have been provided by the authors.
• XLG1, the more common form, in which in vitro PhK activity is deficient in peripheral blood cells and liver
• XLG2, in which in vitro PhK activity in peripheral blood cells is normal or even elevated and activity in liver is variable
## Molecular Pathogenesis
The enzyme phosphorylase kinase (PhK) activates liver glycogen phosphorylase and muscle glycogen phosphorylase in response to neuronal and hormonal stimuli and thus is a key regulatory enzyme in glycogen breakdown. In liver PhK deficiency, the inability to break down glycogen results in risk for hypoglycemia and glycogen accumulation in the liver, which in turn causes hepatomegaly and liver damage.
PhK is a multi-subunit enzyme composed of four copies each of four subunits (α, β, γ, and δ). The gamma (γ) subunit contains the catalytic activity and is regulated by the alpha (α), beta (β), and delta (δ) subunits. The inhibitory effect of the alpha and beta subunits is modulated by phosphorylation (phosphorylation removes the inhibitory effect); calcium levels modulate the regulatory effect of the delta subunit (calmodulin).
Each PhK subunit is encoded by at least one gene:
Of these eight genes, four are known to contain pathogenic variants that cause PhK enzyme deficiency (
The two X-linked genes are:
The two autosomal genes are:
Muscle PhK activity is normal in individuals with pathogenic variants in either
A frameshift variant in mouse ortholog
Two alternatively spliced transcript variants encoding different isoforms have been identified [
The degree of phosphorylation of the alpha subunit regulates the activity of PhK; the greater the phosphorylation, the less the inhibitory effect.
Complete lack of PHKA1 protein is predicted to affect formation or stability of PhK holoenzyme. Production of an altered PHKA1 protein, resulting from missense variants, may affect its ability to interact with other subunits or to activate PhK activity.
Variants listed in the table have been provided by the authors.
XLG1, the more common form, in which in vitro PhK activity is deficient in peripheral blood cells and liver
XLG2, in which in vitro PhK activity in peripheral blood cells is normal or even elevated and activity in liver is variable
While not yet fully understood, there are various theories as to how different pathogenic variants in
Regarding correlation between genotype and biochemical phenotype,
These subtle changes may allow normal amounts of PhK to be made but affect enzyme function [
Further studies are needed to determine the molecular basis of the XLG1 and XLG2 biochemical subtypes. Of note, the same
Two processed pseudogenes have been identified:
Variants listed in the table have been provided by the authors.
• XLG1, the more common form, in which in vitro PhK activity is deficient in peripheral blood cells and liver
• XLG2, in which in vitro PhK activity in peripheral blood cells is normal or even elevated and activity in liver is variable
##
A frameshift variant in mouse ortholog
Two alternatively spliced transcript variants encoding different isoforms have been identified [
The degree of phosphorylation of the alpha subunit regulates the activity of PhK; the greater the phosphorylation, the less the inhibitory effect.
Complete lack of PHKA1 protein is predicted to affect formation or stability of PhK holoenzyme. Production of an altered PHKA1 protein, resulting from missense variants, may affect its ability to interact with other subunits or to activate PhK activity.
##
Variants listed in the table have been provided by the authors.
XLG1, the more common form, in which in vitro PhK activity is deficient in peripheral blood cells and liver
XLG2, in which in vitro PhK activity in peripheral blood cells is normal or even elevated and activity in liver is variable
While not yet fully understood, there are various theories as to how different pathogenic variants in
Regarding correlation between genotype and biochemical phenotype,
These subtle changes may allow normal amounts of PhK to be made but affect enzyme function [
Further studies are needed to determine the molecular basis of the XLG1 and XLG2 biochemical subtypes. Of note, the same
• XLG1, the more common form, in which in vitro PhK activity is deficient in peripheral blood cells and liver
• XLG2, in which in vitro PhK activity in peripheral blood cells is normal or even elevated and activity in liver is variable
##
Two processed pseudogenes have been identified:
Variants listed in the table have been provided by the authors.
##
## Chapter Notes
We would like to thank Dr YT Chen, Denise Petersen, and Keri Fredrickson for their useful discussions and professional contributions to increasing the understanding and knowledge of this complicated disorder.
1 November 2018 (ha) Comprehensive update posted live
31 May 2011 (me) Review posted live
7 September 2010 (db) Original submission
• 1 November 2018 (ha) Comprehensive update posted live
• 31 May 2011 (me) Review posted live
• 7 September 2010 (db) Original submission
## Acknowledgments
We would like to thank Dr YT Chen, Denise Petersen, and Keri Fredrickson for their useful discussions and professional contributions to increasing the understanding and knowledge of this complicated disorder.
## Revision History
1 November 2018 (ha) Comprehensive update posted live
31 May 2011 (me) Review posted live
7 September 2010 (db) Original submission
• 1 November 2018 (ha) Comprehensive update posted live
• 31 May 2011 (me) Review posted live
• 7 September 2010 (db) Original submission
## References
## Literature Cited
Phosphorylase kinase subunit expression
Note: The CALM genes and
Phosphorylase kinase (PhK) enzyme subunits and genes that encode them
|
[] |
31/5/2011
|
1/11/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
h1-4
|
h1-4
|
[
"Rahman Syndrome",
"Rahman Syndrome",
"Histone H1.4",
"H1-4",
"HIST1H1E Syndrome"
] |
HIST1H1E Syndrome
|
Deepika Burkardt, Katrina Tatton-Brown
|
Summary The name HIST1H1E syndrome has been proposed as a mnemonic for the characteristic features of this emerging, recognizable phenotype: The diagnosis of HIST1H1E syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in HIST1H1E syndrome is an autosomal dominant disorder typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for HIST1H1E syndrome have been published.
HIST1H1E syndrome
Generalized hypotonia of infancy
Characteristic facial features including [
In early childhood, full cheeks and a high hairline, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, and hypertelorism
In later childhood and adulthood, a notable high frontal hairline, frontal bossing, and deep-set eyes
Ectodermal abnormalities including thin and/or brittle, slow growing hair, reduced body hair, and thin nails
Abnormal dentition including crumbling teeth, dental caries, and enamel hypoplasia
Behavioral issues including anxiety disorder, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, and/or autism spectrum disorder
Cryptorchidism in males
Congenital cardiac anomalies, most frequently atrial septal defect
Hypothyroidism
Skeletal involvement including combinations of craniosynostosis, kypho/scoliosis, lower limb asymmetry, distal brachydactyly, camptodactyly, overlapping toes, and multiple fractures
The diagnosis of HIST1H1E syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of HIST1H1E syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of HIST1H1E syndrome has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in HIST1H1E Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
To date all individuals reported with the recognizable pattern of findings characteristic of HIST1H1E syndrome have had frameshift variants in the carboxy terminal domain. No affected individuals with other sequence variants or gene dosage abnormalities have been reported.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Generalized hypotonia of infancy
• Characteristic facial features including [
• In early childhood, full cheeks and a high hairline, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, and hypertelorism
• In later childhood and adulthood, a notable high frontal hairline, frontal bossing, and deep-set eyes
• In early childhood, full cheeks and a high hairline, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, and hypertelorism
• In later childhood and adulthood, a notable high frontal hairline, frontal bossing, and deep-set eyes
• Ectodermal abnormalities including thin and/or brittle, slow growing hair, reduced body hair, and thin nails
• Abnormal dentition including crumbling teeth, dental caries, and enamel hypoplasia
• Behavioral issues including anxiety disorder, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, and/or autism spectrum disorder
• Cryptorchidism in males
• Congenital cardiac anomalies, most frequently atrial septal defect
• Hypothyroidism
• Skeletal involvement including combinations of craniosynostosis, kypho/scoliosis, lower limb asymmetry, distal brachydactyly, camptodactyly, overlapping toes, and multiple fractures
• In early childhood, full cheeks and a high hairline, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, and hypertelorism
• In later childhood and adulthood, a notable high frontal hairline, frontal bossing, and deep-set eyes
• For an introduction to multigene panels click
## Suggestive Findings
HIST1H1E syndrome
Generalized hypotonia of infancy
Characteristic facial features including [
In early childhood, full cheeks and a high hairline, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, and hypertelorism
In later childhood and adulthood, a notable high frontal hairline, frontal bossing, and deep-set eyes
Ectodermal abnormalities including thin and/or brittle, slow growing hair, reduced body hair, and thin nails
Abnormal dentition including crumbling teeth, dental caries, and enamel hypoplasia
Behavioral issues including anxiety disorder, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, and/or autism spectrum disorder
Cryptorchidism in males
Congenital cardiac anomalies, most frequently atrial septal defect
Hypothyroidism
Skeletal involvement including combinations of craniosynostosis, kypho/scoliosis, lower limb asymmetry, distal brachydactyly, camptodactyly, overlapping toes, and multiple fractures
• Generalized hypotonia of infancy
• Characteristic facial features including [
• In early childhood, full cheeks and a high hairline, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, and hypertelorism
• In later childhood and adulthood, a notable high frontal hairline, frontal bossing, and deep-set eyes
• In early childhood, full cheeks and a high hairline, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, and hypertelorism
• In later childhood and adulthood, a notable high frontal hairline, frontal bossing, and deep-set eyes
• Ectodermal abnormalities including thin and/or brittle, slow growing hair, reduced body hair, and thin nails
• Abnormal dentition including crumbling teeth, dental caries, and enamel hypoplasia
• Behavioral issues including anxiety disorder, attention-deficit/hyperactivity disorder, aggression, sleep disturbances, and/or autism spectrum disorder
• Cryptorchidism in males
• Congenital cardiac anomalies, most frequently atrial septal defect
• Hypothyroidism
• Skeletal involvement including combinations of craniosynostosis, kypho/scoliosis, lower limb asymmetry, distal brachydactyly, camptodactyly, overlapping toes, and multiple fractures
• In early childhood, full cheeks and a high hairline, bitemporal narrowing, deep-set eyes, downslanting palpebral fissures, and hypertelorism
• In later childhood and adulthood, a notable high frontal hairline, frontal bossing, and deep-set eyes
## Establishing the Diagnosis
The diagnosis of HIST1H1E syndrome
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of HIST1H1E syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of HIST1H1E syndrome has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in HIST1H1E Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
To date all individuals reported with the recognizable pattern of findings characteristic of HIST1H1E syndrome have had frameshift variants in the carboxy terminal domain. No affected individuals with other sequence variants or gene dosage abnormalities have been reported.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of HIST1H1E syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of HIST1H1E syndrome has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in HIST1H1E Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
To date all individuals reported with the recognizable pattern of findings characteristic of HIST1H1E syndrome have had frameshift variants in the carboxy terminal domain. No affected individuals with other sequence variants or gene dosage abnormalities have been reported.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
HIST1H1E syndrome is characterized by intellectual disability and a distinctive facial gestalt [
To date, 47 individuals have been identified with a heterozygous pathogenic variant in
Features of HIST1H1E Syndrome
ID = intellectual disability; ADD = attention-deficit disorder; AS = autism spectrum
Mild ID typically describes an individual who had delayed milestones but attended a mainstream school with additional help, and as an adult lived independently with support (5 individuals described to date).
Moderate ID typically describes an individual who required high-level support in a mainstream school or had special educational needs schooling, and as an adult lived with support (most frequently characterized among individuals old enough for evaluation; 17 individuals described to date).
Severe ID typically describes an individual who required special educational needs schooling, had limited speech, and did not live independently as an adult (4 individuals described in the literature).
Speech was significantly delayed in most individuals, with expressive language more severely affected than receptive language skills.
Sleep issues were reported in three individuals and mostly included restlessness / difficulty staying asleep.
Advanced bone age was identified in four of 20 individuals evaluated in early childhood [
Hearing loss (both sensorineural and/or conductive) was reported in seven individuals, three of whom had recurrent otitis media.
Ophthalmologic abnormalities among those evaluated included strabismus/amblyopia (9 individuals), astigmatism (7), myopia (3), and hypermetropia (1).
Note: Given that this is an ultra-rare disorder, it is uncertain if clinical features reported in one or two individuals are true associations or incidental findings.
While the majority of pregnancies were uneventful and delivery was at term, two had complications. In one, there was ventriculomegaly with macrocephaly on ultrasound examination at 32 weeks' gestation and decreased fetal movement and fetal heart rate decelerations at 38 weeks' gestation; intubation and ventilatory support were required at birth. In the other, delivery at 34 weeks' gestation was followed by a three-week NICU stay.
Two other term neonates required postnatal NICU stays: one for four days of ventilatory support using positive end expiratory pressure; the other for hypoglycemia / feeding difficulties and jaundice [
There is no evidence currently that life expectancy is reduced in HIST1H1E syndrome. The oldest reported individual is age 49 years [
No genotype-phenotype correlations have been identified.
Data are currently insufficient to determine the penetrance of
HIST1H1E neurodevelopmental syndrome (HNDS) has been proposed as an alternative name for HIST1H1E syndrome.
HIST1H1E syndrome was only recently described; data to date are insufficient to estimate prevalence.
• Mild ID typically describes an individual who had delayed milestones but attended a mainstream school with additional help, and as an adult lived independently with support (5 individuals described to date).
• Moderate ID typically describes an individual who required high-level support in a mainstream school or had special educational needs schooling, and as an adult lived with support (most frequently characterized among individuals old enough for evaluation; 17 individuals described to date).
• Severe ID typically describes an individual who required special educational needs schooling, had limited speech, and did not live independently as an adult (4 individuals described in the literature).
## Clinical Description
HIST1H1E syndrome is characterized by intellectual disability and a distinctive facial gestalt [
To date, 47 individuals have been identified with a heterozygous pathogenic variant in
Features of HIST1H1E Syndrome
ID = intellectual disability; ADD = attention-deficit disorder; AS = autism spectrum
Mild ID typically describes an individual who had delayed milestones but attended a mainstream school with additional help, and as an adult lived independently with support (5 individuals described to date).
Moderate ID typically describes an individual who required high-level support in a mainstream school or had special educational needs schooling, and as an adult lived with support (most frequently characterized among individuals old enough for evaluation; 17 individuals described to date).
Severe ID typically describes an individual who required special educational needs schooling, had limited speech, and did not live independently as an adult (4 individuals described in the literature).
Speech was significantly delayed in most individuals, with expressive language more severely affected than receptive language skills.
Sleep issues were reported in three individuals and mostly included restlessness / difficulty staying asleep.
Advanced bone age was identified in four of 20 individuals evaluated in early childhood [
Hearing loss (both sensorineural and/or conductive) was reported in seven individuals, three of whom had recurrent otitis media.
Ophthalmologic abnormalities among those evaluated included strabismus/amblyopia (9 individuals), astigmatism (7), myopia (3), and hypermetropia (1).
Note: Given that this is an ultra-rare disorder, it is uncertain if clinical features reported in one or two individuals are true associations or incidental findings.
While the majority of pregnancies were uneventful and delivery was at term, two had complications. In one, there was ventriculomegaly with macrocephaly on ultrasound examination at 32 weeks' gestation and decreased fetal movement and fetal heart rate decelerations at 38 weeks' gestation; intubation and ventilatory support were required at birth. In the other, delivery at 34 weeks' gestation was followed by a three-week NICU stay.
Two other term neonates required postnatal NICU stays: one for four days of ventilatory support using positive end expiratory pressure; the other for hypoglycemia / feeding difficulties and jaundice [
There is no evidence currently that life expectancy is reduced in HIST1H1E syndrome. The oldest reported individual is age 49 years [
• Mild ID typically describes an individual who had delayed milestones but attended a mainstream school with additional help, and as an adult lived independently with support (5 individuals described to date).
• Moderate ID typically describes an individual who required high-level support in a mainstream school or had special educational needs schooling, and as an adult lived with support (most frequently characterized among individuals old enough for evaluation; 17 individuals described to date).
• Severe ID typically describes an individual who required special educational needs schooling, had limited speech, and did not live independently as an adult (4 individuals described in the literature).
## Phenotypic Features
Mild ID typically describes an individual who had delayed milestones but attended a mainstream school with additional help, and as an adult lived independently with support (5 individuals described to date).
Moderate ID typically describes an individual who required high-level support in a mainstream school or had special educational needs schooling, and as an adult lived with support (most frequently characterized among individuals old enough for evaluation; 17 individuals described to date).
Severe ID typically describes an individual who required special educational needs schooling, had limited speech, and did not live independently as an adult (4 individuals described in the literature).
Speech was significantly delayed in most individuals, with expressive language more severely affected than receptive language skills.
Sleep issues were reported in three individuals and mostly included restlessness / difficulty staying asleep.
Advanced bone age was identified in four of 20 individuals evaluated in early childhood [
• Mild ID typically describes an individual who had delayed milestones but attended a mainstream school with additional help, and as an adult lived independently with support (5 individuals described to date).
• Moderate ID typically describes an individual who required high-level support in a mainstream school or had special educational needs schooling, and as an adult lived with support (most frequently characterized among individuals old enough for evaluation; 17 individuals described to date).
• Severe ID typically describes an individual who required special educational needs schooling, had limited speech, and did not live independently as an adult (4 individuals described in the literature).
## Other
Hearing loss (both sensorineural and/or conductive) was reported in seven individuals, three of whom had recurrent otitis media.
Ophthalmologic abnormalities among those evaluated included strabismus/amblyopia (9 individuals), astigmatism (7), myopia (3), and hypermetropia (1).
Note: Given that this is an ultra-rare disorder, it is uncertain if clinical features reported in one or two individuals are true associations or incidental findings.
## Gestational/Neonatal Course
While the majority of pregnancies were uneventful and delivery was at term, two had complications. In one, there was ventriculomegaly with macrocephaly on ultrasound examination at 32 weeks' gestation and decreased fetal movement and fetal heart rate decelerations at 38 weeks' gestation; intubation and ventilatory support were required at birth. In the other, delivery at 34 weeks' gestation was followed by a three-week NICU stay.
Two other term neonates required postnatal NICU stays: one for four days of ventilatory support using positive end expiratory pressure; the other for hypoglycemia / feeding difficulties and jaundice [
## Prognosis
There is no evidence currently that life expectancy is reduced in HIST1H1E syndrome. The oldest reported individual is age 49 years [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Data are currently insufficient to determine the penetrance of
## Nomenclature
HIST1H1E neurodevelopmental syndrome (HNDS) has been proposed as an alternative name for HIST1H1E syndrome.
## Prevalence
HIST1H1E syndrome was only recently described; data to date are insufficient to estimate prevalence.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
All disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis of HIST1H1E syndrome. See
While it has previously been suggested that HIST1H1E syndrome belongs to the family of overgrowth-intellectual disability syndromes [
## Management
No clinical practice guidelines for HIST1H1E syndrome have been published.
To establish the extent of disease and needs in an individual diagnosed with HIST1H1E syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with HIST1H1E Syndrome
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
EEG if seizures are a concern
Consider brain MRI if there are focal neurologic findings.
Community or
Social work involvement for parental support.
3D = 3-dimensional; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Following initial evaluation, treatment is symptomatic.
Management by multidisciplinary specialists is recommended, including (but not limited to) developmental pediatrics / behavioral psychology, neurosurgery/neurology, urology, cardiology, endocrinology, ophthalmology, orthopedics, and dentistry.
Treatment of Manifestations in Individuals with HIST1H1E Syndrome
Treatment of fractures by orthopedist w/expertise in disorders w/low bone density
Avoidance of activities that ↑ risk of fracture
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Consider evaluation for alternative means of communication (e.g.,
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with HIST1H1E Syndrome
Monitor those w/seizures as clinically indicated.
Assess for new manifestations (e.g., seizures, changes in tone).
Assessment of head shape in infants & young children
Physical examination for presence &/or progression of scoliosis
Enquire about signs &/or symptoms of bony fractures.
TSH = thyroid-stimulating hormone
See
Search
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• EEG if seizures are a concern
• Consider brain MRI if there are focal neurologic findings.
• Community or
• Social work involvement for parental support.
• Treatment of fractures by orthopedist w/expertise in disorders w/low bone density
• Avoidance of activities that ↑ risk of fracture
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations (e.g., seizures, changes in tone).
• Assessment of head shape in infants & young children
• Physical examination for presence &/or progression of scoliosis
• Enquire about signs &/or symptoms of bony fractures.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with HIST1H1E syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with HIST1H1E Syndrome
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
EEG if seizures are a concern
Consider brain MRI if there are focal neurologic findings.
Community or
Social work involvement for parental support.
3D = 3-dimensional; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• EEG if seizures are a concern
• Consider brain MRI if there are focal neurologic findings.
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Following initial evaluation, treatment is symptomatic.
Management by multidisciplinary specialists is recommended, including (but not limited to) developmental pediatrics / behavioral psychology, neurosurgery/neurology, urology, cardiology, endocrinology, ophthalmology, orthopedics, and dentistry.
Treatment of Manifestations in Individuals with HIST1H1E Syndrome
Treatment of fractures by orthopedist w/expertise in disorders w/low bone density
Avoidance of activities that ↑ risk of fracture
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Consider evaluation for alternative means of communication (e.g.,
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Treatment of fractures by orthopedist w/expertise in disorders w/low bone density
• Avoidance of activities that ↑ risk of fracture
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Communication Issues
Consider evaluation for alternative means of communication (e.g.,
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with HIST1H1E Syndrome
Monitor those w/seizures as clinically indicated.
Assess for new manifestations (e.g., seizures, changes in tone).
Assessment of head shape in infants & young children
Physical examination for presence &/or progression of scoliosis
Enquire about signs &/or symptoms of bony fractures.
TSH = thyroid-stimulating hormone
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations (e.g., seizures, changes in tone).
• Assessment of head shape in infants & young children
• Physical examination for presence &/or progression of scoliosis
• Enquire about signs &/or symptoms of bony fractures.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
HIST1H1E syndrome is an autosomal dominant disorder typically caused by a
All probands reported to date with HIST1H1E syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
Theoretically, if the parent is the individual in whom the
If a parent of the proband has the
If the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• All probands reported to date with HIST1H1E syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• Theoretically, if the parent is the individual in whom the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband has the
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
HIST1H1E syndrome is an autosomal dominant disorder typically caused by a
## Risk to Family Members
All probands reported to date with HIST1H1E syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
Theoretically, if the parent is the individual in whom the
If a parent of the proband has the
If the
• All probands reported to date with HIST1H1E syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• Theoretically, if the parent is the individual in whom the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• If a parent of the proband has the
• If the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
HIST1H1E Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for HIST1H1E Syndrome (
Moreover, methylome analysis in individuals with
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Moreover, methylome analysis in individuals with
Notable
Variants listed in the table have been provided by the authors.
## Cancer and Benign Tumors
## Chapter Notes
The authors would like to acknowledge the patients with HIST1H1E syndrome and their families who have taught us a lot about this syndrome and the clinician collaborator teams of physicians, genetic counsellors, nurses, therapists and allied professionals, and trainees who have generously cared for these patients and supported efforts to gather information to clarify features and optimize care for these patients and families.
15 December 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis,
3 December 2020 (bp) Review posted live
19 March 2020 (ktb) Original submission
• 15 December 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis,
• 3 December 2020 (bp) Review posted live
• 19 March 2020 (ktb) Original submission
## Author Notes
## Acknowledgments
The authors would like to acknowledge the patients with HIST1H1E syndrome and their families who have taught us a lot about this syndrome and the clinician collaborator teams of physicians, genetic counsellors, nurses, therapists and allied professionals, and trainees who have generously cared for these patients and supported efforts to gather information to clarify features and optimize care for these patients and families.
## Revision History
15 December 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis,
3 December 2020 (bp) Review posted live
19 March 2020 (ktb) Original submission
• 15 December 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis,
• 3 December 2020 (bp) Review posted live
• 19 March 2020 (ktb) Original submission
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"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"T Takenouchi, T Uehara, K Kosaki, S. Mizuno. Growth pattern of Rahman syndrome.. Am J Med Genet A. 2018;176:712-4",
"K Tatton-Brown, C Loveday, S Yost, M Clarke, E Ramsay, A Zachariou, A Elliott, H Wylie, A Ardissone, O Rittinger, F Stewart, IK Temple, T Cole. Mahamdallie S, Seal S, Ruark E, Rahman N. Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability.. Am J Hum Genet. 2017;100:725-36",
"K Tatton-Brown, S Seal, E Ruark, J Harmer, E Ramsay, S Del Vecchio Duarte, A Zachariou, S Hanks, E O'Brien, L Aksglaede, D Baralle, T Dabir, B Gener, D Goudie, T Homfray, A Kumar, DT Pilz, A Selicorni, IK Temple, L Van Maldergem, N Yachelevich, R van Montfort, N Rahman. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.. Nat Genet. 2014;46:385-8",
"BA Walker, EM Boyle, CP Wardell, A Murison, DB Begum, NM Dahir, PZ Proszek, DC Johnson, MF Kaiser, L Melchor, LI Aronson, M Scales, C Pawlyn, F Mirabella, JR Jones, A Brioli, A Mikulasova, DA Cairns, WM Gregory, A Quartilho, MT Drayson, N Russell, G Cook, GH Jackson, X Leleu, FE Davies, GJ Morgan. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma.. J Clin Oncol. 2015;33:3911-20"
] |
3/12/2020
|
15/12/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
haplo-a20
|
haplo-a20
|
[
"HA20",
"HA20",
"Tumor necrosis factor alpha-induced protein 3",
"TNFAIP3",
"Haploinsufficiency of A20"
] |
Haploinsufficiency of A20
|
Natalie T Deuitch, Daniella M Schwartz, Ivona Aksentijevich
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Summary Haploinsufficiency of A20 (HA20), a complex immune dysregulation disease, is characterized by recurrent systemic immune dysfunction (i.e., inflammation and/or immune deficiency). The most common manifestations and their frequency include: (1) recurrent painful oral/genital ulcers, typically during disease flares (>70% of persons); (2) recurrent fevers (~50%), typically lasting for three to seven days that can rarely progress to a cytokine storm and/or hemophagocytic lymphohistiocytosis; (3) skin involvement (~40%), including pustular rashes, folliculitis, vasculitic purpura, urticaria, lupus-like macular rashes, and eczematoid dermatitis; (4) gastrointestinal disease (~40%), ranging from dull abdominal pain (due to serositis, ulcers, or bowel inflammation) to severe inflammation with risk of bowel perforation; and (5) arthralgia/arthritis (~34%), typically relapsing and/or remitting nonerosive inflammatory polyarthritis with synovitis, and rarely resembling rheumatoid arthritis or psoriatic-like erosions. Other less common but significant findings include lymphoproliferation, most often lymphadenopathy; liver involvement, including severe hepatitis that if untreated can progress to cirrhosis and liver failure; neurologic disease including central nervous system vasculitis/vasculopathy (manifesting as severe headaches and cognitive changes) and in some individuals transient ischemic attacks. Other findings include aseptic meningitis, mononeuritis multiplex, chronic inflammatory demyelinating polyradiculoneuropathy, and/or peripheral neuropathy. HA20 demonstrates both variable expressivity (i.e., different systems may be involved simultaneously and/or over time in an affected individual) and intrafamilial variability (i.e., variability in clinical presentation among affected individuals within the same immediate or extended family). The diagnosis of HA20 is established in an individual by identification of either a heterozygous HA20 is inherited in an autosomal dominant manner. Many individuals diagnosed with HA20 have an affected parent; some individuals have the disorder as the result of a
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## Diagnosis
No consensus diagnostic criteria for haploinsufficiency of A20 (HA20) have been published.
HA20
Mean age of onset is 7 years (range: 1st week of life to age 39 years) [
Note: Because of variable expressivity, manifestations during early childhood may not have been reported to a health care professional due to their mildness and minimal effect on quality of life, or due to social barriers (i.e., genital ulcers).
Relapsing/remitting disease course characterized by unprovoked episodes of acute or chronic immune dysregulation
Episodic fever
Recurrent painful ulcers/abscesses, including oral (~68%), genital (~37%), perianal, cutaneous, and gastrointestinal (~39%; sometimes diagnosed as Crohn disease or inflammatory bowel disease-related arthritis, can lead to bowel obstruction)
Arthralgia/polyarthritis, including polyarticular juvenile idiopathic arthritis and erosive arthritis (~34%)
Cutaneous lesions, including folliculitis-like rashes, acne, and dermal abscesses, psoriasis, erythema nodosum, and immunoglobulin A vasculitis (Henoch-Schonlein purpura) (~42%)
Lymphadenopathy (25%-30%)
Autoimmune cytopenias (~20%)
Chronic hepatic involvement, including hepatitis, hepatomegaly, and/or liver fibrosis (15%)
Autoimmune thyroiditis (~14%)
Neurologic involvement, including chronic inflammatory demyelinating polyradiculoneuropathy, neuropathy, and central nervous system vasculitis (~12%)
Vasculopathy, including vasculitis, coronary vasculitis, or arterial aneurysms (~11%)
Ocular inflammation, including severe treatment-resistant anterior uveitis, retinal vasculitis with chorioretinal scarring, and macular fibrosis (~9%)
Recurrent upper respiratory infections and/or lower respiratory infections (~9%)
Diabetes mellitus type 1 (~4%)
Autoimmune lymphoproliferative syndrome (1%)
Cardiac involvement, including pericardial effusion and/or pericarditis
Pulmonary nodules, pleuritis, and/or interstitial lung disease
Lupus nephritis and/or nephrotic syndrome
Secondary hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome
Pernicious anemia
Hypogammaglobulinemia
Common variable immunodeficiency
Elevated acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, serum ferritin concentration), especially during flares
Note: These may be normal in individuals with findings that are more like an autoimmune disease and less like an autoinflammatory disease.
Fluctuating or sustained presence of various autoantibodies (e.g., rheumatoid factor, antinuclear antibodies, antiphospholipid antibodies, antithyroid antibodies, and antiplatelet antibodies); sometimes high titers
Abnormal (reduced or elevated) leukocyte, neutrophil, or lymphocyte counts
Reduced hemoglobin and/or platelet counts (especially during flares)
Total immunoglobulins (IgG, IgM, IgA) can be elevated or reduced
Reduced responses (i.e., antibody titers) to diphtheria and tetanus vaccinations
Elevated transaminases (AST, ALT), especially during relapses
Elevated fecal calprotectin
Proteinuria or positive urine sediment (i.e., red blood cell / white blood cell casts)
The diagnosis of HA20
A heterozygous
A heterozygous deletion of 6q23 including
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to CMA click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Haploinsufficiency of A20
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Based on
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
To date, a few deletions/duplications have been reported in individuals with haploinsufficiency of A20 [
•
• Mean age of onset is 7 years (range: 1st week of life to age 39 years) [
• Note: Because of variable expressivity, manifestations during early childhood may not have been reported to a health care professional due to their mildness and minimal effect on quality of life, or due to social barriers (i.e., genital ulcers).
• Relapsing/remitting disease course characterized by unprovoked episodes of acute or chronic immune dysregulation
• Mean age of onset is 7 years (range: 1st week of life to age 39 years) [
• Note: Because of variable expressivity, manifestations during early childhood may not have been reported to a health care professional due to their mildness and minimal effect on quality of life, or due to social barriers (i.e., genital ulcers).
• Relapsing/remitting disease course characterized by unprovoked episodes of acute or chronic immune dysregulation
• Episodic fever
• Recurrent painful ulcers/abscesses, including oral (~68%), genital (~37%), perianal, cutaneous, and gastrointestinal (~39%; sometimes diagnosed as Crohn disease or inflammatory bowel disease-related arthritis, can lead to bowel obstruction)
• Arthralgia/polyarthritis, including polyarticular juvenile idiopathic arthritis and erosive arthritis (~34%)
• Cutaneous lesions, including folliculitis-like rashes, acne, and dermal abscesses, psoriasis, erythema nodosum, and immunoglobulin A vasculitis (Henoch-Schonlein purpura) (~42%)
• Lymphadenopathy (25%-30%)
• Autoimmune cytopenias (~20%)
• Episodic fever
• Recurrent painful ulcers/abscesses, including oral (~68%), genital (~37%), perianal, cutaneous, and gastrointestinal (~39%; sometimes diagnosed as Crohn disease or inflammatory bowel disease-related arthritis, can lead to bowel obstruction)
• Arthralgia/polyarthritis, including polyarticular juvenile idiopathic arthritis and erosive arthritis (~34%)
• Cutaneous lesions, including folliculitis-like rashes, acne, and dermal abscesses, psoriasis, erythema nodosum, and immunoglobulin A vasculitis (Henoch-Schonlein purpura) (~42%)
• Lymphadenopathy (25%-30%)
• Autoimmune cytopenias (~20%)
• Chronic hepatic involvement, including hepatitis, hepatomegaly, and/or liver fibrosis (15%)
• Autoimmune thyroiditis (~14%)
• Neurologic involvement, including chronic inflammatory demyelinating polyradiculoneuropathy, neuropathy, and central nervous system vasculitis (~12%)
• Vasculopathy, including vasculitis, coronary vasculitis, or arterial aneurysms (~11%)
• Ocular inflammation, including severe treatment-resistant anterior uveitis, retinal vasculitis with chorioretinal scarring, and macular fibrosis (~9%)
• Recurrent upper respiratory infections and/or lower respiratory infections (~9%)
• Diabetes mellitus type 1 (~4%)
• Autoimmune lymphoproliferative syndrome (1%)
• Cardiac involvement, including pericardial effusion and/or pericarditis
• Pulmonary nodules, pleuritis, and/or interstitial lung disease
• Lupus nephritis and/or nephrotic syndrome
• Secondary hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome
• Pernicious anemia
• Hypogammaglobulinemia
• Common variable immunodeficiency
• Chronic hepatic involvement, including hepatitis, hepatomegaly, and/or liver fibrosis (15%)
• Autoimmune thyroiditis (~14%)
• Neurologic involvement, including chronic inflammatory demyelinating polyradiculoneuropathy, neuropathy, and central nervous system vasculitis (~12%)
• Vasculopathy, including vasculitis, coronary vasculitis, or arterial aneurysms (~11%)
• Ocular inflammation, including severe treatment-resistant anterior uveitis, retinal vasculitis with chorioretinal scarring, and macular fibrosis (~9%)
• Recurrent upper respiratory infections and/or lower respiratory infections (~9%)
• Diabetes mellitus type 1 (~4%)
• Autoimmune lymphoproliferative syndrome (1%)
• Cardiac involvement, including pericardial effusion and/or pericarditis
• Pulmonary nodules, pleuritis, and/or interstitial lung disease
• Lupus nephritis and/or nephrotic syndrome
• Secondary hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome
• Pernicious anemia
• Hypogammaglobulinemia
• Common variable immunodeficiency
• Mean age of onset is 7 years (range: 1st week of life to age 39 years) [
• Note: Because of variable expressivity, manifestations during early childhood may not have been reported to a health care professional due to their mildness and minimal effect on quality of life, or due to social barriers (i.e., genital ulcers).
• Relapsing/remitting disease course characterized by unprovoked episodes of acute or chronic immune dysregulation
• Episodic fever
• Recurrent painful ulcers/abscesses, including oral (~68%), genital (~37%), perianal, cutaneous, and gastrointestinal (~39%; sometimes diagnosed as Crohn disease or inflammatory bowel disease-related arthritis, can lead to bowel obstruction)
• Arthralgia/polyarthritis, including polyarticular juvenile idiopathic arthritis and erosive arthritis (~34%)
• Cutaneous lesions, including folliculitis-like rashes, acne, and dermal abscesses, psoriasis, erythema nodosum, and immunoglobulin A vasculitis (Henoch-Schonlein purpura) (~42%)
• Lymphadenopathy (25%-30%)
• Autoimmune cytopenias (~20%)
• Chronic hepatic involvement, including hepatitis, hepatomegaly, and/or liver fibrosis (15%)
• Autoimmune thyroiditis (~14%)
• Neurologic involvement, including chronic inflammatory demyelinating polyradiculoneuropathy, neuropathy, and central nervous system vasculitis (~12%)
• Vasculopathy, including vasculitis, coronary vasculitis, or arterial aneurysms (~11%)
• Ocular inflammation, including severe treatment-resistant anterior uveitis, retinal vasculitis with chorioretinal scarring, and macular fibrosis (~9%)
• Recurrent upper respiratory infections and/or lower respiratory infections (~9%)
• Diabetes mellitus type 1 (~4%)
• Autoimmune lymphoproliferative syndrome (1%)
• Cardiac involvement, including pericardial effusion and/or pericarditis
• Pulmonary nodules, pleuritis, and/or interstitial lung disease
• Lupus nephritis and/or nephrotic syndrome
• Secondary hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome
• Pernicious anemia
• Hypogammaglobulinemia
• Common variable immunodeficiency
• Elevated acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, serum ferritin concentration), especially during flares
• Note: These may be normal in individuals with findings that are more like an autoimmune disease and less like an autoinflammatory disease.
• Fluctuating or sustained presence of various autoantibodies (e.g., rheumatoid factor, antinuclear antibodies, antiphospholipid antibodies, antithyroid antibodies, and antiplatelet antibodies); sometimes high titers
• Abnormal (reduced or elevated) leukocyte, neutrophil, or lymphocyte counts
• Reduced hemoglobin and/or platelet counts (especially during flares)
• Total immunoglobulins (IgG, IgM, IgA) can be elevated or reduced
• Reduced responses (i.e., antibody titers) to diphtheria and tetanus vaccinations
• Elevated transaminases (AST, ALT), especially during relapses
• Elevated fecal calprotectin
• Proteinuria or positive urine sediment (i.e., red blood cell / white blood cell casts)
• A heterozygous
• A heterozygous deletion of 6q23 including
• For an introduction to multigene panels click
• For an introduction to CMA click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
HA20
Mean age of onset is 7 years (range: 1st week of life to age 39 years) [
Note: Because of variable expressivity, manifestations during early childhood may not have been reported to a health care professional due to their mildness and minimal effect on quality of life, or due to social barriers (i.e., genital ulcers).
Relapsing/remitting disease course characterized by unprovoked episodes of acute or chronic immune dysregulation
Episodic fever
Recurrent painful ulcers/abscesses, including oral (~68%), genital (~37%), perianal, cutaneous, and gastrointestinal (~39%; sometimes diagnosed as Crohn disease or inflammatory bowel disease-related arthritis, can lead to bowel obstruction)
Arthralgia/polyarthritis, including polyarticular juvenile idiopathic arthritis and erosive arthritis (~34%)
Cutaneous lesions, including folliculitis-like rashes, acne, and dermal abscesses, psoriasis, erythema nodosum, and immunoglobulin A vasculitis (Henoch-Schonlein purpura) (~42%)
Lymphadenopathy (25%-30%)
Autoimmune cytopenias (~20%)
Chronic hepatic involvement, including hepatitis, hepatomegaly, and/or liver fibrosis (15%)
Autoimmune thyroiditis (~14%)
Neurologic involvement, including chronic inflammatory demyelinating polyradiculoneuropathy, neuropathy, and central nervous system vasculitis (~12%)
Vasculopathy, including vasculitis, coronary vasculitis, or arterial aneurysms (~11%)
Ocular inflammation, including severe treatment-resistant anterior uveitis, retinal vasculitis with chorioretinal scarring, and macular fibrosis (~9%)
Recurrent upper respiratory infections and/or lower respiratory infections (~9%)
Diabetes mellitus type 1 (~4%)
Autoimmune lymphoproliferative syndrome (1%)
Cardiac involvement, including pericardial effusion and/or pericarditis
Pulmonary nodules, pleuritis, and/or interstitial lung disease
Lupus nephritis and/or nephrotic syndrome
Secondary hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome
Pernicious anemia
Hypogammaglobulinemia
Common variable immunodeficiency
Elevated acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, serum ferritin concentration), especially during flares
Note: These may be normal in individuals with findings that are more like an autoimmune disease and less like an autoinflammatory disease.
Fluctuating or sustained presence of various autoantibodies (e.g., rheumatoid factor, antinuclear antibodies, antiphospholipid antibodies, antithyroid antibodies, and antiplatelet antibodies); sometimes high titers
Abnormal (reduced or elevated) leukocyte, neutrophil, or lymphocyte counts
Reduced hemoglobin and/or platelet counts (especially during flares)
Total immunoglobulins (IgG, IgM, IgA) can be elevated or reduced
Reduced responses (i.e., antibody titers) to diphtheria and tetanus vaccinations
Elevated transaminases (AST, ALT), especially during relapses
Elevated fecal calprotectin
Proteinuria or positive urine sediment (i.e., red blood cell / white blood cell casts)
•
• Mean age of onset is 7 years (range: 1st week of life to age 39 years) [
• Note: Because of variable expressivity, manifestations during early childhood may not have been reported to a health care professional due to their mildness and minimal effect on quality of life, or due to social barriers (i.e., genital ulcers).
• Relapsing/remitting disease course characterized by unprovoked episodes of acute or chronic immune dysregulation
• Mean age of onset is 7 years (range: 1st week of life to age 39 years) [
• Note: Because of variable expressivity, manifestations during early childhood may not have been reported to a health care professional due to their mildness and minimal effect on quality of life, or due to social barriers (i.e., genital ulcers).
• Relapsing/remitting disease course characterized by unprovoked episodes of acute or chronic immune dysregulation
• Episodic fever
• Recurrent painful ulcers/abscesses, including oral (~68%), genital (~37%), perianal, cutaneous, and gastrointestinal (~39%; sometimes diagnosed as Crohn disease or inflammatory bowel disease-related arthritis, can lead to bowel obstruction)
• Arthralgia/polyarthritis, including polyarticular juvenile idiopathic arthritis and erosive arthritis (~34%)
• Cutaneous lesions, including folliculitis-like rashes, acne, and dermal abscesses, psoriasis, erythema nodosum, and immunoglobulin A vasculitis (Henoch-Schonlein purpura) (~42%)
• Lymphadenopathy (25%-30%)
• Autoimmune cytopenias (~20%)
• Episodic fever
• Recurrent painful ulcers/abscesses, including oral (~68%), genital (~37%), perianal, cutaneous, and gastrointestinal (~39%; sometimes diagnosed as Crohn disease or inflammatory bowel disease-related arthritis, can lead to bowel obstruction)
• Arthralgia/polyarthritis, including polyarticular juvenile idiopathic arthritis and erosive arthritis (~34%)
• Cutaneous lesions, including folliculitis-like rashes, acne, and dermal abscesses, psoriasis, erythema nodosum, and immunoglobulin A vasculitis (Henoch-Schonlein purpura) (~42%)
• Lymphadenopathy (25%-30%)
• Autoimmune cytopenias (~20%)
• Chronic hepatic involvement, including hepatitis, hepatomegaly, and/or liver fibrosis (15%)
• Autoimmune thyroiditis (~14%)
• Neurologic involvement, including chronic inflammatory demyelinating polyradiculoneuropathy, neuropathy, and central nervous system vasculitis (~12%)
• Vasculopathy, including vasculitis, coronary vasculitis, or arterial aneurysms (~11%)
• Ocular inflammation, including severe treatment-resistant anterior uveitis, retinal vasculitis with chorioretinal scarring, and macular fibrosis (~9%)
• Recurrent upper respiratory infections and/or lower respiratory infections (~9%)
• Diabetes mellitus type 1 (~4%)
• Autoimmune lymphoproliferative syndrome (1%)
• Cardiac involvement, including pericardial effusion and/or pericarditis
• Pulmonary nodules, pleuritis, and/or interstitial lung disease
• Lupus nephritis and/or nephrotic syndrome
• Secondary hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome
• Pernicious anemia
• Hypogammaglobulinemia
• Common variable immunodeficiency
• Chronic hepatic involvement, including hepatitis, hepatomegaly, and/or liver fibrosis (15%)
• Autoimmune thyroiditis (~14%)
• Neurologic involvement, including chronic inflammatory demyelinating polyradiculoneuropathy, neuropathy, and central nervous system vasculitis (~12%)
• Vasculopathy, including vasculitis, coronary vasculitis, or arterial aneurysms (~11%)
• Ocular inflammation, including severe treatment-resistant anterior uveitis, retinal vasculitis with chorioretinal scarring, and macular fibrosis (~9%)
• Recurrent upper respiratory infections and/or lower respiratory infections (~9%)
• Diabetes mellitus type 1 (~4%)
• Autoimmune lymphoproliferative syndrome (1%)
• Cardiac involvement, including pericardial effusion and/or pericarditis
• Pulmonary nodules, pleuritis, and/or interstitial lung disease
• Lupus nephritis and/or nephrotic syndrome
• Secondary hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome
• Pernicious anemia
• Hypogammaglobulinemia
• Common variable immunodeficiency
• Mean age of onset is 7 years (range: 1st week of life to age 39 years) [
• Note: Because of variable expressivity, manifestations during early childhood may not have been reported to a health care professional due to their mildness and minimal effect on quality of life, or due to social barriers (i.e., genital ulcers).
• Relapsing/remitting disease course characterized by unprovoked episodes of acute or chronic immune dysregulation
• Episodic fever
• Recurrent painful ulcers/abscesses, including oral (~68%), genital (~37%), perianal, cutaneous, and gastrointestinal (~39%; sometimes diagnosed as Crohn disease or inflammatory bowel disease-related arthritis, can lead to bowel obstruction)
• Arthralgia/polyarthritis, including polyarticular juvenile idiopathic arthritis and erosive arthritis (~34%)
• Cutaneous lesions, including folliculitis-like rashes, acne, and dermal abscesses, psoriasis, erythema nodosum, and immunoglobulin A vasculitis (Henoch-Schonlein purpura) (~42%)
• Lymphadenopathy (25%-30%)
• Autoimmune cytopenias (~20%)
• Chronic hepatic involvement, including hepatitis, hepatomegaly, and/or liver fibrosis (15%)
• Autoimmune thyroiditis (~14%)
• Neurologic involvement, including chronic inflammatory demyelinating polyradiculoneuropathy, neuropathy, and central nervous system vasculitis (~12%)
• Vasculopathy, including vasculitis, coronary vasculitis, or arterial aneurysms (~11%)
• Ocular inflammation, including severe treatment-resistant anterior uveitis, retinal vasculitis with chorioretinal scarring, and macular fibrosis (~9%)
• Recurrent upper respiratory infections and/or lower respiratory infections (~9%)
• Diabetes mellitus type 1 (~4%)
• Autoimmune lymphoproliferative syndrome (1%)
• Cardiac involvement, including pericardial effusion and/or pericarditis
• Pulmonary nodules, pleuritis, and/or interstitial lung disease
• Lupus nephritis and/or nephrotic syndrome
• Secondary hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome
• Pernicious anemia
• Hypogammaglobulinemia
• Common variable immunodeficiency
• Elevated acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase, serum ferritin concentration), especially during flares
• Note: These may be normal in individuals with findings that are more like an autoimmune disease and less like an autoinflammatory disease.
• Fluctuating or sustained presence of various autoantibodies (e.g., rheumatoid factor, antinuclear antibodies, antiphospholipid antibodies, antithyroid antibodies, and antiplatelet antibodies); sometimes high titers
• Abnormal (reduced or elevated) leukocyte, neutrophil, or lymphocyte counts
• Reduced hemoglobin and/or platelet counts (especially during flares)
• Total immunoglobulins (IgG, IgM, IgA) can be elevated or reduced
• Reduced responses (i.e., antibody titers) to diphtheria and tetanus vaccinations
• Elevated transaminases (AST, ALT), especially during relapses
• Elevated fecal calprotectin
• Proteinuria or positive urine sediment (i.e., red blood cell / white blood cell casts)
## Establishing the Diagnosis
The diagnosis of HA20
A heterozygous
A heterozygous deletion of 6q23 including
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to CMA click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Haploinsufficiency of A20
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Based on
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
To date, a few deletions/duplications have been reported in individuals with haploinsufficiency of A20 [
• A heterozygous
• A heterozygous deletion of 6q23 including
• For an introduction to multigene panels click
• For an introduction to CMA click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Haploinsufficiency of A20 (HA20), a complex immune dysregulation disease, is characterized by recurrent systemic immune dysfunction (inflammation and/or immune deficiency). HA20 demonstrates both variable expressivity (i.e., in an affected individual, different systems may be involved simultaneously and/or over time) and intrafamilial variability (i.e., variability in clinical presentation among affected individuals within the same immediate or extended family).
To date, more than 180 individuals from 97 families have been identified with HA20 [
Haploinsufficiency of A20: Frequency of Select Rheumatologic Features
Adapted with permission from
No genotype-phenotype correlations have been identified. While it appears that
Most individuals with pathogenic variants in
Because HA20 can mimic Behçet disease, it was originally identified as a monogenic Behçet disease (see
To date ~200 individuals with HA20 have been reported; however, prevalence is unknown.
•
## Clinical Description
Haploinsufficiency of A20 (HA20), a complex immune dysregulation disease, is characterized by recurrent systemic immune dysfunction (inflammation and/or immune deficiency). HA20 demonstrates both variable expressivity (i.e., in an affected individual, different systems may be involved simultaneously and/or over time) and intrafamilial variability (i.e., variability in clinical presentation among affected individuals within the same immediate or extended family).
To date, more than 180 individuals from 97 families have been identified with HA20 [
Haploinsufficiency of A20: Frequency of Select Rheumatologic Features
Adapted with permission from
•
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified. While it appears that
## Penetrance
Most individuals with pathogenic variants in
## Nomenclature
Because HA20 can mimic Behçet disease, it was originally identified as a monogenic Behçet disease (see
## Prevalence
To date ~200 individuals with HA20 have been reported; however, prevalence is unknown.
## Genetically Related (Allelic) Disorders
No monogenic conditions other than those discussed in this
## Differential Diagnosis
Monogenic Disorders of Interest in the Differential Diagnosis of Haploinsufficiency of A20
AD = autosomal dominant; AR = autosomal recessive; CRP = C-reactive protein; HA20 = haploinsufficiency of A20; MOI = mode of inheritance; XL = X-linked
Behçet disease
Systemic lupus erythematosus
Juvenile idiopathic arthritis
Aphthous stomatitis, pharyngitis, and adenitis
Inflammatory bowel disease
• Behçet disease
• Systemic lupus erythematosus
• Juvenile idiopathic arthritis
• Aphthous stomatitis, pharyngitis, and adenitis
• Inflammatory bowel disease
## Management
No clinical practice guidelines for haploinsufficiency of A20 (HA20) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with HA20 and similar disorders.
To establish the extent of disease and needs in an individual diagnosed with HA20 (i.e., an individual with either a
Haploinsufficiency of A20: Recommended Evaluations Following Initial Diagnosis
Quantitative blood immunoglobulins (IgG, IgA, IgM)
Vaccine-specific responses (tetanus, diphtheria)
T/B/NK cell counts
To assess for rashes
Consider dermatology consultation for mgmt.
Referral to gastroenterologist for endoscopy, enteroscopy, &/or colonoscopy
Can consider imaging (CT, ultrasound, MR enterography)
When cytopenias are detected on CBC, perform bone marrow biopsy.
Assess for hemolysis, reticulocyte count.
Measure antiplatelet antibodies.
Thyroid function tests
Assess for diabetes: obtain fasting blood glucose concentration & consider oral glucose tolerance test or hemoglobin A1c.
Possible CNS involvement: consider MRI w/MRA & MRV (noninvasive angiography) or DSA (direct angiography) if CNS vasculitis is suspected.
Possible aseptic meningitis: lumbar puncture w/cell counts / protein / glucose concentration & bacterial/viral cultures
Possible peripheral nerve involvement: consider referral to neurologist for EMG &/or nerve biopsy if mononeuritis or vasculitic neuropathy is suspected.
Consider referral to neurologist.
Diagnosis of vasculitic neuropathy requires treatment w/escalating immunomodulators to prevent permanent nerve damage.
Community or
Social work involvement for parental support
Home nursing referral
ALT = alanine transaminase; ANA = antinuclear antibodies; ANCA = antineutrophil cytoplasmic antibodies; AST = aspartate transaminase; CBC = complete blood count; CCP = cyclic citrullinated peptide; CNS = central nervous system; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor; SAA = serum amyloid A
There is no cure for HA20. In addition to use of a variety of biologic agents under the care of a rheumatologist, other supportive treatments can improve quality of life, maximize function, and reduce complications.
In addition, interleukin-1 (IL-1) therapy and Janus kinase (JAK) inhibitors are effective in many individuals.
Corticosteroids, colchicine, methotrexate, azathioprine, thalidomide, mycophenolate, phosphodiesterase-4 inhibitors, and calcineurin inhibitors may also be useful. For more information on these medications from the American College of Rheumatology, see
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.
Rheumatologic features (see
A low threshold for evaluation of subclinical inflammation by relevant subspecialists should be maintained:
Gastroenterologist for inflammatory bowel disease-like symptoms
Neurologist for aseptic meningitis
Ophthalmologist for symptoms of ocular inflammation
Endocrinologist for symptoms of thyroid disease, diabetes mellitus type 1
Nephrologist for manifestations of nephritis
Hematologist for manifestations of hematologic features
Neurologist for chronic inflammatory demyelinating polyradiculoneuropathy / encephalitis
Immunologist for immunodeficiency
Cardiologist for coronary vasculitis
Note: Because many individuals with HA20 may not be able to tolerate prolonged cessation of continuous biologic therapy, risks/benefits should be considered before receiving any live vaccinations.
See
Maternal medications should be discussed with a health care provider ideally prior to conception or as soon as a pregnancy has been recognized.
Information regarding adverse outcomes due to the use of TNF inhibitors in human pregnancy is limited; to date, no pattern of birth anomalies with any of the TNF inhibitor medications has been reported. Per the American College of Rheumatology guidelines [
Information regarding the safety of the use of IL-1 inhibitors in human pregnancy is limited; to date, no pattern of birth anomalies in humans have been reported with IL-1 or IL-1R inhibitor medication classes. These medications are often continued during pregnancy; it is recommended that clinicians discuss risks and benefits with affected individuals.
Colchicine, azathioprine, and hydroxychloroquine are generally continued during pregnancy; however, it is recommended that clinicians discuss risks and benefits with affected individuals.
Mycophenolate, methotrexate, and thalidomide are all known human teratogens and should be avoided during pregnancy. Less information is available for JAK inhibitors, although these are generally also avoided during pregnancy due to concerns about potential embryo disruption in animal models.
The use of corticosteroids during human pregnancy has been associated with an increased risk of cleft lip with or without cleft palate and growth restriction in exposed fetuses; however, the risks and benefits of treatment should be weighed carefully, as uncontrolled inflammation may also have risks [
See
Search
• Quantitative blood immunoglobulins (IgG, IgA, IgM)
• Vaccine-specific responses (tetanus, diphtheria)
• T/B/NK cell counts
• To assess for rashes
• Consider dermatology consultation for mgmt.
• Referral to gastroenterologist for endoscopy, enteroscopy, &/or colonoscopy
• Can consider imaging (CT, ultrasound, MR enterography)
• When cytopenias are detected on CBC, perform bone marrow biopsy.
• Assess for hemolysis, reticulocyte count.
• Measure antiplatelet antibodies.
• Thyroid function tests
• Assess for diabetes: obtain fasting blood glucose concentration & consider oral glucose tolerance test or hemoglobin A1c.
• Possible CNS involvement: consider MRI w/MRA & MRV (noninvasive angiography) or DSA (direct angiography) if CNS vasculitis is suspected.
• Possible aseptic meningitis: lumbar puncture w/cell counts / protein / glucose concentration & bacterial/viral cultures
• Possible peripheral nerve involvement: consider referral to neurologist for EMG &/or nerve biopsy if mononeuritis or vasculitic neuropathy is suspected.
• Consider referral to neurologist.
• Diagnosis of vasculitic neuropathy requires treatment w/escalating immunomodulators to prevent permanent nerve damage.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Rheumatologic features (see
• A low threshold for evaluation of subclinical inflammation by relevant subspecialists should be maintained:
• Gastroenterologist for inflammatory bowel disease-like symptoms
• Neurologist for aseptic meningitis
• Ophthalmologist for symptoms of ocular inflammation
• Endocrinologist for symptoms of thyroid disease, diabetes mellitus type 1
• Nephrologist for manifestations of nephritis
• Hematologist for manifestations of hematologic features
• Neurologist for chronic inflammatory demyelinating polyradiculoneuropathy / encephalitis
• Immunologist for immunodeficiency
• Cardiologist for coronary vasculitis
• Gastroenterologist for inflammatory bowel disease-like symptoms
• Neurologist for aseptic meningitis
• Ophthalmologist for symptoms of ocular inflammation
• Endocrinologist for symptoms of thyroid disease, diabetes mellitus type 1
• Nephrologist for manifestations of nephritis
• Hematologist for manifestations of hematologic features
• Neurologist for chronic inflammatory demyelinating polyradiculoneuropathy / encephalitis
• Immunologist for immunodeficiency
• Cardiologist for coronary vasculitis
• Gastroenterologist for inflammatory bowel disease-like symptoms
• Neurologist for aseptic meningitis
• Ophthalmologist for symptoms of ocular inflammation
• Endocrinologist for symptoms of thyroid disease, diabetes mellitus type 1
• Nephrologist for manifestations of nephritis
• Hematologist for manifestations of hematologic features
• Neurologist for chronic inflammatory demyelinating polyradiculoneuropathy / encephalitis
• Immunologist for immunodeficiency
• Cardiologist for coronary vasculitis
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with HA20 (i.e., an individual with either a
Haploinsufficiency of A20: Recommended Evaluations Following Initial Diagnosis
Quantitative blood immunoglobulins (IgG, IgA, IgM)
Vaccine-specific responses (tetanus, diphtheria)
T/B/NK cell counts
To assess for rashes
Consider dermatology consultation for mgmt.
Referral to gastroenterologist for endoscopy, enteroscopy, &/or colonoscopy
Can consider imaging (CT, ultrasound, MR enterography)
When cytopenias are detected on CBC, perform bone marrow biopsy.
Assess for hemolysis, reticulocyte count.
Measure antiplatelet antibodies.
Thyroid function tests
Assess for diabetes: obtain fasting blood glucose concentration & consider oral glucose tolerance test or hemoglobin A1c.
Possible CNS involvement: consider MRI w/MRA & MRV (noninvasive angiography) or DSA (direct angiography) if CNS vasculitis is suspected.
Possible aseptic meningitis: lumbar puncture w/cell counts / protein / glucose concentration & bacterial/viral cultures
Possible peripheral nerve involvement: consider referral to neurologist for EMG &/or nerve biopsy if mononeuritis or vasculitic neuropathy is suspected.
Consider referral to neurologist.
Diagnosis of vasculitic neuropathy requires treatment w/escalating immunomodulators to prevent permanent nerve damage.
Community or
Social work involvement for parental support
Home nursing referral
ALT = alanine transaminase; ANA = antinuclear antibodies; ANCA = antineutrophil cytoplasmic antibodies; AST = aspartate transaminase; CBC = complete blood count; CCP = cyclic citrullinated peptide; CNS = central nervous system; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor; SAA = serum amyloid A
• Quantitative blood immunoglobulins (IgG, IgA, IgM)
• Vaccine-specific responses (tetanus, diphtheria)
• T/B/NK cell counts
• To assess for rashes
• Consider dermatology consultation for mgmt.
• Referral to gastroenterologist for endoscopy, enteroscopy, &/or colonoscopy
• Can consider imaging (CT, ultrasound, MR enterography)
• When cytopenias are detected on CBC, perform bone marrow biopsy.
• Assess for hemolysis, reticulocyte count.
• Measure antiplatelet antibodies.
• Thyroid function tests
• Assess for diabetes: obtain fasting blood glucose concentration & consider oral glucose tolerance test or hemoglobin A1c.
• Possible CNS involvement: consider MRI w/MRA & MRV (noninvasive angiography) or DSA (direct angiography) if CNS vasculitis is suspected.
• Possible aseptic meningitis: lumbar puncture w/cell counts / protein / glucose concentration & bacterial/viral cultures
• Possible peripheral nerve involvement: consider referral to neurologist for EMG &/or nerve biopsy if mononeuritis or vasculitic neuropathy is suspected.
• Consider referral to neurologist.
• Diagnosis of vasculitic neuropathy requires treatment w/escalating immunomodulators to prevent permanent nerve damage.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for HA20. In addition to use of a variety of biologic agents under the care of a rheumatologist, other supportive treatments can improve quality of life, maximize function, and reduce complications.
In addition, interleukin-1 (IL-1) therapy and Janus kinase (JAK) inhibitors are effective in many individuals.
Corticosteroids, colchicine, methotrexate, azathioprine, thalidomide, mycophenolate, phosphodiesterase-4 inhibitors, and calcineurin inhibitors may also be useful. For more information on these medications from the American College of Rheumatology, see
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.
Rheumatologic features (see
A low threshold for evaluation of subclinical inflammation by relevant subspecialists should be maintained:
Gastroenterologist for inflammatory bowel disease-like symptoms
Neurologist for aseptic meningitis
Ophthalmologist for symptoms of ocular inflammation
Endocrinologist for symptoms of thyroid disease, diabetes mellitus type 1
Nephrologist for manifestations of nephritis
Hematologist for manifestations of hematologic features
Neurologist for chronic inflammatory demyelinating polyradiculoneuropathy / encephalitis
Immunologist for immunodeficiency
Cardiologist for coronary vasculitis
• Rheumatologic features (see
• A low threshold for evaluation of subclinical inflammation by relevant subspecialists should be maintained:
• Gastroenterologist for inflammatory bowel disease-like symptoms
• Neurologist for aseptic meningitis
• Ophthalmologist for symptoms of ocular inflammation
• Endocrinologist for symptoms of thyroid disease, diabetes mellitus type 1
• Nephrologist for manifestations of nephritis
• Hematologist for manifestations of hematologic features
• Neurologist for chronic inflammatory demyelinating polyradiculoneuropathy / encephalitis
• Immunologist for immunodeficiency
• Cardiologist for coronary vasculitis
• Gastroenterologist for inflammatory bowel disease-like symptoms
• Neurologist for aseptic meningitis
• Ophthalmologist for symptoms of ocular inflammation
• Endocrinologist for symptoms of thyroid disease, diabetes mellitus type 1
• Nephrologist for manifestations of nephritis
• Hematologist for manifestations of hematologic features
• Neurologist for chronic inflammatory demyelinating polyradiculoneuropathy / encephalitis
• Immunologist for immunodeficiency
• Cardiologist for coronary vasculitis
• Gastroenterologist for inflammatory bowel disease-like symptoms
• Neurologist for aseptic meningitis
• Ophthalmologist for symptoms of ocular inflammation
• Endocrinologist for symptoms of thyroid disease, diabetes mellitus type 1
• Nephrologist for manifestations of nephritis
• Hematologist for manifestations of hematologic features
• Neurologist for chronic inflammatory demyelinating polyradiculoneuropathy / encephalitis
• Immunologist for immunodeficiency
• Cardiologist for coronary vasculitis
## Agents/Circumstances to Avoid
Note: Because many individuals with HA20 may not be able to tolerate prolonged cessation of continuous biologic therapy, risks/benefits should be considered before receiving any live vaccinations.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Maternal medications should be discussed with a health care provider ideally prior to conception or as soon as a pregnancy has been recognized.
Information regarding adverse outcomes due to the use of TNF inhibitors in human pregnancy is limited; to date, no pattern of birth anomalies with any of the TNF inhibitor medications has been reported. Per the American College of Rheumatology guidelines [
Information regarding the safety of the use of IL-1 inhibitors in human pregnancy is limited; to date, no pattern of birth anomalies in humans have been reported with IL-1 or IL-1R inhibitor medication classes. These medications are often continued during pregnancy; it is recommended that clinicians discuss risks and benefits with affected individuals.
Colchicine, azathioprine, and hydroxychloroquine are generally continued during pregnancy; however, it is recommended that clinicians discuss risks and benefits with affected individuals.
Mycophenolate, methotrexate, and thalidomide are all known human teratogens and should be avoided during pregnancy. Less information is available for JAK inhibitors, although these are generally also avoided during pregnancy due to concerns about potential embryo disruption in animal models.
The use of corticosteroids during human pregnancy has been associated with an increased risk of cleft lip with or without cleft palate and growth restriction in exposed fetuses; however, the risks and benefits of treatment should be weighed carefully, as uncontrolled inflammation may also have risks [
See
## Therapies Under Investigation
Search
## Genetic Counseling
Haploinsufficiency of A20 (HA20) is inherited in an autosomal dominant manner.
Many individuals diagnosed with HA20 have an affected parent.
Some individuals diagnosed with HA20 have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, intrafamilial variability, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and gonadal mosaicism for a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial variability is considerable among family members who have the same
If the
If the parents have not been tested for the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Many individuals diagnosed with HA20 have an affected parent.
• Some individuals diagnosed with HA20 have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, intrafamilial variability, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial variability is considerable among family members who have the same
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Haploinsufficiency of A20 (HA20) is inherited in an autosomal dominant manner.
## Risk to Family Members
Many individuals diagnosed with HA20 have an affected parent.
Some individuals diagnosed with HA20 have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, intrafamilial variability, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
* A parent with somatic and gonadal mosaicism for a
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial variability is considerable among family members who have the same
If the
If the parents have not been tested for the
• Many individuals diagnosed with HA20 have an affected parent.
• Some individuals diagnosed with HA20 have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, intrafamilial variability, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• * A parent with somatic and gonadal mosaicism for a
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Intrafamilial variability is considerable among family members who have the same
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Italy
•
•
•
•
•
•
•
•
• Italy
•
## Molecular Genetics
Haploinsufficiency of A20: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Haploinsufficiency of A20 (
Although a few missense variants have been described, their segregation in families is not clear, leading to speculation that they may be associated with milder disease.
Missense variants should be evaluated with functional assays to confirm pathogenicity [
## Molecular Pathogenesis
Although a few missense variants have been described, their segregation in families is not clear, leading to speculation that they may be associated with milder disease.
Missense variants should be evaluated with functional assays to confirm pathogenicity [
## Chapter Notes
Daniella M Schwartz (
Natalie Deuitch (
Contact any of the authors to inquire about review of
We would like to thank the patients and their families for helping us to better understand this condition.
19 December 2024 (bp) Review posted live
8 April 2024 (nd) Original submission
• 19 December 2024 (bp) Review posted live
• 8 April 2024 (nd) Original submission
## Author Notes
Daniella M Schwartz (
Natalie Deuitch (
Contact any of the authors to inquire about review of
## Acknowledgments
We would like to thank the patients and their families for helping us to better understand this condition.
## Revision History
19 December 2024 (bp) Review posted live
8 April 2024 (nd) Original submission
• 19 December 2024 (bp) Review posted live
• 8 April 2024 (nd) Original submission
## References
## Literature Cited
|
[] |
19/12/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
hartsfield
|
hartsfield
|
[
"Fibroblast growth factor receptor 1",
"FGFR1",
"FGFR1-Related Hartsfield Syndrome"
] |
Radhika Dhamija, Dusica Babovic-Vuksanovic
|
Summary HPE spectrum disorder, resulting from failed or incomplete forebrain division early in gestation, includes alobar, semilobar, or lobar HPE. Other observed midline brain malformations include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Other findings associated with the HPE spectrum such as craniofacial dysmorphism, neurologic issues (developmental delay, spasticity, seizures, hypothalamic dysfunction), feeding problems, and endocrine issues (hypogonadotropic hypogonadism and central insipidus diabetes) are common. Ectrodactyly spectrum disorders are unilateral or bilateral malformations of the hands and/or feet characterized by a median cleft of hand or foot due to absence of the longitudinal central rays (also called split-hand/foot malformation). The number of digits on the right and left can vary. Polydactyly and syndactyly can also be seen. The diagnosis of Once the
|
## Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Suggestive Findings
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
To date, 35 individuals with
Microcephaly; hypotelorism or hypertelorism; eye anomalies such as microphthalmia and coloboma; malformed, low-set, and posteriorly rotated ears; and cleft lip and or palate (median or bilateral) are common.
Craniosynostosis (metopic and coronal) has been reported [
Varying degrees of developmental delay can occur.
Spasticity is common.
Seizures are common and may be difficult to control.
Hypothalamic dysfunction, manifesting as temperature dysregulation and erratic sleep patterns, can occur.
Compared with four individuals with a heterozygous
Alobar holoprosencephaly (1/2)
Diminished cortical thickening (2/2)
Absent corpus callosum (2/2)
Median cleft (1/2)
Hypotelorism (2/2)
Severe developmental delay and growth restriction (2/2)
In the older literature,
Holoprosencephaly and split-hand/foot syndrome;
Holoprosencephaly, hypertelorism, and ectrodactyly syndrome (HHES).
No genotype-phenotype correlations have been identified.
Biallelic pathogenic variants in
Thirty-five individuals with
• Microcephaly; hypotelorism or hypertelorism; eye anomalies such as microphthalmia and coloboma; malformed, low-set, and posteriorly rotated ears; and cleft lip and or palate (median or bilateral) are common.
• Craniosynostosis (metopic and coronal) has been reported [
• Varying degrees of developmental delay can occur.
• Spasticity is common.
• Seizures are common and may be difficult to control.
• Hypothalamic dysfunction, manifesting as temperature dysregulation and erratic sleep patterns, can occur.
•
• Alobar holoprosencephaly (1/2)
• Diminished cortical thickening (2/2)
• Absent corpus callosum (2/2)
• Median cleft (1/2)
• Hypotelorism (2/2)
• Severe developmental delay and growth restriction (2/2)
• Alobar holoprosencephaly (1/2)
• Diminished cortical thickening (2/2)
• Absent corpus callosum (2/2)
• Median cleft (1/2)
• Hypotelorism (2/2)
• Severe developmental delay and growth restriction (2/2)
• Alobar holoprosencephaly (1/2)
• Diminished cortical thickening (2/2)
• Absent corpus callosum (2/2)
• Median cleft (1/2)
• Hypotelorism (2/2)
• Severe developmental delay and growth restriction (2/2)
• Holoprosencephaly and split-hand/foot syndrome;
• Holoprosencephaly, hypertelorism, and ectrodactyly syndrome (HHES).
## Clinical Description
To date, 35 individuals with
Microcephaly; hypotelorism or hypertelorism; eye anomalies such as microphthalmia and coloboma; malformed, low-set, and posteriorly rotated ears; and cleft lip and or palate (median or bilateral) are common.
Craniosynostosis (metopic and coronal) has been reported [
Varying degrees of developmental delay can occur.
Spasticity is common.
Seizures are common and may be difficult to control.
Hypothalamic dysfunction, manifesting as temperature dysregulation and erratic sleep patterns, can occur.
Compared with four individuals with a heterozygous
Alobar holoprosencephaly (1/2)
Diminished cortical thickening (2/2)
Absent corpus callosum (2/2)
Median cleft (1/2)
Hypotelorism (2/2)
Severe developmental delay and growth restriction (2/2)
• Microcephaly; hypotelorism or hypertelorism; eye anomalies such as microphthalmia and coloboma; malformed, low-set, and posteriorly rotated ears; and cleft lip and or palate (median or bilateral) are common.
• Craniosynostosis (metopic and coronal) has been reported [
• Varying degrees of developmental delay can occur.
• Spasticity is common.
• Seizures are common and may be difficult to control.
• Hypothalamic dysfunction, manifesting as temperature dysregulation and erratic sleep patterns, can occur.
•
• Alobar holoprosencephaly (1/2)
• Diminished cortical thickening (2/2)
• Absent corpus callosum (2/2)
• Median cleft (1/2)
• Hypotelorism (2/2)
• Severe developmental delay and growth restriction (2/2)
• Alobar holoprosencephaly (1/2)
• Diminished cortical thickening (2/2)
• Absent corpus callosum (2/2)
• Median cleft (1/2)
• Hypotelorism (2/2)
• Severe developmental delay and growth restriction (2/2)
• Alobar holoprosencephaly (1/2)
• Diminished cortical thickening (2/2)
• Absent corpus callosum (2/2)
• Median cleft (1/2)
• Hypotelorism (2/2)
• Severe developmental delay and growth restriction (2/2)
## Phenotype of Autosomal Recessive
Compared with four individuals with a heterozygous
Alobar holoprosencephaly (1/2)
Diminished cortical thickening (2/2)
Absent corpus callosum (2/2)
Median cleft (1/2)
Hypotelorism (2/2)
Severe developmental delay and growth restriction (2/2)
•
• Alobar holoprosencephaly (1/2)
• Diminished cortical thickening (2/2)
• Absent corpus callosum (2/2)
• Median cleft (1/2)
• Hypotelorism (2/2)
• Severe developmental delay and growth restriction (2/2)
• Alobar holoprosencephaly (1/2)
• Diminished cortical thickening (2/2)
• Absent corpus callosum (2/2)
• Median cleft (1/2)
• Hypotelorism (2/2)
• Severe developmental delay and growth restriction (2/2)
• Alobar holoprosencephaly (1/2)
• Diminished cortical thickening (2/2)
• Absent corpus callosum (2/2)
• Median cleft (1/2)
• Hypotelorism (2/2)
• Severe developmental delay and growth restriction (2/2)
## Nomenclature
In the older literature,
Holoprosencephaly and split-hand/foot syndrome;
Holoprosencephaly, hypertelorism, and ectrodactyly syndrome (HHES).
• Holoprosencephaly and split-hand/foot syndrome;
• Holoprosencephaly, hypertelorism, and ectrodactyly syndrome (HHES).
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Biallelic pathogenic variants in
## Prevalence
Thirty-five individuals with
## Genetically Related (Allelic) Disorders
Germline pathogenic variants in
Mosaic activating pathogenic variants in
## Differential Diagnosis
Limb anomalies in 68%-90% of individuals, with 60% having tetramelic involvement. A cohort of 152 individuals with EEC3 showed split-hand/foot malformation in 68% and syndactyly in 43%.
Ectodermal defects. Skin tends to be dry but erosions are not present. Hair changes become more obvious with age and are seen in 60%-80% of individuals. Hair is typically silvery blond, coarse, and dry. Eyebrows and eyelashes are sparse. Nail dysplasia is common. Dental anomalies include malformed teeth and hypodontia.
Cleft lip with or without cleft palate, present in 60%-75% and bilateral in half of cases. Clefting can include submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, or the combination of cleft lip and cleft palate.
Absent lacrimal puncta (90% of individuals)
Genitourinary malformations (45% of individuals)
• Limb anomalies in 68%-90% of individuals, with 60% having tetramelic involvement. A cohort of 152 individuals with EEC3 showed split-hand/foot malformation in 68% and syndactyly in 43%.
• Ectodermal defects. Skin tends to be dry but erosions are not present. Hair changes become more obvious with age and are seen in 60%-80% of individuals. Hair is typically silvery blond, coarse, and dry. Eyebrows and eyelashes are sparse. Nail dysplasia is common. Dental anomalies include malformed teeth and hypodontia.
• Cleft lip with or without cleft palate, present in 60%-75% and bilateral in half of cases. Clefting can include submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, or the combination of cleft lip and cleft palate.
• Absent lacrimal puncta (90% of individuals)
• Genitourinary malformations (45% of individuals)
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Consider EEG if seizures are a concern.
Eval for evidence of central diabetes insipidus, temperature dysregulation, &/or disturbance of sleep-wake cycles
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Extent of ectrodactyly
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with
Central diabetes insipidus may require treatment w/desmopressin.
Temperature dysregulation can be managed by modifying environment.
Manage disturbance of sleep-wake cycles w/good sleep hygiene & (if needed) use of melatonin or other sleep aids such as clonidine.
Medically refractory epilepsy typically requires multiple ASMs.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
PT, OT, & bracing
Muscle relaxants may be used to treat moderate or severe spasticity.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
OT, PT, & adaptive devices
Surgery may be needed to improve dexterity.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
OT = occupational therapy; PT = physical therapy
See
Search
• Consider EEG if seizures are a concern.
• Eval for evidence of central diabetes insipidus, temperature dysregulation, &/or disturbance of sleep-wake cycles
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Extent of ectrodactyly
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Central diabetes insipidus may require treatment w/desmopressin.
• Temperature dysregulation can be managed by modifying environment.
• Manage disturbance of sleep-wake cycles w/good sleep hygiene & (if needed) use of melatonin or other sleep aids such as clonidine.
• Medically refractory epilepsy typically requires multiple ASMs.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• PT, OT, & bracing
• Muscle relaxants may be used to treat moderate or severe spasticity.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• OT, PT, & adaptive devices
• Surgery may be needed to improve dexterity.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Consider EEG if seizures are a concern.
Eval for evidence of central diabetes insipidus, temperature dysregulation, &/or disturbance of sleep-wake cycles
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Extent of ectrodactyly
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Consider EEG if seizures are a concern.
• Eval for evidence of central diabetes insipidus, temperature dysregulation, &/or disturbance of sleep-wake cycles
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Extent of ectrodactyly
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Central diabetes insipidus may require treatment w/desmopressin.
Temperature dysregulation can be managed by modifying environment.
Manage disturbance of sleep-wake cycles w/good sleep hygiene & (if needed) use of melatonin or other sleep aids such as clonidine.
Medically refractory epilepsy typically requires multiple ASMs.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
PT, OT, & bracing
Muscle relaxants may be used to treat moderate or severe spasticity.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
OT, PT, & adaptive devices
Surgery may be needed to improve dexterity.
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Central diabetes insipidus may require treatment w/desmopressin.
• Temperature dysregulation can be managed by modifying environment.
• Manage disturbance of sleep-wake cycles w/good sleep hygiene & (if needed) use of melatonin or other sleep aids such as clonidine.
• Medically refractory epilepsy typically requires multiple ASMs.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• PT, OT, & bracing
• Muscle relaxants may be used to treat moderate or severe spasticity.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• OT, PT, & adaptive devices
• Surgery may be needed to improve dexterity.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most probands reported to date with
Molecular genetic testing for the
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If the
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a proband with autosomal recessive
If both parents are known to be heterozygous for an
The heterozygous sibs of a proband with autosomal recessive
Carrier testing for at-risk relatives requires prior identification of the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most probands reported to date with
• Molecular genetic testing for the
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If the
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a proband with autosomal recessive
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• The heterozygous sibs of a proband with autosomal recessive
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Mode of Inheritance
## Autosomal Dominant Inheritance – Risk to Family Members
Most probands reported to date with
Molecular genetic testing for the
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If the
• Most probands reported to date with
• Molecular genetic testing for the
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If the
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a proband with autosomal recessive
If both parents are known to be heterozygous for an
The heterozygous sibs of a proband with autosomal recessive
Carrier testing for at-risk relatives requires prior identification of the
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a proband with autosomal recessive
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• The heterozygous sibs of a proband with autosomal recessive
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 5801
Bethesda MD 20824
•
•
•
• PO Box 5801
• Bethesda MD 20824
•
## Molecular Genetics
FGFR1-Related Hartsfield Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for FGFR1-Related Hartsfield Syndrome (
FGFR1 is a member of the receptor tyrosine kinase superfamily. The fibroblast growth factor (FGF) signaling pathway is a major factor in embryonic development. FGFR1 is expressed in cranial neural crest cell-derived mesenchyme and plays an important role during embryogenesis by deregulating cell death at early stages of limb initiation. A full-length representative protein consists of an extracellular region, comprising three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation [
Sporadic tumors occurring as single tumors in the absence of any other findings of Hartsfield syndrome may contain somatic variants and/or copy number changes in
## Molecular Pathogenesis
FGFR1 is a member of the receptor tyrosine kinase superfamily. The fibroblast growth factor (FGF) signaling pathway is a major factor in embryonic development. FGFR1 is expressed in cranial neural crest cell-derived mesenchyme and plays an important role during embryogenesis by deregulating cell death at early stages of limb initiation. A full-length representative protein consists of an extracellular region, comprising three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation [
## Cancer and Benign Tumors
Sporadic tumors occurring as single tumors in the absence of any other findings of Hartsfield syndrome may contain somatic variants and/or copy number changes in
## Chapter Notes
12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to
2 December 2021 (ha) Comprehensive update posted live
3 March 2016 (bp) Review posted live
12 November 2015 (rd) Original submission
• 12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to
• 2 December 2021 (ha) Comprehensive update posted live
• 3 March 2016 (bp) Review posted live
• 12 November 2015 (rd) Original submission
## Revision History
12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to
2 December 2021 (ha) Comprehensive update posted live
3 March 2016 (bp) Review posted live
12 November 2015 (rd) Original submission
• 12 May 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to
• 2 December 2021 (ha) Comprehensive update posted live
• 3 March 2016 (bp) Review posted live
• 12 November 2015 (rd) Original submission
## References
## Literature Cited
|
[] |
3/3/2016
|
2/12/2021
|
12/5/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
hcp
|
hcp
|
[
"Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial",
"CPOX",
"Hereditary Coproporphyria"
] |
Hereditary Coproporphyria
|
Bruce Wang, D Montgomery Bissell
|
Summary Hereditary coproporphyria (HCP) is an acute (hepatic) porphyria in which the acute symptoms are neurovisceral and occur in discrete episodes. Attacks typically start in the abdomen with low-grade pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting. In some individuals, the pain is predominantly in the back or extremities. When an acute attack is untreated, a motor neuropathy may develop over a period of days or a few weeks. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Some individuals experience respiratory insufficiency due to loss of innervation of the diaphragm and muscles of respiration. Acute attacks are associated commonly with use of certain medications, caloric deprivation, and changes in female reproductive hormones. About 20% of those with an acute attack also experience photosensitivity associated with bullae and skin fragility. The most sensitive and specific biochemical screening test for any one of the acute porphyrias (including HCP) during an acute attack is a striking increase in urinary porphobilinogen. Quantitative analysis of porphyrins in both urine and feces is essential to distinguish between the different acute porphyrias and establish the diagnosis of HCP. Identification of a heterozygous pathogenic variant in HCP is inherited in an autosomal dominant manner with low penetrance. Most individuals with HCP have an affected parent; the proportion with a
|
## Diagnosis
Hereditary coproporphyria (HCP) is classified as both an acute (hepatic) porphyria (with neurologic manifestations that occur as discrete, severe episodes) and a chronic (cutaneous) porphyria with long-standing photosensitivity.
Diagnostic criteria for HCP have been published [
Acute hepatic porphyria
Nausea for at least 48 hours
Abdominal, back, or extremity pain for at least 48 hours
New-onset seizures
Hyponatremia
Family history of porphyria
Note: (1) Although
The diagnosis of HCP
For an individual with pain and neurologic signs, the initial goal is to determine if the symptoms can be attributed to an attack related to any one of the acute porphyrias (i.e., ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria) (see
The most sensitive and specific biochemical diagnostic tests for HCP are detailed in
Active HCP is suggested by a quantitative urinary PBG that is at least threefold the upper limit of normal.
The characteristic finding in stool is COPRO >> PROTO, quantified as units/g dry weight of feces. Note: Some laboratories report units/24 hours, which is inherently inaccurate. US laboratories that do the more precise analysis include
The diagnosis is further substantiated by analysis of the COPRO-III/COPRO-I fecal porphyrin ratio, showing that 60%-95% of the total COPRO is isomer-III. In a normal (or "negative") test, the predominant fecal porphyrin is PROTO, and the COPRO isomer III/I ratio in many cases is <0.5 [
Biochemical Characteristics of Hereditary Coproporphyria
Active = symptomatic
Also known as coproporphyrinogen oxidase and coproporphyrinogen decarboxylase
The enzyme assay is not widely available and is not used for diagnostic purposes.
Active HCP is suggested by a quantitative urine PBG that is at least threefold the upper limit of normal.
Commercial laboratories offer quantitative delta-aminolevulinic acid (ALA), PBG, and fractionated urine porphyrins. Values normalized to urine creatinine are satisfactory for clinical use, making a 24-hour collection unnecessary.
See
Fractionated urine porphyrins may reveal a minor rise in COPRO (<3-fold the upper limit of normal); however, this is nonspecific and insufficient for diagnosis (see
60%-95% of the total COPRO is isomer-III.
Fecal porphyrin analysis is the best test for distinguishing HCP from nonspecific coproporphyrinuria: heterozygotes show a predominance of fecal COPRO and an elevated COPRO III/I ratio (see
The molecular testing approach typically includes
Sequence analysis of
If detailed
Molecular Genetic Testing Used in Hereditary Coproporphyria
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis identified a pathogenic variant in 31 of 32 (97%) individuals with the clinical and biochemical diagnosis of HCP [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A 13-kb deletion extending from exon 4 to the 3'UTR [
• Nausea for at least 48 hours
• Abdominal, back, or extremity pain for at least 48 hours
• New-onset seizures
• Hyponatremia
• Family history of porphyria
• Active HCP is suggested by a quantitative urinary PBG that is at least threefold the upper limit of normal.
• The characteristic finding in stool is COPRO >> PROTO, quantified as units/g dry weight of feces. Note: Some laboratories report units/24 hours, which is inherently inaccurate. US laboratories that do the more precise analysis include
• The diagnosis is further substantiated by analysis of the COPRO-III/COPRO-I fecal porphyrin ratio, showing that 60%-95% of the total COPRO is isomer-III. In a normal (or "negative") test, the predominant fecal porphyrin is PROTO, and the COPRO isomer III/I ratio in many cases is <0.5 [
• Sequence analysis of
• If detailed
## Suggestive Findings
Acute hepatic porphyria
Nausea for at least 48 hours
Abdominal, back, or extremity pain for at least 48 hours
New-onset seizures
Hyponatremia
Family history of porphyria
Note: (1) Although
• Nausea for at least 48 hours
• Abdominal, back, or extremity pain for at least 48 hours
• New-onset seizures
• Hyponatremia
• Family history of porphyria
## Establishing the Diagnosis
The diagnosis of HCP
For an individual with pain and neurologic signs, the initial goal is to determine if the symptoms can be attributed to an attack related to any one of the acute porphyrias (i.e., ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria) (see
The most sensitive and specific biochemical diagnostic tests for HCP are detailed in
Active HCP is suggested by a quantitative urinary PBG that is at least threefold the upper limit of normal.
The characteristic finding in stool is COPRO >> PROTO, quantified as units/g dry weight of feces. Note: Some laboratories report units/24 hours, which is inherently inaccurate. US laboratories that do the more precise analysis include
The diagnosis is further substantiated by analysis of the COPRO-III/COPRO-I fecal porphyrin ratio, showing that 60%-95% of the total COPRO is isomer-III. In a normal (or "negative") test, the predominant fecal porphyrin is PROTO, and the COPRO isomer III/I ratio in many cases is <0.5 [
Biochemical Characteristics of Hereditary Coproporphyria
Active = symptomatic
Also known as coproporphyrinogen oxidase and coproporphyrinogen decarboxylase
The enzyme assay is not widely available and is not used for diagnostic purposes.
Active HCP is suggested by a quantitative urine PBG that is at least threefold the upper limit of normal.
Commercial laboratories offer quantitative delta-aminolevulinic acid (ALA), PBG, and fractionated urine porphyrins. Values normalized to urine creatinine are satisfactory for clinical use, making a 24-hour collection unnecessary.
See
Fractionated urine porphyrins may reveal a minor rise in COPRO (<3-fold the upper limit of normal); however, this is nonspecific and insufficient for diagnosis (see
60%-95% of the total COPRO is isomer-III.
Fecal porphyrin analysis is the best test for distinguishing HCP from nonspecific coproporphyrinuria: heterozygotes show a predominance of fecal COPRO and an elevated COPRO III/I ratio (see
The molecular testing approach typically includes
Sequence analysis of
If detailed
Molecular Genetic Testing Used in Hereditary Coproporphyria
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis identified a pathogenic variant in 31 of 32 (97%) individuals with the clinical and biochemical diagnosis of HCP [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A 13-kb deletion extending from exon 4 to the 3'UTR [
• Active HCP is suggested by a quantitative urinary PBG that is at least threefold the upper limit of normal.
• The characteristic finding in stool is COPRO >> PROTO, quantified as units/g dry weight of feces. Note: Some laboratories report units/24 hours, which is inherently inaccurate. US laboratories that do the more precise analysis include
• The diagnosis is further substantiated by analysis of the COPRO-III/COPRO-I fecal porphyrin ratio, showing that 60%-95% of the total COPRO is isomer-III. In a normal (or "negative") test, the predominant fecal porphyrin is PROTO, and the COPRO isomer III/I ratio in many cases is <0.5 [
• Sequence analysis of
• If detailed
## Biochemical Testing
For an individual with pain and neurologic signs, the initial goal is to determine if the symptoms can be attributed to an attack related to any one of the acute porphyrias (i.e., ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria) (see
The most sensitive and specific biochemical diagnostic tests for HCP are detailed in
Active HCP is suggested by a quantitative urinary PBG that is at least threefold the upper limit of normal.
The characteristic finding in stool is COPRO >> PROTO, quantified as units/g dry weight of feces. Note: Some laboratories report units/24 hours, which is inherently inaccurate. US laboratories that do the more precise analysis include
The diagnosis is further substantiated by analysis of the COPRO-III/COPRO-I fecal porphyrin ratio, showing that 60%-95% of the total COPRO is isomer-III. In a normal (or "negative") test, the predominant fecal porphyrin is PROTO, and the COPRO isomer III/I ratio in many cases is <0.5 [
Biochemical Characteristics of Hereditary Coproporphyria
Active = symptomatic
Also known as coproporphyrinogen oxidase and coproporphyrinogen decarboxylase
The enzyme assay is not widely available and is not used for diagnostic purposes.
Active HCP is suggested by a quantitative urine PBG that is at least threefold the upper limit of normal.
Commercial laboratories offer quantitative delta-aminolevulinic acid (ALA), PBG, and fractionated urine porphyrins. Values normalized to urine creatinine are satisfactory for clinical use, making a 24-hour collection unnecessary.
See
Fractionated urine porphyrins may reveal a minor rise in COPRO (<3-fold the upper limit of normal); however, this is nonspecific and insufficient for diagnosis (see
60%-95% of the total COPRO is isomer-III.
Fecal porphyrin analysis is the best test for distinguishing HCP from nonspecific coproporphyrinuria: heterozygotes show a predominance of fecal COPRO and an elevated COPRO III/I ratio (see
• Active HCP is suggested by a quantitative urinary PBG that is at least threefold the upper limit of normal.
• The characteristic finding in stool is COPRO >> PROTO, quantified as units/g dry weight of feces. Note: Some laboratories report units/24 hours, which is inherently inaccurate. US laboratories that do the more precise analysis include
• The diagnosis is further substantiated by analysis of the COPRO-III/COPRO-I fecal porphyrin ratio, showing that 60%-95% of the total COPRO is isomer-III. In a normal (or "negative") test, the predominant fecal porphyrin is PROTO, and the COPRO isomer III/I ratio in many cases is <0.5 [
## Molecular Genetic Testing
The molecular testing approach typically includes
Sequence analysis of
If detailed
Molecular Genetic Testing Used in Hereditary Coproporphyria
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Sequence analysis identified a pathogenic variant in 31 of 32 (97%) individuals with the clinical and biochemical diagnosis of HCP [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
A 13-kb deletion extending from exon 4 to the 3'UTR [
• Sequence analysis of
• If detailed
## Clinical Characteristics
Hereditary coproporphyria (HCP) is classified as both an acute and a chronic porphyria. Porphyrias with neurologic manifestations are considered acute, because the symptoms occur as discrete, severe episodes. Porphyrias with cutaneous manifestations are considered chronic, because photosensitivity is long standing (see
In a German study of 46 individuals with acute HCP, 90% had abdominal pain; only 13% had cutaneous findings despite substantial overproduction of coproporphyrin [
Symptoms prior to puberty in individuals who are heterozygous for a
Fertility and longevity do not appear to be reduced in
The initial symptoms of an acute attack are nonspecific, consisting of low-grade abdominal pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting of all oral intake.
Typically the pain is not well localized but in some instances does mimic acute inflammation of the gallbladder, appendix, or other intra-abdominal organ. In most instances the abdominal examination is unremarkable except for diminished bowel sounds consistent with ileus, which is common and can be seen on abdominal radiography. Typically fever is absent. In a young woman of reproductive age, the symptoms may raise the question of early pregnancy.
Prior to the widespread use of abdominal imaging in the emergency room setting, some individuals with abdominal pain and undiagnosed acute porphyria underwent urgent exploratory surgery. Thus, a history of abdominal surgery with negative findings was considered characteristic of acute porphyria.
A minority of affected individuals has predominantly back or extremity pain, which is usually deep and aching, not localized to joints or muscle groups.
When an attack is unrecognized as such or treated with inappropriate medications, it may progress to a motor neuropathy, which typically occurs many days to a few weeks after the onset of symptoms. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Neurosensory function remains largely intact.
In some individuals the motor neuropathy eventually involves nerves serving the diaphragm and muscles of respiration. Ventilator support may be needed.
Tachycardia and bowel dysmotility (manifest as constipation) are common in acute attacks and believed to represent involvement of the autonomic nervous system.
Of note, when the acute attack is recognized early and treated appropriately (see
Because of the altered affect in acute porphyria, it has been speculated that mental illness is a long-term consequence of an attack and that mental institutions may house disproportionately large numbers of individuals with undiagnosed acute porphyria. Screening of residents in mental health facilities by urinary porphobilinogen (PBG) and/or PBG deaminase activity in blood (which diagnoses
Inasmuch as ALA and PBG tend to be minimally elevated or normal in HCP heterozygotes, the risk of hepatic and renal complications may be less in HCP than in
The cutaneous findings in HCP resemble those in porphyria cutanea tarda (PCT) and in variegate porphyria (VP).
Clinically active acute porphyria is associated with substantial elevation of the precursors ALA and PBG in the blood and urine; the cutaneous porphyrias are associated with increased porphyrins in blood, urine, and feces. In the acute porphyrias and cutaneous porphyrias, a threshold for symptoms appears to exist.
In contrast, in asymptomatic individuals the baseline urinary PBG excretion varies widely, usually low or normal but occasionally exceeding 25 mg/g creatinine. For this reason, it is advisable to establish the baseline urinary PBG excretion for
Of note, in individuals with HCP and chronic liver disease the cutaneous component may be more prominent than expected for the observed urine or plasma PBG concentration. Coproporphyrin leaves the plasma largely via the liver going into bile. In chronic liver disease, bile transport processes or bile formation may be impaired, leading to accumulation of coproporphyrin in plasma, which then results in photosensitivity.
The regulation of heme synthesis differs in liver and in bone marrow, the principal sites of heme production in the body. The liver is the main source of precursors in the acute (hepatic) porphyrias: acute attacks are precipitated when environmental factors stimulate increased hepatic heme synthesis and the genetically altered step in heme production becomes rate limiting (
It is estimated that 20%-25% of total heme production normally occurs in the liver [
Liver transplantation has established that this organ is responsible for acute attacks. Liver transplantation has cured individuals with refractory acute symptoms [
Because population studies to determine the prevalence of HCP heterozygosity have not been done, the penetrance of
HCP, along with AIP and VP, are genetic disorders with reduced penetrance. Heme production in most heterozygotes appears to be adequate for physiologic homeostasis. Thus, environmental or physiologic factors play a role in the pathogenesis of acute attacks (see Management,
"Coproporphyrinuria" describes urine with an elevated level of coproporphyrin of any cause.
Coproporphyria in individuals heterozygous for a
Clinical experience suggests that HCP is the least prevalent of the three principal types of acute porphyria: AIP, VP, and HCP. However, symptoms in HCP may be less frequent than in AIP or VP. Population surveys for
• In contrast, in asymptomatic individuals the baseline urinary PBG excretion varies widely, usually low or normal but occasionally exceeding 25 mg/g creatinine. For this reason, it is advisable to establish the baseline urinary PBG excretion for
## Clinical Description
Hereditary coproporphyria (HCP) is classified as both an acute and a chronic porphyria. Porphyrias with neurologic manifestations are considered acute, because the symptoms occur as discrete, severe episodes. Porphyrias with cutaneous manifestations are considered chronic, because photosensitivity is long standing (see
In a German study of 46 individuals with acute HCP, 90% had abdominal pain; only 13% had cutaneous findings despite substantial overproduction of coproporphyrin [
Symptoms prior to puberty in individuals who are heterozygous for a
Fertility and longevity do not appear to be reduced in
The initial symptoms of an acute attack are nonspecific, consisting of low-grade abdominal pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting of all oral intake.
Typically the pain is not well localized but in some instances does mimic acute inflammation of the gallbladder, appendix, or other intra-abdominal organ. In most instances the abdominal examination is unremarkable except for diminished bowel sounds consistent with ileus, which is common and can be seen on abdominal radiography. Typically fever is absent. In a young woman of reproductive age, the symptoms may raise the question of early pregnancy.
Prior to the widespread use of abdominal imaging in the emergency room setting, some individuals with abdominal pain and undiagnosed acute porphyria underwent urgent exploratory surgery. Thus, a history of abdominal surgery with negative findings was considered characteristic of acute porphyria.
A minority of affected individuals has predominantly back or extremity pain, which is usually deep and aching, not localized to joints or muscle groups.
When an attack is unrecognized as such or treated with inappropriate medications, it may progress to a motor neuropathy, which typically occurs many days to a few weeks after the onset of symptoms. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Neurosensory function remains largely intact.
In some individuals the motor neuropathy eventually involves nerves serving the diaphragm and muscles of respiration. Ventilator support may be needed.
Tachycardia and bowel dysmotility (manifest as constipation) are common in acute attacks and believed to represent involvement of the autonomic nervous system.
Of note, when the acute attack is recognized early and treated appropriately (see
Because of the altered affect in acute porphyria, it has been speculated that mental illness is a long-term consequence of an attack and that mental institutions may house disproportionately large numbers of individuals with undiagnosed acute porphyria. Screening of residents in mental health facilities by urinary porphobilinogen (PBG) and/or PBG deaminase activity in blood (which diagnoses
Inasmuch as ALA and PBG tend to be minimally elevated or normal in HCP heterozygotes, the risk of hepatic and renal complications may be less in HCP than in
The cutaneous findings in HCP resemble those in porphyria cutanea tarda (PCT) and in variegate porphyria (VP).
Clinically active acute porphyria is associated with substantial elevation of the precursors ALA and PBG in the blood and urine; the cutaneous porphyrias are associated with increased porphyrins in blood, urine, and feces. In the acute porphyrias and cutaneous porphyrias, a threshold for symptoms appears to exist.
In contrast, in asymptomatic individuals the baseline urinary PBG excretion varies widely, usually low or normal but occasionally exceeding 25 mg/g creatinine. For this reason, it is advisable to establish the baseline urinary PBG excretion for
Of note, in individuals with HCP and chronic liver disease the cutaneous component may be more prominent than expected for the observed urine or plasma PBG concentration. Coproporphyrin leaves the plasma largely via the liver going into bile. In chronic liver disease, bile transport processes or bile formation may be impaired, leading to accumulation of coproporphyrin in plasma, which then results in photosensitivity.
• In contrast, in asymptomatic individuals the baseline urinary PBG excretion varies widely, usually low or normal but occasionally exceeding 25 mg/g creatinine. For this reason, it is advisable to establish the baseline urinary PBG excretion for
## Acute Attacks
The initial symptoms of an acute attack are nonspecific, consisting of low-grade abdominal pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting of all oral intake.
Typically the pain is not well localized but in some instances does mimic acute inflammation of the gallbladder, appendix, or other intra-abdominal organ. In most instances the abdominal examination is unremarkable except for diminished bowel sounds consistent with ileus, which is common and can be seen on abdominal radiography. Typically fever is absent. In a young woman of reproductive age, the symptoms may raise the question of early pregnancy.
Prior to the widespread use of abdominal imaging in the emergency room setting, some individuals with abdominal pain and undiagnosed acute porphyria underwent urgent exploratory surgery. Thus, a history of abdominal surgery with negative findings was considered characteristic of acute porphyria.
A minority of affected individuals has predominantly back or extremity pain, which is usually deep and aching, not localized to joints or muscle groups.
When an attack is unrecognized as such or treated with inappropriate medications, it may progress to a motor neuropathy, which typically occurs many days to a few weeks after the onset of symptoms. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Neurosensory function remains largely intact.
In some individuals the motor neuropathy eventually involves nerves serving the diaphragm and muscles of respiration. Ventilator support may be needed.
Tachycardia and bowel dysmotility (manifest as constipation) are common in acute attacks and believed to represent involvement of the autonomic nervous system.
Of note, when the acute attack is recognized early and treated appropriately (see
Because of the altered affect in acute porphyria, it has been speculated that mental illness is a long-term consequence of an attack and that mental institutions may house disproportionately large numbers of individuals with undiagnosed acute porphyria. Screening of residents in mental health facilities by urinary porphobilinogen (PBG) and/or PBG deaminase activity in blood (which diagnoses
Inasmuch as ALA and PBG tend to be minimally elevated or normal in HCP heterozygotes, the risk of hepatic and renal complications may be less in HCP than in
The cutaneous findings in HCP resemble those in porphyria cutanea tarda (PCT) and in variegate porphyria (VP).
## Threshold for a Pathogenic Effect of Porphyrins and Their Precursors
Clinically active acute porphyria is associated with substantial elevation of the precursors ALA and PBG in the blood and urine; the cutaneous porphyrias are associated with increased porphyrins in blood, urine, and feces. In the acute porphyrias and cutaneous porphyrias, a threshold for symptoms appears to exist.
In contrast, in asymptomatic individuals the baseline urinary PBG excretion varies widely, usually low or normal but occasionally exceeding 25 mg/g creatinine. For this reason, it is advisable to establish the baseline urinary PBG excretion for
Of note, in individuals with HCP and chronic liver disease the cutaneous component may be more prominent than expected for the observed urine or plasma PBG concentration. Coproporphyrin leaves the plasma largely via the liver going into bile. In chronic liver disease, bile transport processes or bile formation may be impaired, leading to accumulation of coproporphyrin in plasma, which then results in photosensitivity.
• In contrast, in asymptomatic individuals the baseline urinary PBG excretion varies widely, usually low or normal but occasionally exceeding 25 mg/g creatinine. For this reason, it is advisable to establish the baseline urinary PBG excretion for
## Pathophysiology
The regulation of heme synthesis differs in liver and in bone marrow, the principal sites of heme production in the body. The liver is the main source of precursors in the acute (hepatic) porphyrias: acute attacks are precipitated when environmental factors stimulate increased hepatic heme synthesis and the genetically altered step in heme production becomes rate limiting (
It is estimated that 20%-25% of total heme production normally occurs in the liver [
Liver transplantation has established that this organ is responsible for acute attacks. Liver transplantation has cured individuals with refractory acute symptoms [
## Genotype-Phenotype Correlations
## Penetrance
Because population studies to determine the prevalence of HCP heterozygosity have not been done, the penetrance of
HCP, along with AIP and VP, are genetic disorders with reduced penetrance. Heme production in most heterozygotes appears to be adequate for physiologic homeostasis. Thus, environmental or physiologic factors play a role in the pathogenesis of acute attacks (see Management,
## Nomenclature
"Coproporphyrinuria" describes urine with an elevated level of coproporphyrin of any cause.
Coproporphyria in individuals heterozygous for a
## Prevalence
Clinical experience suggests that HCP is the least prevalent of the three principal types of acute porphyria: AIP, VP, and HCP. However, symptoms in HCP may be less frequent than in AIP or VP. Population surveys for
## Genetically Related (Allelic) Disorders
Heterozygotes for a
## Differential Diagnosis
In
Porphyrias with neurovisceral manifestations are considered acute because the symptoms occur as discrete, severe episodes, which may be spontaneous but frequently are induced by external factors. The four acute porphyrias are: ALA dehydratase deficiency porphyria (ADP),
Porphyrias with cutaneous manifestations include either chronic blistering skin lesions (i.e., VP as well as PCT, HCP, CEP, and
Classification of the Hereditary Porphyrias
0 = no symptoms; + = mild to severe symptoms; AD = autosomal dominant; ADP = ALA dehydratase deficiency porphyria; AIP = acute intermittent porphyria; AR = autosomal recessive; CEP = congenital erythropoietic porphyria; EPP = erythropoietic protoporphyria; HCP = hereditary coproporphyria; MOI = mode of inheritance; PCT = porphyria cutanea tarda; VP = variegate porphyria; XL = X-linked; XLP = X-Linked protoporphyria
Porphyrias with neurovisceral manifestations have been considered "acute" in part because the most common of these disorders, named "acute intermittent porphyria," is the prototype for the neurovisceral porphyrias in which symptoms can occur acutely as discrete, severe episodes; however, some affected individuals develop chronic manifestations, and a few remain susceptible to exacerbating factors throughout their lives.
Photocutaneous manifestations of EPP are acute and non-blistering, in contrast to the chronic blistering in the other cutaneous porphyrias (including VP).
While these clinical distinctions are important for the differential diagnosis, biochemical analysis is always necessary; however, biochemical testing may fail to distinguish HCP from VP, in which case molecular genetic testing of
In individuals with progressive weakness due to the motor neuropathy caused by one of the acute porphyrias (AIP, VP, HCP, and ADP), the entity most likely to be considered is acute ascending polyneuropathy, the
Two tests helpful for the differential diagnosis of coproporphyrinuria are:
Urine PBG, which is more than tenfold elevated in the inherited acute porphyrias with active symptoms;
The ratio of copro-III to copro-I in feces as measured by high-performance liquid chromatography (used for fecal porphyrin fractionation in most commercial labs). In nonspecific coproporphyrinuria the ratio is usually similar to that in normal controls [
For a case example of misdiagnosis of nonspecific coproporphyrinuria, click
• Porphyrias with neurovisceral manifestations are considered acute because the symptoms occur as discrete, severe episodes, which may be spontaneous but frequently are induced by external factors. The four acute porphyrias are: ALA dehydratase deficiency porphyria (ADP),
• Porphyrias with cutaneous manifestations include either chronic blistering skin lesions (i.e., VP as well as PCT, HCP, CEP, and
• Two tests helpful for the differential diagnosis of coproporphyrinuria are:
• Urine PBG, which is more than tenfold elevated in the inherited acute porphyrias with active symptoms;
• The ratio of copro-III to copro-I in feces as measured by high-performance liquid chromatography (used for fecal porphyrin fractionation in most commercial labs). In nonspecific coproporphyrinuria the ratio is usually similar to that in normal controls [
• For a case example of misdiagnosis of nonspecific coproporphyrinuria, click
• Urine PBG, which is more than tenfold elevated in the inherited acute porphyrias with active symptoms;
• The ratio of copro-III to copro-I in feces as measured by high-performance liquid chromatography (used for fecal porphyrin fractionation in most commercial labs). In nonspecific coproporphyrinuria the ratio is usually similar to that in normal controls [
• Urine PBG, which is more than tenfold elevated in the inherited acute porphyrias with active symptoms;
• The ratio of copro-III to copro-I in feces as measured by high-performance liquid chromatography (used for fecal porphyrin fractionation in most commercial labs). In nonspecific coproporphyrinuria the ratio is usually similar to that in normal controls [
## Management
To establish the extent of disease and needs of an individual diagnosed with hereditary coproporphyria (HCP), the evaluations listed in
Recommended Evaluations Following Initial Diagnosis of Hereditary Coproporphyria
For signs of motor neuropathy (indicating a more advanced attack & thus, need for early treatment w/hematin; see
Inquiry into possibility of seizures
PBG = porphobilinogen
In an acute attack urinary excretion of PBG is substantially elevated over the baseline.
Treatment guidelines for HCP have been published [
No curative therapy for HCP exists.
Supportive therapy by multidisciplinary specialists is summarized in
Details regarding treatment with givosiran, which was approved for prophylactic treatment for individuals with HCP with frequent recurrent acute neurovisceral pain episodes (defined as more than four attacks per year) in the US, but not necessarily in all countries, follow
Treatment of Acute Attacks in Individuals with Hereditary Coproporphyria
For use in any attack that requires hospitalization. For those w/a confirmed diagnosis & recurrent attacks, hematin is given as soon as it can be obtained, in addition to IV fluids & glucose.
Hematin is not stocked by most hospital pharmacies but can be obtained by overnight express from the manufacturer (Panhematin
Responses to hematin infusion can include: ↓ urine concentration of PBG (the 1st sign) after 2 doses; clinical improvement after 3-4 doses (typically dramatic) w/no further need of narcotic analgesia.
The status of the disease in candidates for liver transplantation must be well documented biochemically.
Candidates must not have responded to multiple courses of hematin & must demonstrate neurologic complication.
PBG = porphobilinogen
Hyponatremia is characteristic and may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction with due regard for the risk of central pontine myelinolysis.
Aggressive administration of dextrose in water may cause the serum sodium concentration to drop to a critically low level.
Hematin (350-mg vial) is reconstituted at the bedside as described in the package insert. Human albumin may be used in place of water (147 mL of a 25% albumin solution) to reduce the risk of a chemical phlebitis, which is the main side effect of hematin administration [
The infusion is started without delay, as hematin in solution decays rapidly [
The preparation is given into a large peripheral vein or via central line over 10-15 minutes to minimize the risk of phlebitis. The dose is weight based at 3-4 mg/kg; 200 mg once daily is appropriate for most individuals.
An alternative in Europe and elsewhere is heme arginate (Normosang
Return of function requires axonal regeneration and takes many months. Although it can be complete, some individuals have residual wrist drop or foot drop.
This treatment has been used to control eclamptic seizures [
Oral contraceptives and progestins should be avoided.
Treatment of iron overload is indicated when the serum ferritin exceeds 1,500 ng/mL.
An oral chelator, such as deferasirox or deferiprone, is convenient but causes side effects of gastric distress and nausea in some users.
A small phlebotomy can be done with each hematin infusion, provided the hemoglobin is >10 g/dL. Withdrawal of 100 mL of blood is sufficient for maintaining iron balance, relative to the amount of iron in a 250-mg dose of injectable hematin.
For those with a significant iron burden, withdrawal of 200 cc of blood with each hematin infusion will produce net negative iron balance.
Givosiran is a delta-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA (siRNA) covalently linked to N-acetyl galactosamine (GalNAc) that is taken up selectively by hepatocytes, leading to destruction of ALAS1 mRNA and decreased ALAS1 protein levels within hepatocytes [
A multinational Phase 3 study of givosiran in 94 individuals with acute hepatic porphyria showed the following [
Annualized attack rates were reduced by 74%.
Sustained delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) were reduced by 86% and 91%, respectively, relative to baseline during the six-month study.
Half of affected individuals treated with givosiran experienced no acute attacks during the six-month study, compared with 17% of affected individuals on placebo.
Most common side effects reported were injection site reactions. Serious adverse events observed more frequently with givosiran included increased serum transaminases and decreased estimated glomerular filtration rate (eGFR).
Of note, only two individuals with HCP were included in the givosiran Phase 3 study. Individuals on givosiran can still experience acute attacks, and these should still be treated with hematin therapy.
Treatment of Low-Grade Chronic or Seasonal Cutaneous Symptoms in Individuals with Hereditary Coproporphyria
Damage is caused by blue light and long-wave ultraviolet light (UVA), both of which pass through window glass.
Note: The association of cutaneous manifestations with severe attacks (in which porphyrins as well as ALA and PBG are markedly increased) suggests that the cutaneous as well as the neurovisceral symptoms could respond to hematin administration. Indeed, this is the finding of a case report of an individual with severe HCP who was given "maintenance" hematin [
Prevention of Acute Attacks in
A copper-releasing IUD is theoretically the safest in women w/porphyria.
A hormone-releasing IUD may also be safe because the systemic ↑ in hormone is quite small; however, little information exists on its use in women w/acute porphyria.
Leuprolide, nafarelin, & other GnRH agonists may help those who experience monthly exacerbations.
If menopausal side effects occur, they can be treated by adding low-dose estrogen.
GnRH = gonadotropin-releasing hormone; IUD = intrauterine device
Oral contraceptives (birth control pills) are risky and not recommended.
For those who have chronically elevated ALA (which is infrequent in those who are asymptomatic) and/or are older than age 60 years, an annual assessment of liver and kidney function is recommended.
Current noninvasive techniques for evaluation of fibrosis in the liver include transient elastography (FibroScan
For affected individuals older than age 60 and anyone with evidence of chronic liver injury, annual screening for hepatocellular carcinoma with abdominal imaging (e.g., ultrasound) and serum alpha-fetoprotein is indicated [
Avoid the following:
In theory, the most dangerous medications are inducers of CYPs, such as barbiturates and the related compound, phenytoin.
It is appropriate to evaluate relatives at risk for HCP in order to identify as early as possible those who would benefit from education regarding the risk factors associated with acute attacks.
If the
If the
See
The effect of pregnancy on inducing acute attacks is unpredictable. In general, serious problems during pregnancy are unusual. In fact, some women with recurrent symptoms associated with the menstrual cycle report improvement during pregnancy. Attacks, if they occur, are usually in the first trimester. The women most at risk are those with hyperemesis gravidarum and inadequate caloric intake [
The experience with administration of hematin (or heme arginate, which is not available in the US) during pregnancy is limited.
No human pregnancies have been reported during or after treatment with givosiran. In animal studies of reproduction, doses of givosiran that caused maternal toxicity in rabbits also resulted in adverse developmental outcomes. In pregnant rats, givosiran given at doses up to 30 mg/kg did not cause developmental defects in the offspring. There are no data on the presence of givosiran in human milk. Women with HCP should discuss the risks and benefits of continuing givosiran with their physician prior to conception.
See
Hematin for infusion (Panhematin
Alternatives are under investigation. One is gene therapy in which the normal gene (
Search
• For signs of motor neuropathy (indicating a more advanced attack & thus, need for early treatment w/hematin; see
• Inquiry into possibility of seizures
• For use in any attack that requires hospitalization. For those w/a confirmed diagnosis & recurrent attacks, hematin is given as soon as it can be obtained, in addition to IV fluids & glucose.
• Hematin is not stocked by most hospital pharmacies but can be obtained by overnight express from the manufacturer (Panhematin
• Responses to hematin infusion can include: ↓ urine concentration of PBG (the 1st sign) after 2 doses; clinical improvement after 3-4 doses (typically dramatic) w/no further need of narcotic analgesia.
• The status of the disease in candidates for liver transplantation must be well documented biochemically.
• Candidates must not have responded to multiple courses of hematin & must demonstrate neurologic complication.
• Annualized attack rates were reduced by 74%.
• Sustained delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) were reduced by 86% and 91%, respectively, relative to baseline during the six-month study.
• Half of affected individuals treated with givosiran experienced no acute attacks during the six-month study, compared with 17% of affected individuals on placebo.
• Most common side effects reported were injection site reactions. Serious adverse events observed more frequently with givosiran included increased serum transaminases and decreased estimated glomerular filtration rate (eGFR).
• A copper-releasing IUD is theoretically the safest in women w/porphyria.
• A hormone-releasing IUD may also be safe because the systemic ↑ in hormone is quite small; however, little information exists on its use in women w/acute porphyria.
• Leuprolide, nafarelin, & other GnRH agonists may help those who experience monthly exacerbations.
• If menopausal side effects occur, they can be treated by adding low-dose estrogen.
• In theory, the most dangerous medications are inducers of CYPs, such as barbiturates and the related compound, phenytoin.
• If the
• If the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with hereditary coproporphyria (HCP), the evaluations listed in
Recommended Evaluations Following Initial Diagnosis of Hereditary Coproporphyria
For signs of motor neuropathy (indicating a more advanced attack & thus, need for early treatment w/hematin; see
Inquiry into possibility of seizures
PBG = porphobilinogen
In an acute attack urinary excretion of PBG is substantially elevated over the baseline.
• For signs of motor neuropathy (indicating a more advanced attack & thus, need for early treatment w/hematin; see
• Inquiry into possibility of seizures
## Treatment of Manifestations
Treatment guidelines for HCP have been published [
No curative therapy for HCP exists.
Supportive therapy by multidisciplinary specialists is summarized in
Details regarding treatment with givosiran, which was approved for prophylactic treatment for individuals with HCP with frequent recurrent acute neurovisceral pain episodes (defined as more than four attacks per year) in the US, but not necessarily in all countries, follow
Treatment of Acute Attacks in Individuals with Hereditary Coproporphyria
For use in any attack that requires hospitalization. For those w/a confirmed diagnosis & recurrent attacks, hematin is given as soon as it can be obtained, in addition to IV fluids & glucose.
Hematin is not stocked by most hospital pharmacies but can be obtained by overnight express from the manufacturer (Panhematin
Responses to hematin infusion can include: ↓ urine concentration of PBG (the 1st sign) after 2 doses; clinical improvement after 3-4 doses (typically dramatic) w/no further need of narcotic analgesia.
The status of the disease in candidates for liver transplantation must be well documented biochemically.
Candidates must not have responded to multiple courses of hematin & must demonstrate neurologic complication.
PBG = porphobilinogen
Hyponatremia is characteristic and may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction with due regard for the risk of central pontine myelinolysis.
Aggressive administration of dextrose in water may cause the serum sodium concentration to drop to a critically low level.
Hematin (350-mg vial) is reconstituted at the bedside as described in the package insert. Human albumin may be used in place of water (147 mL of a 25% albumin solution) to reduce the risk of a chemical phlebitis, which is the main side effect of hematin administration [
The infusion is started without delay, as hematin in solution decays rapidly [
The preparation is given into a large peripheral vein or via central line over 10-15 minutes to minimize the risk of phlebitis. The dose is weight based at 3-4 mg/kg; 200 mg once daily is appropriate for most individuals.
An alternative in Europe and elsewhere is heme arginate (Normosang
Return of function requires axonal regeneration and takes many months. Although it can be complete, some individuals have residual wrist drop or foot drop.
This treatment has been used to control eclamptic seizures [
Oral contraceptives and progestins should be avoided.
Treatment of iron overload is indicated when the serum ferritin exceeds 1,500 ng/mL.
An oral chelator, such as deferasirox or deferiprone, is convenient but causes side effects of gastric distress and nausea in some users.
A small phlebotomy can be done with each hematin infusion, provided the hemoglobin is >10 g/dL. Withdrawal of 100 mL of blood is sufficient for maintaining iron balance, relative to the amount of iron in a 250-mg dose of injectable hematin.
For those with a significant iron burden, withdrawal of 200 cc of blood with each hematin infusion will produce net negative iron balance.
Givosiran is a delta-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA (siRNA) covalently linked to N-acetyl galactosamine (GalNAc) that is taken up selectively by hepatocytes, leading to destruction of ALAS1 mRNA and decreased ALAS1 protein levels within hepatocytes [
A multinational Phase 3 study of givosiran in 94 individuals with acute hepatic porphyria showed the following [
Annualized attack rates were reduced by 74%.
Sustained delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) were reduced by 86% and 91%, respectively, relative to baseline during the six-month study.
Half of affected individuals treated with givosiran experienced no acute attacks during the six-month study, compared with 17% of affected individuals on placebo.
Most common side effects reported were injection site reactions. Serious adverse events observed more frequently with givosiran included increased serum transaminases and decreased estimated glomerular filtration rate (eGFR).
Of note, only two individuals with HCP were included in the givosiran Phase 3 study. Individuals on givosiran can still experience acute attacks, and these should still be treated with hematin therapy.
Treatment of Low-Grade Chronic or Seasonal Cutaneous Symptoms in Individuals with Hereditary Coproporphyria
Damage is caused by blue light and long-wave ultraviolet light (UVA), both of which pass through window glass.
Note: The association of cutaneous manifestations with severe attacks (in which porphyrins as well as ALA and PBG are markedly increased) suggests that the cutaneous as well as the neurovisceral symptoms could respond to hematin administration. Indeed, this is the finding of a case report of an individual with severe HCP who was given "maintenance" hematin [
• For use in any attack that requires hospitalization. For those w/a confirmed diagnosis & recurrent attacks, hematin is given as soon as it can be obtained, in addition to IV fluids & glucose.
• Hematin is not stocked by most hospital pharmacies but can be obtained by overnight express from the manufacturer (Panhematin
• Responses to hematin infusion can include: ↓ urine concentration of PBG (the 1st sign) after 2 doses; clinical improvement after 3-4 doses (typically dramatic) w/no further need of narcotic analgesia.
• The status of the disease in candidates for liver transplantation must be well documented biochemically.
• Candidates must not have responded to multiple courses of hematin & must demonstrate neurologic complication.
• Annualized attack rates were reduced by 74%.
• Sustained delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) were reduced by 86% and 91%, respectively, relative to baseline during the six-month study.
• Half of affected individuals treated with givosiran experienced no acute attacks during the six-month study, compared with 17% of affected individuals on placebo.
• Most common side effects reported were injection site reactions. Serious adverse events observed more frequently with givosiran included increased serum transaminases and decreased estimated glomerular filtration rate (eGFR).
## Acute Attacks
No curative therapy for HCP exists.
Supportive therapy by multidisciplinary specialists is summarized in
Details regarding treatment with givosiran, which was approved for prophylactic treatment for individuals with HCP with frequent recurrent acute neurovisceral pain episodes (defined as more than four attacks per year) in the US, but not necessarily in all countries, follow
Treatment of Acute Attacks in Individuals with Hereditary Coproporphyria
For use in any attack that requires hospitalization. For those w/a confirmed diagnosis & recurrent attacks, hematin is given as soon as it can be obtained, in addition to IV fluids & glucose.
Hematin is not stocked by most hospital pharmacies but can be obtained by overnight express from the manufacturer (Panhematin
Responses to hematin infusion can include: ↓ urine concentration of PBG (the 1st sign) after 2 doses; clinical improvement after 3-4 doses (typically dramatic) w/no further need of narcotic analgesia.
The status of the disease in candidates for liver transplantation must be well documented biochemically.
Candidates must not have responded to multiple courses of hematin & must demonstrate neurologic complication.
PBG = porphobilinogen
Hyponatremia is characteristic and may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction with due regard for the risk of central pontine myelinolysis.
Aggressive administration of dextrose in water may cause the serum sodium concentration to drop to a critically low level.
Hematin (350-mg vial) is reconstituted at the bedside as described in the package insert. Human albumin may be used in place of water (147 mL of a 25% albumin solution) to reduce the risk of a chemical phlebitis, which is the main side effect of hematin administration [
The infusion is started without delay, as hematin in solution decays rapidly [
The preparation is given into a large peripheral vein or via central line over 10-15 minutes to minimize the risk of phlebitis. The dose is weight based at 3-4 mg/kg; 200 mg once daily is appropriate for most individuals.
An alternative in Europe and elsewhere is heme arginate (Normosang
Return of function requires axonal regeneration and takes many months. Although it can be complete, some individuals have residual wrist drop or foot drop.
This treatment has been used to control eclamptic seizures [
Oral contraceptives and progestins should be avoided.
Treatment of iron overload is indicated when the serum ferritin exceeds 1,500 ng/mL.
An oral chelator, such as deferasirox or deferiprone, is convenient but causes side effects of gastric distress and nausea in some users.
A small phlebotomy can be done with each hematin infusion, provided the hemoglobin is >10 g/dL. Withdrawal of 100 mL of blood is sufficient for maintaining iron balance, relative to the amount of iron in a 250-mg dose of injectable hematin.
For those with a significant iron burden, withdrawal of 200 cc of blood with each hematin infusion will produce net negative iron balance.
• For use in any attack that requires hospitalization. For those w/a confirmed diagnosis & recurrent attacks, hematin is given as soon as it can be obtained, in addition to IV fluids & glucose.
• Hematin is not stocked by most hospital pharmacies but can be obtained by overnight express from the manufacturer (Panhematin
• Responses to hematin infusion can include: ↓ urine concentration of PBG (the 1st sign) after 2 doses; clinical improvement after 3-4 doses (typically dramatic) w/no further need of narcotic analgesia.
• The status of the disease in candidates for liver transplantation must be well documented biochemically.
• Candidates must not have responded to multiple courses of hematin & must demonstrate neurologic complication.
## Treatment with Givosiran
Givosiran is a delta-aminolevulinic acid synthase 1 (ALAS1)-directed small interfering RNA (siRNA) covalently linked to N-acetyl galactosamine (GalNAc) that is taken up selectively by hepatocytes, leading to destruction of ALAS1 mRNA and decreased ALAS1 protein levels within hepatocytes [
A multinational Phase 3 study of givosiran in 94 individuals with acute hepatic porphyria showed the following [
Annualized attack rates were reduced by 74%.
Sustained delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) were reduced by 86% and 91%, respectively, relative to baseline during the six-month study.
Half of affected individuals treated with givosiran experienced no acute attacks during the six-month study, compared with 17% of affected individuals on placebo.
Most common side effects reported were injection site reactions. Serious adverse events observed more frequently with givosiran included increased serum transaminases and decreased estimated glomerular filtration rate (eGFR).
Of note, only two individuals with HCP were included in the givosiran Phase 3 study. Individuals on givosiran can still experience acute attacks, and these should still be treated with hematin therapy.
• Annualized attack rates were reduced by 74%.
• Sustained delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) were reduced by 86% and 91%, respectively, relative to baseline during the six-month study.
• Half of affected individuals treated with givosiran experienced no acute attacks during the six-month study, compared with 17% of affected individuals on placebo.
• Most common side effects reported were injection site reactions. Serious adverse events observed more frequently with givosiran included increased serum transaminases and decreased estimated glomerular filtration rate (eGFR).
## Chronic (Cutaneous) Manifestations
Treatment of Low-Grade Chronic or Seasonal Cutaneous Symptoms in Individuals with Hereditary Coproporphyria
Damage is caused by blue light and long-wave ultraviolet light (UVA), both of which pass through window glass.
Note: The association of cutaneous manifestations with severe attacks (in which porphyrins as well as ALA and PBG are markedly increased) suggests that the cutaneous as well as the neurovisceral symptoms could respond to hematin administration. Indeed, this is the finding of a case report of an individual with severe HCP who was given "maintenance" hematin [
## Prevention of Primary Manifestations
Prevention of Acute Attacks in
A copper-releasing IUD is theoretically the safest in women w/porphyria.
A hormone-releasing IUD may also be safe because the systemic ↑ in hormone is quite small; however, little information exists on its use in women w/acute porphyria.
Leuprolide, nafarelin, & other GnRH agonists may help those who experience monthly exacerbations.
If menopausal side effects occur, they can be treated by adding low-dose estrogen.
GnRH = gonadotropin-releasing hormone; IUD = intrauterine device
Oral contraceptives (birth control pills) are risky and not recommended.
• A copper-releasing IUD is theoretically the safest in women w/porphyria.
• A hormone-releasing IUD may also be safe because the systemic ↑ in hormone is quite small; however, little information exists on its use in women w/acute porphyria.
• Leuprolide, nafarelin, & other GnRH agonists may help those who experience monthly exacerbations.
• If menopausal side effects occur, they can be treated by adding low-dose estrogen.
## Surveillance
For those who have chronically elevated ALA (which is infrequent in those who are asymptomatic) and/or are older than age 60 years, an annual assessment of liver and kidney function is recommended.
Current noninvasive techniques for evaluation of fibrosis in the liver include transient elastography (FibroScan
For affected individuals older than age 60 and anyone with evidence of chronic liver injury, annual screening for hepatocellular carcinoma with abdominal imaging (e.g., ultrasound) and serum alpha-fetoprotein is indicated [
## Agents/Circumstances to Avoid
Avoid the following:
In theory, the most dangerous medications are inducers of CYPs, such as barbiturates and the related compound, phenytoin.
• In theory, the most dangerous medications are inducers of CYPs, such as barbiturates and the related compound, phenytoin.
## Evaluation of Relatives at Risk
It is appropriate to evaluate relatives at risk for HCP in order to identify as early as possible those who would benefit from education regarding the risk factors associated with acute attacks.
If the
If the
See
• If the
• If the
## Pregnancy Management
The effect of pregnancy on inducing acute attacks is unpredictable. In general, serious problems during pregnancy are unusual. In fact, some women with recurrent symptoms associated with the menstrual cycle report improvement during pregnancy. Attacks, if they occur, are usually in the first trimester. The women most at risk are those with hyperemesis gravidarum and inadequate caloric intake [
The experience with administration of hematin (or heme arginate, which is not available in the US) during pregnancy is limited.
No human pregnancies have been reported during or after treatment with givosiran. In animal studies of reproduction, doses of givosiran that caused maternal toxicity in rabbits also resulted in adverse developmental outcomes. In pregnant rats, givosiran given at doses up to 30 mg/kg did not cause developmental defects in the offspring. There are no data on the presence of givosiran in human milk. Women with HCP should discuss the risks and benefits of continuing givosiran with their physician prior to conception.
See
## Therapies Under Investigation
Hematin for infusion (Panhematin
Alternatives are under investigation. One is gene therapy in which the normal gene (
Search
## Genetic Counseling
Hereditary coproporphyria (HCP) is inherited in an autosomal dominant manner.
Most individuals with HCP have an affected parent.
A proband with HCP may harbor a
Recommendations for the evaluation of parents of a proband with an apparent
Evaluation of parents may determine that one has a
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is heterozygous for the
If the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. Parents are encouraged to seek genetic counseling before reaching a decision on the use of prenatal testing.
Note: The presence of a
• Most individuals with HCP have an affected parent.
• A proband with HCP may harbor a
• Recommendations for the evaluation of parents of a proband with an apparent
• Evaluation of parents may determine that one has a
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is heterozygous for the
• If the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Hereditary coproporphyria (HCP) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals with HCP have an affected parent.
A proband with HCP may harbor a
Recommendations for the evaluation of parents of a proband with an apparent
Evaluation of parents may determine that one has a
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
If a parent of the proband is heterozygous for the
If the
• Most individuals with HCP have an affected parent.
• A proband with HCP may harbor a
• Recommendations for the evaluation of parents of a proband with an apparent
• Evaluation of parents may determine that one has a
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is heterozygous for the
• If the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. Parents are encouraged to seek genetic counseling before reaching a decision on the use of prenatal testing.
Note: The presence of a
## Resources
United Kingdom
Canada
American Porphyria Foundation
South Africa
United Kingdom
Sweden
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•
•
• United Kingdom
•
•
• Canada
•
•
• American Porphyria Foundation
•
•
•
•
• South Africa
•
•
•
•
•
• United Kingdom
•
•
•
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• Sweden
•
## Molecular Genetics
Hereditary Coproporphyria: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hereditary Coproporphyria (
The 110-residue N-terminal segment is responsible for targeting the enzyme to mitochondria and is the site of its action on the substrate, coproporphyrinogen. Pathogenic variants in this region may affect translocation of the protein and, thus, reduce enzymatic function in tissues without changing activity in cell extracts.
## Chapter Notes
The work has been carried out under the auspices of the Porphyria Rare Disease Clinical Research Consortium (KE Anderson, Galveston, TX; DM Bissell, San Francisco, CA; JR Bloomer, Birmingham AL; HL Bonkowsky, Charlotte, NC; RJ Desnick, New York, NY; and JD Phillips, Salt Lake City, UT). The Consortium receives essential support from the NIH/NIDDK (1 U54 DK083909) and the American Porphyria Foundation.
D Montgomery Bissell, MD (2012-present)Theora Cimino, BS; University of California San Francisco (2012-2015)Jennifer Lai, MD; University of California San Francisco (2012-2018)Bruce Wang, MD (2012-present)
19 May 2022 (bp) Revision: added information about givosiran, an FDA-approved prophylactic treatment for individuals with HCP with frequent recurrent acute neurovisceral pain episodes, in
8 November 2018 (ma) Comprehensive update posted live
1 July 2015 (me) Comprehensive update posted live
13 December 2012 (me) Review posted live
9 April 2012 (mb/bw) Original submission
• 19 May 2022 (bp) Revision: added information about givosiran, an FDA-approved prophylactic treatment for individuals with HCP with frequent recurrent acute neurovisceral pain episodes, in
• 8 November 2018 (ma) Comprehensive update posted live
• 1 July 2015 (me) Comprehensive update posted live
• 13 December 2012 (me) Review posted live
• 9 April 2012 (mb/bw) Original submission
## Acknowledgments
The work has been carried out under the auspices of the Porphyria Rare Disease Clinical Research Consortium (KE Anderson, Galveston, TX; DM Bissell, San Francisco, CA; JR Bloomer, Birmingham AL; HL Bonkowsky, Charlotte, NC; RJ Desnick, New York, NY; and JD Phillips, Salt Lake City, UT). The Consortium receives essential support from the NIH/NIDDK (1 U54 DK083909) and the American Porphyria Foundation.
## Author History
D Montgomery Bissell, MD (2012-present)Theora Cimino, BS; University of California San Francisco (2012-2015)Jennifer Lai, MD; University of California San Francisco (2012-2018)Bruce Wang, MD (2012-present)
## Revision History
19 May 2022 (bp) Revision: added information about givosiran, an FDA-approved prophylactic treatment for individuals with HCP with frequent recurrent acute neurovisceral pain episodes, in
8 November 2018 (ma) Comprehensive update posted live
1 July 2015 (me) Comprehensive update posted live
13 December 2012 (me) Review posted live
9 April 2012 (mb/bw) Original submission
• 19 May 2022 (bp) Revision: added information about givosiran, an FDA-approved prophylactic treatment for individuals with HCP with frequent recurrent acute neurovisceral pain episodes, in
• 8 November 2018 (ma) Comprehensive update posted live
• 1 July 2015 (me) Comprehensive update posted live
• 13 December 2012 (me) Review posted live
• 9 April 2012 (mb/bw) Original submission
## References
## Literature Cited
Excretion profile of the hepatic porphyrias
Profile of heme precursor excretion for the types of hepatic porphyria. The pathway of heme synthesis (arrows) is served by a series of enzymes (boxes). Pathogenic variants that decrease the function of a particular enzyme change the profile of heme precursors in urine and/or stool (vertical dashed lines) to one that is characteristic of the specific type of porphyria. The vertical bars depict the relative change in each metabolite, not the absolute amount. To illustrate, the urine PBG in HCP and AIP during an attack may reach similar levels.
Enzyme abbreviations:
ALAD = delta-aminolevulinic acid (ALA) dehydratase
HMBS = hydroxymethylbilane synthase; also known as porphobilinogen (PBG) deaminase
UROD = uroporphyrinogen (UROgen) decarboxylase
CPOX = coproporphyrinogen(COPROgen) decarboxylase
PPOX = protoporphyrinogen(PROTOgen) decarboxylase
FECH = ferrochelatase
|
[
"N Aggarwal, R Bagga, H Sawhney, V Suri, K Vasishta. Pregnancy with acute intermittent porphyria: a case report and review of literature.. J Obstet Gynaecol Res. 2002;28:160-2",
"R Akagi, R Inoue, S Muranaka, T Tahara, S Taketani, KE Anderson, JD Phillips, S Sassa. Dual gene defects involving delta-aminolaevulinate dehydratase and coproporphyrinogen oxidase in a porphyria patient.. Br J Haematol. 2006;132:237-43",
"KE Anderson, JR Bloomer, HL Bonkovsky, JP Kushner, CA Pierach, NR Pimstone, RJ Desnick. Recommendations for the diagnosis and treatment of the acute porphyrias.. Ann Intern Med. 2005;142:439-50",
"KE Anderson, HL Bonkovsky, JR Bloomer, SI Shedlofsky. Reconstitution of hematin for intravenous infusion.. Ann Intern Med. 2006;144:537-8",
"C Andersson, E Innala, T Bäckström. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden.. J Intern Med. 2003;254:176-83",
"MN Badminton, JC Deybach. Treatment of an acute attack of porphyria during pregnancy.. Eur J Neurol. 2006;13:668-9",
"M Balwani, E Sardh, P Ventura, PA Peiró, DC Rees, U Stölzel, DM Bissell, HL Bonkovsky, J Windyga, KE Anderson, C Parker, SM Silver, SB Keel, JD Wang, PE Stein, P Harper, D Vassiliou, B Wang, J Phillips, A Ivanova, JG Langendonk, R Kauppinen, E Minder, Y Horie, C Penz, J Chen, S Liu, JJ Ko, MT Sweetser, P Garg, A Vaishnaw, JB Kim, AR Simon, L Gouya. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria.. N Engl J Med. 2020;382:2289-301",
"M Balwani, B Wang, KE Anderson, JR Bloomer, DM Bissell, HL Bonkovsky, JD Phillips, RJ Desnick. Acute hepatic porphyrias: recommendations for evaluation and long-term management.. Hepatology. 2017;66:1314-22",
"M Barbaro, M Kotajärvi, P Harper, Y. Floderus. Identification of an AluY-mediated deletion of exon 5 in the CPOX gene by MLPA analysis in patients with hereditary coproporphyria.. Clin Genet. 2012;81:249-56",
"BH Billing. Twenty-five years of progress in bilirubin metabolism (1952-77).. Gut. 1978;19:481-91",
"DM Bissell, JC Lai, RK Meister, PD Blanc. Role of delta-aminolevulinic acid in the symptoms of acute porphyria.. Am J Med. 2015;128:313-7",
"D Blake, J McManus, V Cronin, S Ratnaike. Fecal coproporphyrin isomers in hereditary coproporphyria.. Clin Chem. 1992;38:96-100",
"HL Bonkovsky, P Siao, Z Roig, ET Hedley-Whyte, TJ Flotte. Case records of the Massachusetts General Hospital. Case 20-2008. A 57-year-old woman with abdominal pain and weakness after gastric bypass surgery.. N Engl J Med. 2008;358:2813-25",
"MJ Brodie, GG Thompson, MR Moore, AD Beattie, A Goldberg. Hereditary coproporphyria. Demonstration of the abnormalities in haem biosynthesis in peripheral blood.. Q J Med. 1977;46:229-41",
"A Chan, A Liebow, M Yasuda, L Gan, T Racie, M Maier, S Kuchimanchi, D Foster, S Milstein, K Charisse, A Sehgal, M Manoharan, R Meyers, K Fitzgerald, A Simon, RJ Desnick, W Querbes. Preclinical development of a subcutaneous ALAS1 RNAi therapeutic for treatment of hepatic porphyrias using circulating RNA quantification.. Mol Ther Nucleic Acids. 2015;4",
"JK Dowman, BK Gunson, S Bramhall, MN Badminton, PN Newsome. Liver transplantation from donors with acute intermittent porphyria.. Ann Intern Med. 2011;154:571-2",
"A Farfaras, F Zagouri, G Zografos, A Kostopoulou, TN Sergentanis, S Antoniou. Acute intermittent porphyria in pregnancy: a common misdiagnosis.. Clin Exp Obstet Gynecol. 2010;37:256-60",
"PR Gibson, J Grant, V Cronin, D Blake, S Ratnaike. Effect of hepatobiliary disease, chronic hepatitis C and hepatitis B virus infections and interferon-alpha on porphyrin profiles in plasma, urine and faeces.. J Gastroenterol Hepatol. 2000;15:192-201",
"CA Goetsch, DM Bissell. Instability of hematin used in the treatment of acute hepatic porphyria.. N Engl J Med. 1986;315:235-8",
"R Grimes, Y Gilleece, T Appleby, S Stockwell, N Pinto-Sander, T Sahabandu, P Stein, D. Bradshaw. A case of hereditary coproporphyria precipitated by efavirenz.. AIDS 2016;30:2142-3",
"S Haimowitz, J Hsieh, M Shcherba, Y. Averbukh. Liver failure after Hydroxycut™ use in a patient with undiagnosed hereditary coproporphyria.. J Gen Intern Med. 2015;30:856-9",
"A Hasanoglu, M Balwani, CS Kasapkara, FS Ezgü, I Okur, L Tümer, A Cakmak, I Nazarenko, C Yu, S Clavero, DF Bishop, RJ Desnick. Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R.. J Inherit Metab Dis. 2011;34:225-31",
"K Hasegawa, H Tanaka, M Yamashita, Y Higuchi, T Miyai, J Yoshimoto, A Okada, N Suzuki, K Iwatsuki, H. Tsukahara. Neonatal-onset hereditary coproporphyria: a new variant of hereditary coproporphyria.. JIMD Rep. 2017;37:99-106",
"M Isenschmid, C König, C Fässli, A Haenel, W Hänggi, H Schneider. Acute intermittent porphyria in pregnancy: glucose or hematin therapy?. Schweiz Med Wochenschr. 1992;122:1741-5",
"A Jara-Prado, P Yescas, FJ Sánchez, C Ríos, R Garnica, E Alonso. Prevalence of acute intermittent porphyria in a Mexican psychiatric population.. Arch Med Res. 2000;31:404-8",
"A Kühnel, U Gross, MO Doss. Hereditary coproporphyria in Germany: clinical-biochemical studies in 53 patients.. Clin Biochem. 2000;33:465-73",
"D Lambie, C Florkowski, C Sies, A Raizis, WK Siu, C Towns. A case of hereditary coproporphyria with posterior reversible encephalopathy and novel coproporphyrinogen oxidase gene mutation c.863T>G (p.Leu288Trp).. Ann Clin Biochem. 2018;55:616-19",
"J Lamoril, H Puy, SD Whatley, C Martin, JR Woolf, V Da Silva, JC Deybach, GH Elder. Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria.. Am J Hum Genet. 2001;68:1130-8",
"DS Lee, E Flachsová, M Bodnárová, B Demeler, P Martásek, CS Raman. Structural basis of hereditary coproporphyria.. Proc Natl Acad Sci U S A. 2005;102:14232-7",
"E Ma, V Mar, G Varigos, A Nicoll, G Ross. Haem arginate as effective maintenance therapy for hereditary coproporphyria.. Australas J Dermatol. 2011;52:135-8",
"R Rosipal, J Lamoril, H Puy, V Da Silva, L Gouya, FW De Rooij, K Te Velde, Y Nordmann, P Martàsek, JC Deybach. Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update.. Hum Mutat. 1999;13:44-53",
"M Sadeh, I Blatt, G Martonovits, A Karni, Y Goldhammer. Treatment of porphyric convulsions with magnesium sulfate.. Epilepsia. 1991;32:712-5",
"E Sardh, S Wahlin, M Björnstedt, P Harper, DE Andersson. High risk of primary liver cancer in a cohort of 179 patients with acute hepatic porphyria.. J Inherit Metab Dis. 2013;36:1063-71",
"C Schmitt, L Gouya, E Malonova, J Lamoril, JM Camadro, M Flamme, C Rose, S Lyoumi, V Da Silva, C Boileau, B Grandchamp, C Beaumont, JC Deybach, H Puy. Mutations in human CPO gene predict clinical expression of either hepatic hereditary coproporphyria or erythropoietic harderoporphyria.. Hum Mol Genet. 2005;14:3089-98",
"S Shenhav, O Gemer, E Sassoon, S Segal. Acute intermittent porphyria precipitated by hyperemesis and metoclopramide treatment in pregnancy.. Acta Obstet Gynecol Scand. 1997;76:484-5",
"ZF Soonawalla, T Orug, MN Badminton, GH Elder, JM Rhodes, SR Bramhall, E Elias. Liver transplantation as a cure for acute intermittent porphyria.. Lancet. 2004;363:705-6",
"TP Tran, K Leduc, M Savard, N Dupré, D Rivest, DK Nguyen. Acute porphyria presenting as epilepsia partialis continua.. Case Rep Neurol. 2013;5:116-24",
"E van de Steeg, V Stránecký, H Hartmannová, L Nosková, M Hřebíček, E Wagenaar, A van Esch, DR de Waart, RP Oude Elferink, KE Kenworthy, E Sticová, M al-Edreesi, AS Knisely, S Kmoch, M Jirsa, AH Schinkel. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.. J Clin Invest. 2012;122:519-28",
"AM van Tuyll van Serooskerken, FW de Rooij, A Edixhoven, RS Bladergroen, JM Baron, S Joussen, HF Merk, PM Steijlen, P Poblete-Gutiérrez, K te Velde, JH Wilson, RH Koole, M van Geel, J Frank. Digenic inheritance of mutations in the coproporphyrinogen oxidase and protoporphyrinogen oxidase genes in a unique type of porphyria.. J Invest Dermatol. 2011;131:2249-54",
"AE Vercesi, RF Castilho, AR Meinicke, VG Valle, M Hermes-Lima, EJ Bechara. Oxidative damage of mitochondria induced by 5-aminolevulinic acid: role of Ca2+ and membrane protein thiols.. Biochim Biophys Acta. 1994;1188:86-92",
"SD Whatley, NG Mason, JR Woolf, RG Newcombe, GH Elder, MN Badminton. Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX, or PPOX gene.. Clin Chem. 2009;55:1406-14"
] |
13/12/2012
|
8/11/2018
|
19/5/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
hd-l2
|
hd-l2
|
[
"Junctophilin-3",
"JPH3",
"Huntington Disease-Like 2"
] |
Huntington Disease-Like 2
|
David G Anderson, Amanda Krause, Russell L Margolis
|
Summary Huntington disease-like 2 (HDL2) typically presents in midlife with a relentless progressive triad of movement, emotional, and cognitive abnormalities that lead to death within ten to 20 years. HDL2 cannot be differentiated from Huntington disease (HD) clinically. Neurologic abnormalities include chorea, hypokinesia (rigidity, bradykinesia), dysarthria, abnormalities of eye movements and gait, and hyperreflexia in the later stages of the disease. There is a strong correlation between the duration of the disease and the progression of motor and cognitive signs and symptoms. The diagnosis of HDL2 is established in a proband with characteristic clinical findings and heterozygous expansion of 40 or more CTG trinucleotide repeats in HDL2 is inherited in an autosomal dominant manner. Most individuals with HDL2 have an affected parent. At conception, each child of an individual with HDL2 has a 50% chance of inheriting the HDL2-causing allele. Offspring who inherit a pathogenic (full-penetrance) HDL2-causing allele (≥40 CTG repeats) are considered at risk of developing HDL2 in their lifetime; offspring who inherit an allele of questionable significance (29-39 CTG repeats) may or may not develop manifestations of HDL2. Testing of asymptomatic adults at risk for HDL2 is possible once a heterozygous expansion of a CTG repeat in
|
## Diagnosis
Huntington disease-like 2 (HDL2)
Progressive motor disability featuring involuntary movements (especially chorea) and affecting voluntary movement (e.g., gait, speech, swallowing). Rigidity and bradykinesia may predominate in the later stages of the disease.
Psychiatric disturbances including changes in personality and depression
Progressive dementia
The diagnosis of HDL2
Note: (1) A woman age 48 years with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus with little or no progression) had a
Notes: (1) One individual (in a family with a proband with clinically, neuropathologically, and molecularly defined HDL2) had an expanded allele of 44 CTG repeats without clear evidence of clinical HDL2 at age 65 years. It is possible that the effects of a mild stroke several years prior to examination masked signs of HDL2. (2) PCR-based assays, standard in genetic laboratories, are typically accurate to within ~±1 triplet, complicating interpretation of alleles of borderline length. (3) An allele with 39 CTG repeats has been reported in an individual with an HDL2 phenotype. (4) The longest repeat expansion detected to date is 63 CTG repeats.
Molecular Genetic Testing Used in Huntington Disease-Like 2
See
See
Detects CTG trinucleotide repeat number. PCR-based methods can detect expanded alleles, including the largest reported allele of 63 CTG repeats [
The test should detect nearly all expanded alleles [
• Progressive motor disability featuring involuntary movements (especially chorea) and affecting voluntary movement (e.g., gait, speech, swallowing). Rigidity and bradykinesia may predominate in the later stages of the disease.
• Psychiatric disturbances including changes in personality and depression
• Progressive dementia
• Note: (1) A woman age 48 years with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus with little or no progression) had a
• Note: (1) A woman age 48 years with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus with little or no progression) had a
• Notes: (1) One individual (in a family with a proband with clinically, neuropathologically, and molecularly defined HDL2) had an expanded allele of 44 CTG repeats without clear evidence of clinical HDL2 at age 65 years. It is possible that the effects of a mild stroke several years prior to examination masked signs of HDL2. (2) PCR-based assays, standard in genetic laboratories, are typically accurate to within ~±1 triplet, complicating interpretation of alleles of borderline length. (3) An allele with 39 CTG repeats has been reported in an individual with an HDL2 phenotype. (4) The longest repeat expansion detected to date is 63 CTG repeats.
• Note: (1) A woman age 48 years with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus with little or no progression) had a
## Suggestive Findings
Huntington disease-like 2 (HDL2)
Progressive motor disability featuring involuntary movements (especially chorea) and affecting voluntary movement (e.g., gait, speech, swallowing). Rigidity and bradykinesia may predominate in the later stages of the disease.
Psychiatric disturbances including changes in personality and depression
Progressive dementia
• Progressive motor disability featuring involuntary movements (especially chorea) and affecting voluntary movement (e.g., gait, speech, swallowing). Rigidity and bradykinesia may predominate in the later stages of the disease.
• Psychiatric disturbances including changes in personality and depression
• Progressive dementia
## Establishing the Diagnosis
The diagnosis of HDL2
Note: (1) A woman age 48 years with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus with little or no progression) had a
Notes: (1) One individual (in a family with a proband with clinically, neuropathologically, and molecularly defined HDL2) had an expanded allele of 44 CTG repeats without clear evidence of clinical HDL2 at age 65 years. It is possible that the effects of a mild stroke several years prior to examination masked signs of HDL2. (2) PCR-based assays, standard in genetic laboratories, are typically accurate to within ~±1 triplet, complicating interpretation of alleles of borderline length. (3) An allele with 39 CTG repeats has been reported in an individual with an HDL2 phenotype. (4) The longest repeat expansion detected to date is 63 CTG repeats.
Molecular Genetic Testing Used in Huntington Disease-Like 2
See
See
Detects CTG trinucleotide repeat number. PCR-based methods can detect expanded alleles, including the largest reported allele of 63 CTG repeats [
The test should detect nearly all expanded alleles [
• Note: (1) A woman age 48 years with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus with little or no progression) had a
• Note: (1) A woman age 48 years with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus with little or no progression) had a
• Notes: (1) One individual (in a family with a proband with clinically, neuropathologically, and molecularly defined HDL2) had an expanded allele of 44 CTG repeats without clear evidence of clinical HDL2 at age 65 years. It is possible that the effects of a mild stroke several years prior to examination masked signs of HDL2. (2) PCR-based assays, standard in genetic laboratories, are typically accurate to within ~±1 triplet, complicating interpretation of alleles of borderline length. (3) An allele with 39 CTG repeats has been reported in an individual with an HDL2 phenotype. (4) The longest repeat expansion detected to date is 63 CTG repeats.
• Note: (1) A woman age 48 years with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus with little or no progression) had a
## Clinical Characteristics
Like
As in HD, longer CTG repeat length correlates with an earlier age of onset in HDL2 [
For ethical reasons, only a few unaffected individuals from families with HDL2 have been tested; therefore, the penetrance is unknown. One individual with a repeat of 44 triplets did not have evidence of HDL2 at age 65 years, suggesting the possibility of reduced penetrance in some individuals.
Limited evidence from a large index pedigree suggests that anticipation may occur [
HDL2 is occasionally (and incorrectly) referred to as HD2.
Although rare, HDL2 appears to be the most common HD phenocopy in populations with African ancestry, and overall the most prevalent HD-like disorder. These populations include France [
The highest number of affected individuals are from South Africa [
Outside of South Africa, HDL2 has been identified in as few as 1% of individuals with clinically or pathologically defined HD who do not have an
In Brazil, where an estimated 44% of the population is of African descent, as many as 10% of individuals with an HD-like disorder may have HDL2 [
In Venezuela, of 260 unrelated individuals referred for testing based on an HD-like phenotype, 11 (4.2%) had an expanded allele at the
Of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing who had tested negative for the HD-causing expansion, two were found to have the HDL2-causing expansion.
A male age 47 years was the first individual with HDL2 described from Botswana [
A family with HDL2 consisting of a proband and his two children were diagnosed in Mali, the first individuals identified with HDL2 in West Africa [
Among 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, 36% of whom had an autosomal dominant inheritance pattern [
Among 1,600 individuals with movement disorders referred for genetic testing by neurologists in Germany and Austria who did not have an expanded HD allele (including 147 individuals with a family history of chorea), no HDL2-related expansions were found [
If the cases described above are narrowly defined, the frequency of HDL2 is much higher than indicated. For instance, of four individuals identified by
HDL2 has not been identified in any individuals in Japan, though only a small number of individuals have been tested.
HDL2 has been identified in affected individuals from multiple families in the Caribbean.
• The highest number of affected individuals are from South Africa [
• Outside of South Africa, HDL2 has been identified in as few as 1% of individuals with clinically or pathologically defined HD who do not have an
• In Brazil, where an estimated 44% of the population is of African descent, as many as 10% of individuals with an HD-like disorder may have HDL2 [
• In Venezuela, of 260 unrelated individuals referred for testing based on an HD-like phenotype, 11 (4.2%) had an expanded allele at the
• Of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing who had tested negative for the HD-causing expansion, two were found to have the HDL2-causing expansion.
• A male age 47 years was the first individual with HDL2 described from Botswana [
• A family with HDL2 consisting of a proband and his two children were diagnosed in Mali, the first individuals identified with HDL2 in West Africa [
• Among 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, 36% of whom had an autosomal dominant inheritance pattern [
• Among 1,600 individuals with movement disorders referred for genetic testing by neurologists in Germany and Austria who did not have an expanded HD allele (including 147 individuals with a family history of chorea), no HDL2-related expansions were found [
• If the cases described above are narrowly defined, the frequency of HDL2 is much higher than indicated. For instance, of four individuals identified by
• In Brazil, where an estimated 44% of the population is of African descent, as many as 10% of individuals with an HD-like disorder may have HDL2 [
• In Venezuela, of 260 unrelated individuals referred for testing based on an HD-like phenotype, 11 (4.2%) had an expanded allele at the
• Of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing who had tested negative for the HD-causing expansion, two were found to have the HDL2-causing expansion.
• A male age 47 years was the first individual with HDL2 described from Botswana [
• A family with HDL2 consisting of a proband and his two children were diagnosed in Mali, the first individuals identified with HDL2 in West Africa [
• Among 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, 36% of whom had an autosomal dominant inheritance pattern [
• Among 1,600 individuals with movement disorders referred for genetic testing by neurologists in Germany and Austria who did not have an expanded HD allele (including 147 individuals with a family history of chorea), no HDL2-related expansions were found [
• HDL2 has not been identified in any individuals in Japan, though only a small number of individuals have been tested.
• HDL2 has been identified in affected individuals from multiple families in the Caribbean.
• In Brazil, where an estimated 44% of the population is of African descent, as many as 10% of individuals with an HD-like disorder may have HDL2 [
• In Venezuela, of 260 unrelated individuals referred for testing based on an HD-like phenotype, 11 (4.2%) had an expanded allele at the
• Of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing who had tested negative for the HD-causing expansion, two were found to have the HDL2-causing expansion.
• A male age 47 years was the first individual with HDL2 described from Botswana [
• A family with HDL2 consisting of a proband and his two children were diagnosed in Mali, the first individuals identified with HDL2 in West Africa [
• Among 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, 36% of whom had an autosomal dominant inheritance pattern [
• Among 1,600 individuals with movement disorders referred for genetic testing by neurologists in Germany and Austria who did not have an expanded HD allele (including 147 individuals with a family history of chorea), no HDL2-related expansions were found [
## Clinical Description
Like
## Genotype-Phenotype Correlations
As in HD, longer CTG repeat length correlates with an earlier age of onset in HDL2 [
## Penetrance
For ethical reasons, only a few unaffected individuals from families with HDL2 have been tested; therefore, the penetrance is unknown. One individual with a repeat of 44 triplets did not have evidence of HDL2 at age 65 years, suggesting the possibility of reduced penetrance in some individuals.
## Anticipation
Limited evidence from a large index pedigree suggests that anticipation may occur [
## Nomenclature
HDL2 is occasionally (and incorrectly) referred to as HD2.
## Prevalence
Although rare, HDL2 appears to be the most common HD phenocopy in populations with African ancestry, and overall the most prevalent HD-like disorder. These populations include France [
The highest number of affected individuals are from South Africa [
Outside of South Africa, HDL2 has been identified in as few as 1% of individuals with clinically or pathologically defined HD who do not have an
In Brazil, where an estimated 44% of the population is of African descent, as many as 10% of individuals with an HD-like disorder may have HDL2 [
In Venezuela, of 260 unrelated individuals referred for testing based on an HD-like phenotype, 11 (4.2%) had an expanded allele at the
Of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing who had tested negative for the HD-causing expansion, two were found to have the HDL2-causing expansion.
A male age 47 years was the first individual with HDL2 described from Botswana [
A family with HDL2 consisting of a proband and his two children were diagnosed in Mali, the first individuals identified with HDL2 in West Africa [
Among 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, 36% of whom had an autosomal dominant inheritance pattern [
Among 1,600 individuals with movement disorders referred for genetic testing by neurologists in Germany and Austria who did not have an expanded HD allele (including 147 individuals with a family history of chorea), no HDL2-related expansions were found [
If the cases described above are narrowly defined, the frequency of HDL2 is much higher than indicated. For instance, of four individuals identified by
HDL2 has not been identified in any individuals in Japan, though only a small number of individuals have been tested.
HDL2 has been identified in affected individuals from multiple families in the Caribbean.
• The highest number of affected individuals are from South Africa [
• Outside of South Africa, HDL2 has been identified in as few as 1% of individuals with clinically or pathologically defined HD who do not have an
• In Brazil, where an estimated 44% of the population is of African descent, as many as 10% of individuals with an HD-like disorder may have HDL2 [
• In Venezuela, of 260 unrelated individuals referred for testing based on an HD-like phenotype, 11 (4.2%) had an expanded allele at the
• Of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing who had tested negative for the HD-causing expansion, two were found to have the HDL2-causing expansion.
• A male age 47 years was the first individual with HDL2 described from Botswana [
• A family with HDL2 consisting of a proband and his two children were diagnosed in Mali, the first individuals identified with HDL2 in West Africa [
• Among 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, 36% of whom had an autosomal dominant inheritance pattern [
• Among 1,600 individuals with movement disorders referred for genetic testing by neurologists in Germany and Austria who did not have an expanded HD allele (including 147 individuals with a family history of chorea), no HDL2-related expansions were found [
• If the cases described above are narrowly defined, the frequency of HDL2 is much higher than indicated. For instance, of four individuals identified by
• In Brazil, where an estimated 44% of the population is of African descent, as many as 10% of individuals with an HD-like disorder may have HDL2 [
• In Venezuela, of 260 unrelated individuals referred for testing based on an HD-like phenotype, 11 (4.2%) had an expanded allele at the
• Of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing who had tested negative for the HD-causing expansion, two were found to have the HDL2-causing expansion.
• A male age 47 years was the first individual with HDL2 described from Botswana [
• A family with HDL2 consisting of a proband and his two children were diagnosed in Mali, the first individuals identified with HDL2 in West Africa [
• Among 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, 36% of whom had an autosomal dominant inheritance pattern [
• Among 1,600 individuals with movement disorders referred for genetic testing by neurologists in Germany and Austria who did not have an expanded HD allele (including 147 individuals with a family history of chorea), no HDL2-related expansions were found [
• HDL2 has not been identified in any individuals in Japan, though only a small number of individuals have been tested.
• HDL2 has been identified in affected individuals from multiple families in the Caribbean.
• In Brazil, where an estimated 44% of the population is of African descent, as many as 10% of individuals with an HD-like disorder may have HDL2 [
• In Venezuela, of 260 unrelated individuals referred for testing based on an HD-like phenotype, 11 (4.2%) had an expanded allele at the
• Of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing who had tested negative for the HD-causing expansion, two were found to have the HDL2-causing expansion.
• A male age 47 years was the first individual with HDL2 described from Botswana [
• A family with HDL2 consisting of a proband and his two children were diagnosed in Mali, the first individuals identified with HDL2 in West Africa [
• Among 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, 36% of whom had an autosomal dominant inheritance pattern [
• Among 1,600 individuals with movement disorders referred for genetic testing by neurologists in Germany and Austria who did not have an expanded HD allele (including 147 individuals with a family history of chorea), no HDL2-related expansions were found [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
## Differential Diagnosis
The differential diagnosis of Huntington disease-like 2 (HDL2) is the same as for
The most obvious diagnosis to exclude is HD. HD and other genetic disorders to consider are summarized in
Genetic Disorders of Interest in the Differential Diagnosis of Huntington Disease-Like 2
Progressive movement disorder & dementia
Psychiatric disturbances
Prominent ataxia & myoclonus
Extremely rare outside of Japanese populations
Movement disorders
Psychiatric disorders
Liver disease
Kayser-Fleischer rings
Copper abnormalities
Note: Exclusion is essential, as Wilson disease is treatable.
Dystonia or chorea (38%)
Dementia (37%)
Parkinsonism
Oculomotor dysfunction
Choreiform movement disorders
Dementia
Neuropsychiatric manifestations
Chorea
Dystonia
Speech & swallowing deficits
Dementia rare
From disease onset, all affected persons have evidence of excess brain iron accumulation on T
Parkinsonian manifestations
Dementia
Behavioral & psychiatric manifestations
Infancy or childhood onset
Chorea is non-progressive.
Not assoc w/dementia
Parkinsonism
Dystonia
Dementia
Childhood onset w/early falls & visual disturbances
MRI features
Progressive movement disorder (clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping)
Neuropsychiatric features (ranging from mild difficulty w/concentration & memory to changes in personality &/or behavior, psychosis, & dementia)
Progressive dementia
Movement disorders
Psychiatric manifestations
Progresses more rapidly than HDL2
Prominent myoclonus
Chorea
Dementia
Psychiatric disturbances
Progressive movement disorder
Progressive cognitive & behavior changes
Myopathy
↑ serum concentration of muscle CK
Acanthocytosis
Seizures common
Mean onset age ~30 yrs
Cognitive impairment
Psychiatric manifestations
Chorea
Acanthocytosis, compensated hemolysis, & McLeod blood group phenotype
Seizures
Peripheral neuropathy
Hyporeflexia
Cardiomyopathy
Hepatosplenomegaly
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; HDL2 = Huntington disease-like 2; MOI = mode of inheritance; XL = X-linked
Other genetic disorders to consider in the differential diagnosis of HDL2 include the following:
Hereditary cerebellar ataxia (See
HDL2-like manifestations can also arise from drugs including antipsychotics, anticonvulsants, oral contraceptives, lithium, and stimulants.
• Progressive movement disorder & dementia
• Psychiatric disturbances
• Prominent ataxia & myoclonus
• Extremely rare outside of Japanese populations
• Movement disorders
• Psychiatric disorders
• Liver disease
• Kayser-Fleischer rings
• Copper abnormalities
• Note: Exclusion is essential, as Wilson disease is treatable.
• Dystonia or chorea (38%)
• Dementia (37%)
• Parkinsonism
• Oculomotor dysfunction
• Choreiform movement disorders
• Dementia
• Neuropsychiatric manifestations
• Chorea
• Dystonia
• Speech & swallowing deficits
• Dementia rare
• From disease onset, all affected persons have evidence of excess brain iron accumulation on T
• Parkinsonian manifestations
• Dementia
• Behavioral & psychiatric manifestations
• Infancy or childhood onset
• Chorea is non-progressive.
• Not assoc w/dementia
• Parkinsonism
• Dystonia
• Dementia
• Childhood onset w/early falls & visual disturbances
• MRI features
• Progressive movement disorder (clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping)
• Neuropsychiatric features (ranging from mild difficulty w/concentration & memory to changes in personality &/or behavior, psychosis, & dementia)
• Progressive dementia
• Movement disorders
• Psychiatric manifestations
• Progresses more rapidly than HDL2
• Prominent myoclonus
• Chorea
• Dementia
• Psychiatric disturbances
• Progressive movement disorder
• Progressive cognitive & behavior changes
• Myopathy
• ↑ serum concentration of muscle CK
• Acanthocytosis
• Seizures common
• Mean onset age ~30 yrs
• Cognitive impairment
• Psychiatric manifestations
• Chorea
• Acanthocytosis, compensated hemolysis, & McLeod blood group phenotype
• Seizures
• Peripheral neuropathy
• Hyporeflexia
• Cardiomyopathy
• Hepatosplenomegaly
•
• Hereditary cerebellar ataxia (See
•
## Management
Systematic clinical practice guidelines for Huntington disease-like 2 (HDL2) have not been established, though potential treatment, primarily based on
To establish the extent of disease and needs in an individual diagnosed with HDL2, the evaluations summarized in
Huntington Disease-Like 2: Recommended Evaluations Following Initial Diagnosis
Assessment of full range of motor & cognitive skills
Assessment for abnormal movements
Assessment for speech & swallowing abnormalities
Speech-language pathologist eval as needed
Community or
Social work involvement
Home nursing referral
Legal assistance (e.g., power of attorney, estate planning)
Financial planning
CQNE = Clinical Quantitative Neurological Examination; HDL2 = Huntington disease-like 2; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; MOI = mode of inheritance; UHDRS = Unified Huntington Disease Rating Scale
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Supportive care to improve quality of life, maximize function, and reduce complications is based on the treatment for HD and other neurodegenerative disorders. This ideally involves multidisciplinary care by specialists in relevant fields (see
Huntington Disease-Like 2: Treatment of Manifestations
Implementation of safety precautions, particularly at home: removal of loose rugs & clutter, minimizing or elimination of need for stairs
PT eval & mgmt to provide strategies/devices to minimize falls
Speech therapy referral
Communication devices
Environmental modifications
Speech-language pathology & nutrition referrals
Food preparation may need to be altered to prevent choking.
Feeding changes should be implemented when necessary to minimize risk of aspiration.
Careful assessment of competency for driving
Planning for financial matters (e.g., assigning power of attorney)
Environmental interventions (establishing regular schedules, easing of expectations to maintain family finances, encouraging use of lists to assist w/memory) may help.
The affected person, family members, & care providers should be educated re likely course of disease.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support (see
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Assurance that cognitive decline, depression, apathy, & irritability are manifestations of the disease rather than the "fault" of the affected person can decrease stress & guilt.
Ongoing assessment of need for palliative care involvement &/or home nursing
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Huntington Disease-Like 2: Recommended Surveillance
Assessment of fine motor & gross motor skills incl gait (using UHDRS or CQNE)
Assessment for use of assistive devices
Assessment for abnormal movements
PT assessment of mobility & appropriate strategies/devices to minimize risk of falls
Assessment of cognitive skills (using MMSE or MoCA)
Assessment of driving safety
Consider formal driving safety evaluations if safety is uncertain.
Assessment of weight
Assessment of nutrition, swallowing, & risk of aspiration
Assessment for mood, suicidality, threats to others, personality changes, apathy, irritability, aggression, hallucinations, delusions, & obsessive-compulsive symptoms
Must include reports from informants
Goal is to implement treatment or environmental modifications to decrease distress & physical risks for affected person & family / care providers
Assessment of sleep & sexual concerns
CQNE = Clinical Quantitative Neurological Examination; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; PT = physical therapy; UHDRS = Unified Huntington Disease Rating Scale
Any agents that increase ataxia should be used with caution.
Individuals with HDL2, like those with other neurodegenerative disorders, are vulnerable to delirium from medical illnesses and medicines. Particular caution is necessary to minimize polypharmacy, high doses, or rapid dose increases of medicines.
See
There is no specific information available about disease management during pregnancy. Prudence suggests close attention to prevention of falls and monitoring for swallowing difficulties. Medications should be reviewed to assess their safety during pregnancy. See
Search
• Assessment of full range of motor & cognitive skills
• Assessment for abnormal movements
• Assessment for speech & swallowing abnormalities
• Speech-language pathologist eval as needed
• Community or
• Social work involvement
• Home nursing referral
• Legal assistance (e.g., power of attorney, estate planning)
• Financial planning
• Implementation of safety precautions, particularly at home: removal of loose rugs & clutter, minimizing or elimination of need for stairs
• PT eval & mgmt to provide strategies/devices to minimize falls
• Speech therapy referral
• Communication devices
• Environmental modifications
• Speech-language pathology & nutrition referrals
• Food preparation may need to be altered to prevent choking.
• Feeding changes should be implemented when necessary to minimize risk of aspiration.
• Careful assessment of competency for driving
• Planning for financial matters (e.g., assigning power of attorney)
• Environmental interventions (establishing regular schedules, easing of expectations to maintain family finances, encouraging use of lists to assist w/memory) may help.
• The affected person, family members, & care providers should be educated re likely course of disease.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support (see
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Assurance that cognitive decline, depression, apathy, & irritability are manifestations of the disease rather than the "fault" of the affected person can decrease stress & guilt.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Assessment of fine motor & gross motor skills incl gait (using UHDRS or CQNE)
• Assessment for use of assistive devices
• Assessment for abnormal movements
• PT assessment of mobility & appropriate strategies/devices to minimize risk of falls
• Assessment of cognitive skills (using MMSE or MoCA)
• Assessment of driving safety
• Consider formal driving safety evaluations if safety is uncertain.
• Assessment of weight
• Assessment of nutrition, swallowing, & risk of aspiration
• Assessment for mood, suicidality, threats to others, personality changes, apathy, irritability, aggression, hallucinations, delusions, & obsessive-compulsive symptoms
• Must include reports from informants
• Goal is to implement treatment or environmental modifications to decrease distress & physical risks for affected person & family / care providers
• Assessment of sleep & sexual concerns
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with HDL2, the evaluations summarized in
Huntington Disease-Like 2: Recommended Evaluations Following Initial Diagnosis
Assessment of full range of motor & cognitive skills
Assessment for abnormal movements
Assessment for speech & swallowing abnormalities
Speech-language pathologist eval as needed
Community or
Social work involvement
Home nursing referral
Legal assistance (e.g., power of attorney, estate planning)
Financial planning
CQNE = Clinical Quantitative Neurological Examination; HDL2 = Huntington disease-like 2; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; MOI = mode of inheritance; UHDRS = Unified Huntington Disease Rating Scale
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Assessment of full range of motor & cognitive skills
• Assessment for abnormal movements
• Assessment for speech & swallowing abnormalities
• Speech-language pathologist eval as needed
• Community or
• Social work involvement
• Home nursing referral
• Legal assistance (e.g., power of attorney, estate planning)
• Financial planning
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is based on the treatment for HD and other neurodegenerative disorders. This ideally involves multidisciplinary care by specialists in relevant fields (see
Huntington Disease-Like 2: Treatment of Manifestations
Implementation of safety precautions, particularly at home: removal of loose rugs & clutter, minimizing or elimination of need for stairs
PT eval & mgmt to provide strategies/devices to minimize falls
Speech therapy referral
Communication devices
Environmental modifications
Speech-language pathology & nutrition referrals
Food preparation may need to be altered to prevent choking.
Feeding changes should be implemented when necessary to minimize risk of aspiration.
Careful assessment of competency for driving
Planning for financial matters (e.g., assigning power of attorney)
Environmental interventions (establishing regular schedules, easing of expectations to maintain family finances, encouraging use of lists to assist w/memory) may help.
The affected person, family members, & care providers should be educated re likely course of disease.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support (see
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Assurance that cognitive decline, depression, apathy, & irritability are manifestations of the disease rather than the "fault" of the affected person can decrease stress & guilt.
Ongoing assessment of need for palliative care involvement &/or home nursing
• Implementation of safety precautions, particularly at home: removal of loose rugs & clutter, minimizing or elimination of need for stairs
• PT eval & mgmt to provide strategies/devices to minimize falls
• Speech therapy referral
• Communication devices
• Environmental modifications
• Speech-language pathology & nutrition referrals
• Food preparation may need to be altered to prevent choking.
• Feeding changes should be implemented when necessary to minimize risk of aspiration.
• Careful assessment of competency for driving
• Planning for financial matters (e.g., assigning power of attorney)
• Environmental interventions (establishing regular schedules, easing of expectations to maintain family finances, encouraging use of lists to assist w/memory) may help.
• The affected person, family members, & care providers should be educated re likely course of disease.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support (see
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Assurance that cognitive decline, depression, apathy, & irritability are manifestations of the disease rather than the "fault" of the affected person can decrease stress & guilt.
• Ongoing assessment of need for palliative care involvement &/or home nursing
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Huntington Disease-Like 2: Recommended Surveillance
Assessment of fine motor & gross motor skills incl gait (using UHDRS or CQNE)
Assessment for use of assistive devices
Assessment for abnormal movements
PT assessment of mobility & appropriate strategies/devices to minimize risk of falls
Assessment of cognitive skills (using MMSE or MoCA)
Assessment of driving safety
Consider formal driving safety evaluations if safety is uncertain.
Assessment of weight
Assessment of nutrition, swallowing, & risk of aspiration
Assessment for mood, suicidality, threats to others, personality changes, apathy, irritability, aggression, hallucinations, delusions, & obsessive-compulsive symptoms
Must include reports from informants
Goal is to implement treatment or environmental modifications to decrease distress & physical risks for affected person & family / care providers
Assessment of sleep & sexual concerns
CQNE = Clinical Quantitative Neurological Examination; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; PT = physical therapy; UHDRS = Unified Huntington Disease Rating Scale
• Assessment of fine motor & gross motor skills incl gait (using UHDRS or CQNE)
• Assessment for use of assistive devices
• Assessment for abnormal movements
• PT assessment of mobility & appropriate strategies/devices to minimize risk of falls
• Assessment of cognitive skills (using MMSE or MoCA)
• Assessment of driving safety
• Consider formal driving safety evaluations if safety is uncertain.
• Assessment of weight
• Assessment of nutrition, swallowing, & risk of aspiration
• Assessment for mood, suicidality, threats to others, personality changes, apathy, irritability, aggression, hallucinations, delusions, & obsessive-compulsive symptoms
• Must include reports from informants
• Goal is to implement treatment or environmental modifications to decrease distress & physical risks for affected person & family / care providers
• Assessment of sleep & sexual concerns
## Agents/Circumstances to Avoid
Any agents that increase ataxia should be used with caution.
Individuals with HDL2, like those with other neurodegenerative disorders, are vulnerable to delirium from medical illnesses and medicines. Particular caution is necessary to minimize polypharmacy, high doses, or rapid dose increases of medicines.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
There is no specific information available about disease management during pregnancy. Prudence suggests close attention to prevention of falls and monitoring for swallowing difficulties. Medications should be reviewed to assess their safety during pregnancy. See
## Therapies Under Investigation
Search
## Genetic Counseling
Huntington disease-like 2 (HDL2) is inherited in an autosomal dominant manner.
Note: HDL2 and
Most individuals with HDL2 have an affected parent.
The family history of some individuals diagnosed with HDL2 may appear to be negative for one of the following reasons:
Failure to recognize the disorder in family members
Early death of the parent before the onset of symptoms
Late onset of the disease in the affected parent
Adoption, misidentified paternity, alternate maternity (via fertility interventions)
Expansion of a mutable normal allele / reduced-penetrance allele (29-39 CTG repeats in
It is appropriate to offer molecular genetic testing to asymptomatic parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Note: Testing for the expansion in the absence of manifestations of the disease is predictive testing and genetic counseling, both before and after testing, is essential.
If a parent of the proband has a
If a parent of the proband has a CTG repeat size close to 40 CTG repeats, the risk to sibs of inheriting an HDL2-causing allele is predicted to be significant, though not yet quantifiable. Theoretically, a parent with a CTG repeat size close to 40 CTG repeats could transmit an expanded allele to one sib and an unexpanded allele to another sib; however, this has not been reported to date.
A sib who inherits a
Limited evidence from a large index pedigree suggests that anticipation may occur [
Pathogenic (full-penetrance) HDL2-causing allele (≥40 CTG repeats) are considered at risk of developing HDL2 in their lifetime.
Offspring who inherit an allele of questionable significance (29-39 CTG repeats) may or may not develop manifestations of HDL2 (as described in
At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members involves pre-test counseling in which the motives for requesting the test, the individual's knowledge of HDL2, the possible impact of positive and negative test results, and neurologic status are discussed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members and the limited information available about HDL2. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.
The best model for HDL2 predictive testing is HD predictive testing. Prudence suggests following the same genetic testing guidelines used for HD, including counseling prior to testing, a confidant to serve as a social support, and availability of counseling following the disclosure of genetic results.
In a family with an established diagnosis of HDL2, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
A PGT exclusion protocol may be an option for testing of the embryo of couples in an at-risk family who do not wish to undergo predictive testing for the HDL2-causing allele themselves. While there is no known example of PGT applied to HDL2, the concepts and procedures would be nearly identical to those of HD.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate.
• Most individuals with HDL2 have an affected parent.
• The family history of some individuals diagnosed with HDL2 may appear to be negative for one of the following reasons:
• Failure to recognize the disorder in family members
• Early death of the parent before the onset of symptoms
• Late onset of the disease in the affected parent
• Adoption, misidentified paternity, alternate maternity (via fertility interventions)
• Expansion of a mutable normal allele / reduced-penetrance allele (29-39 CTG repeats in
• Failure to recognize the disorder in family members
• Early death of the parent before the onset of symptoms
• Late onset of the disease in the affected parent
• Adoption, misidentified paternity, alternate maternity (via fertility interventions)
• Expansion of a mutable normal allele / reduced-penetrance allele (29-39 CTG repeats in
• It is appropriate to offer molecular genetic testing to asymptomatic parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Note: Testing for the expansion in the absence of manifestations of the disease is predictive testing and genetic counseling, both before and after testing, is essential.
• Failure to recognize the disorder in family members
• Early death of the parent before the onset of symptoms
• Late onset of the disease in the affected parent
• Adoption, misidentified paternity, alternate maternity (via fertility interventions)
• Expansion of a mutable normal allele / reduced-penetrance allele (29-39 CTG repeats in
• If a parent of the proband has a
• If a parent of the proband has a CTG repeat size close to 40 CTG repeats, the risk to sibs of inheriting an HDL2-causing allele is predicted to be significant, though not yet quantifiable. Theoretically, a parent with a CTG repeat size close to 40 CTG repeats could transmit an expanded allele to one sib and an unexpanded allele to another sib; however, this has not been reported to date.
• A sib who inherits a
• Limited evidence from a large index pedigree suggests that anticipation may occur [
• Pathogenic (full-penetrance) HDL2-causing allele (≥40 CTG repeats) are considered at risk of developing HDL2 in their lifetime.
• Offspring who inherit an allele of questionable significance (29-39 CTG repeats) may or may not develop manifestations of HDL2 (as described in
• At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members involves pre-test counseling in which the motives for requesting the test, the individual's knowledge of HDL2, the possible impact of positive and negative test results, and neurologic status are discussed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members and the limited information available about HDL2. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.
• The best model for HDL2 predictive testing is HD predictive testing. Prudence suggests following the same genetic testing guidelines used for HD, including counseling prior to testing, a confidant to serve as a social support, and availability of counseling following the disclosure of genetic results.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Huntington disease-like 2 (HDL2) is inherited in an autosomal dominant manner.
Note: HDL2 and
## Risk to Family Members
Most individuals with HDL2 have an affected parent.
The family history of some individuals diagnosed with HDL2 may appear to be negative for one of the following reasons:
Failure to recognize the disorder in family members
Early death of the parent before the onset of symptoms
Late onset of the disease in the affected parent
Adoption, misidentified paternity, alternate maternity (via fertility interventions)
Expansion of a mutable normal allele / reduced-penetrance allele (29-39 CTG repeats in
It is appropriate to offer molecular genetic testing to asymptomatic parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Note: Testing for the expansion in the absence of manifestations of the disease is predictive testing and genetic counseling, both before and after testing, is essential.
If a parent of the proband has a
If a parent of the proband has a CTG repeat size close to 40 CTG repeats, the risk to sibs of inheriting an HDL2-causing allele is predicted to be significant, though not yet quantifiable. Theoretically, a parent with a CTG repeat size close to 40 CTG repeats could transmit an expanded allele to one sib and an unexpanded allele to another sib; however, this has not been reported to date.
A sib who inherits a
Limited evidence from a large index pedigree suggests that anticipation may occur [
Pathogenic (full-penetrance) HDL2-causing allele (≥40 CTG repeats) are considered at risk of developing HDL2 in their lifetime.
Offspring who inherit an allele of questionable significance (29-39 CTG repeats) may or may not develop manifestations of HDL2 (as described in
• Most individuals with HDL2 have an affected parent.
• The family history of some individuals diagnosed with HDL2 may appear to be negative for one of the following reasons:
• Failure to recognize the disorder in family members
• Early death of the parent before the onset of symptoms
• Late onset of the disease in the affected parent
• Adoption, misidentified paternity, alternate maternity (via fertility interventions)
• Expansion of a mutable normal allele / reduced-penetrance allele (29-39 CTG repeats in
• Failure to recognize the disorder in family members
• Early death of the parent before the onset of symptoms
• Late onset of the disease in the affected parent
• Adoption, misidentified paternity, alternate maternity (via fertility interventions)
• Expansion of a mutable normal allele / reduced-penetrance allele (29-39 CTG repeats in
• It is appropriate to offer molecular genetic testing to asymptomatic parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Note: Testing for the expansion in the absence of manifestations of the disease is predictive testing and genetic counseling, both before and after testing, is essential.
• Failure to recognize the disorder in family members
• Early death of the parent before the onset of symptoms
• Late onset of the disease in the affected parent
• Adoption, misidentified paternity, alternate maternity (via fertility interventions)
• Expansion of a mutable normal allele / reduced-penetrance allele (29-39 CTG repeats in
• If a parent of the proband has a
• If a parent of the proband has a CTG repeat size close to 40 CTG repeats, the risk to sibs of inheriting an HDL2-causing allele is predicted to be significant, though not yet quantifiable. Theoretically, a parent with a CTG repeat size close to 40 CTG repeats could transmit an expanded allele to one sib and an unexpanded allele to another sib; however, this has not been reported to date.
• A sib who inherits a
• Limited evidence from a large index pedigree suggests that anticipation may occur [
• Pathogenic (full-penetrance) HDL2-causing allele (≥40 CTG repeats) are considered at risk of developing HDL2 in their lifetime.
• Offspring who inherit an allele of questionable significance (29-39 CTG repeats) may or may not develop manifestations of HDL2 (as described in
## Related Genetic Counseling Issues
At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members involves pre-test counseling in which the motives for requesting the test, the individual's knowledge of HDL2, the possible impact of positive and negative test results, and neurologic status are discussed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members and the limited information available about HDL2. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.
The best model for HDL2 predictive testing is HD predictive testing. Prudence suggests following the same genetic testing guidelines used for HD, including counseling prior to testing, a confidant to serve as a social support, and availability of counseling following the disclosure of genetic results.
In a family with an established diagnosis of HDL2, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members involves pre-test counseling in which the motives for requesting the test, the individual's knowledge of HDL2, the possible impact of positive and negative test results, and neurologic status are discussed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members and the limited information available about HDL2. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.
• The best model for HDL2 predictive testing is HD predictive testing. Prudence suggests following the same genetic testing guidelines used for HD, including counseling prior to testing, a confidant to serve as a social support, and availability of counseling following the disclosure of genetic results.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
A PGT exclusion protocol may be an option for testing of the embryo of couples in an at-risk family who do not wish to undergo predictive testing for the HDL2-causing allele themselves. While there is no known example of PGT applied to HDL2, the concepts and procedures would be nearly identical to those of HD.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
Canada
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• Canada
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## Molecular Genetics
Huntington Disease-Like 2: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Huntington Disease-Like 2 (
HDL2 is caused by a CTG expansion on chromosome 16q24.2, which is located on the sense strand in exon 2A of
A
The expression pattern and function of the exon 1 to exon 2A transcript variants are not known. This short transcript contains the plasma membrane recognition motif but not the ER insertion domain present in the full-length transcript.
In the antisense strand in
Loss of expression of junctophilin-3, potentially by sequestration and loss of translation of
Toxic properties of
Toxic gain of function from the expression of protein containing an expanded polyglutamine tract from
• Loss of expression of junctophilin-3, potentially by sequestration and loss of translation of
• Toxic properties of
• Toxic gain of function from the expression of protein containing an expanded polyglutamine tract from
## Molecular Pathogenesis
HDL2 is caused by a CTG expansion on chromosome 16q24.2, which is located on the sense strand in exon 2A of
A
The expression pattern and function of the exon 1 to exon 2A transcript variants are not known. This short transcript contains the plasma membrane recognition motif but not the ER insertion domain present in the full-length transcript.
In the antisense strand in
Loss of expression of junctophilin-3, potentially by sequestration and loss of translation of
Toxic properties of
Toxic gain of function from the expression of protein containing an expanded polyglutamine tract from
• Loss of expression of junctophilin-3, potentially by sequestration and loss of translation of
• Toxic properties of
• Toxic gain of function from the expression of protein containing an expanded polyglutamine tract from
## Chapter Notes
The laboratory of Dr Russell L Margolis at Johns Hopkins School of Medicine, Baltimore, MD, USA, which identified the first known family with HDL2 as well as the genetic cause, is actively investigating the phenotype and pathogenesis of HDL2 and welcomes questions regarding individuals possibly affected with HDL2. Contact Dr Margolis at
The Division of Human Genetics, at the National Health Laboratory Services and the School of Pathology, the University of the Witwatersrand, Johannesburg, South Africa, is studying the detailed molecular genetics of the HDL2 locus and its association with clinical manifestations of HDL2. The laboratory will offer diagnostic testing for HDL2 for individuals from outside of South Africa. For further details, contact Professor Amanda Krause at
Clinical expertise in the UK: Dr David Anderson, Consultant Neurologist at the Queen Elizabeth University Hospital and Honorary Senior Lecturer, University of Glasgow:
Clinical expertise in Brazil: Dr Vitor Tumas, Universidade de São Paulo, Ribeirão Preto:
Clinical expertise in the Caribbean: Dr Remi Ballance, Centre de Référence Caribéen des maladies neuromusculaires rares, Centre Hospitalier de Martinique:
Genetic expertise in Venezuela: Dr Irene Paradisi, Human Genetics Laboratory, Venezuelan Institute for Scientific Research:
The authors would like to be informed of all newly diagnosed individuals with HDL2 to expand information about this rare disease.
The authors would like to acknowledge individuals with HDL2 and their families who have made progress in understanding HDL2 possible. We also acknowledge funding from the National Institute of Neurological Diseases and Stroke (USA), the South African Medical Research Council, and the ABCD Charitable Trust. Many scientists and clinicians have contributed to the understanding of HDL2, including Dr Susan E Holmes, Dr Christopher A Ross, Dr Aline Ferreira-Correia, Dr Dobrila D Rudnicki, Dr Anna I Seixas, Dr X William Yang, Dr Brian Wilburn, Dr Juan C Troncoso, Dr Olga Pletnikova, Dr Vitor Tumas, Dr Irene Paradisi, Dr Ruth Walker, and Dr Peggy E Greenstein. Many others listed in the references have also made significant contributions; our apologies for not naming them all.
10 April 2025 (sw) Comprehensive update posted live
27 June 2019 (sw) Comprehensive update posted live
26 April 2012 (me) Comprehensive update posted live
13 August 2009 (me) Comprehensive update posted live
10 March 2006 (me) Comprehensive update review posted live
30 January 2004 (me) Review posted live
15 September 2003 (rm) Original submission
• 10 April 2025 (sw) Comprehensive update posted live
• 27 June 2019 (sw) Comprehensive update posted live
• 26 April 2012 (me) Comprehensive update posted live
• 13 August 2009 (me) Comprehensive update posted live
• 10 March 2006 (me) Comprehensive update review posted live
• 30 January 2004 (me) Review posted live
• 15 September 2003 (rm) Original submission
## Author Notes
The laboratory of Dr Russell L Margolis at Johns Hopkins School of Medicine, Baltimore, MD, USA, which identified the first known family with HDL2 as well as the genetic cause, is actively investigating the phenotype and pathogenesis of HDL2 and welcomes questions regarding individuals possibly affected with HDL2. Contact Dr Margolis at
The Division of Human Genetics, at the National Health Laboratory Services and the School of Pathology, the University of the Witwatersrand, Johannesburg, South Africa, is studying the detailed molecular genetics of the HDL2 locus and its association with clinical manifestations of HDL2. The laboratory will offer diagnostic testing for HDL2 for individuals from outside of South Africa. For further details, contact Professor Amanda Krause at
Clinical expertise in the UK: Dr David Anderson, Consultant Neurologist at the Queen Elizabeth University Hospital and Honorary Senior Lecturer, University of Glasgow:
Clinical expertise in Brazil: Dr Vitor Tumas, Universidade de São Paulo, Ribeirão Preto:
Clinical expertise in the Caribbean: Dr Remi Ballance, Centre de Référence Caribéen des maladies neuromusculaires rares, Centre Hospitalier de Martinique:
Genetic expertise in Venezuela: Dr Irene Paradisi, Human Genetics Laboratory, Venezuelan Institute for Scientific Research:
The authors would like to be informed of all newly diagnosed individuals with HDL2 to expand information about this rare disease.
## Acknowledgments
The authors would like to acknowledge individuals with HDL2 and their families who have made progress in understanding HDL2 possible. We also acknowledge funding from the National Institute of Neurological Diseases and Stroke (USA), the South African Medical Research Council, and the ABCD Charitable Trust. Many scientists and clinicians have contributed to the understanding of HDL2, including Dr Susan E Holmes, Dr Christopher A Ross, Dr Aline Ferreira-Correia, Dr Dobrila D Rudnicki, Dr Anna I Seixas, Dr X William Yang, Dr Brian Wilburn, Dr Juan C Troncoso, Dr Olga Pletnikova, Dr Vitor Tumas, Dr Irene Paradisi, Dr Ruth Walker, and Dr Peggy E Greenstein. Many others listed in the references have also made significant contributions; our apologies for not naming them all.
## Revision History
10 April 2025 (sw) Comprehensive update posted live
27 June 2019 (sw) Comprehensive update posted live
26 April 2012 (me) Comprehensive update posted live
13 August 2009 (me) Comprehensive update posted live
10 March 2006 (me) Comprehensive update review posted live
30 January 2004 (me) Review posted live
15 September 2003 (rm) Original submission
• 10 April 2025 (sw) Comprehensive update posted live
• 27 June 2019 (sw) Comprehensive update posted live
• 26 April 2012 (me) Comprehensive update posted live
• 13 August 2009 (me) Comprehensive update posted live
• 10 March 2006 (me) Comprehensive update review posted live
• 30 January 2004 (me) Review posted live
• 15 September 2003 (rm) Original submission
## References
## Literature Cited
|
[] |
30/1/2004
|
10/4/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
hdls
|
hdls
|
[
"Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis (BANDDOS)",
"Pigmentary Orthochromatic Leukodystrophy (POLD)",
"Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)",
"Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS)",
"CSF1R-Related Leukoencephalopathy",
"Early-Onset CSF1R-Related Disorder",
"Late-Onset CSF1R-Related Disorder",
"Macrophage colony-stimulating factor 1 receptor",
"CSF1R",
"CSF1R-Related Disorder"
] |
Jaroslaw Dulski, Christina Sundal, Zbigniew K Wszolek
|
Summary The spectrum of The diagnosis of Early-onset Once the
|
Neurologic manifestations
Skeletal abnormalities
Nonspecific dysmorphic facial features
Congenital brain abnormalities
Adult-onset leukoencephalopathy w/axonal spheroids & pigmented glia (ALSP)
Pigmentary orthochromatic leukodystrophy (POLD)
Hereditary diffuse leukoencephalopathy w/spheroids (HDLS)
Adapted from
PV = pathogenic variant
See
The original Swedish family with HDLS had a heterozygous pathogenic variant in
• Neurologic manifestations
• Skeletal abnormalities
• Nonspecific dysmorphic facial features
• Congenital brain abnormalities
• Adult-onset leukoencephalopathy w/axonal spheroids & pigmented glia (ALSP)
• Pigmentary orthochromatic leukodystrophy (POLD)
• Hereditary diffuse leukoencephalopathy w/spheroids (HDLS)
## Diagnosis
Speech disturbances
Developmental delay and/or cognitive decline
Spasticity with abnormal reflexes and other pyramidal signs
Parkinsonism
Dysphagia
Seizures
Diffuse osteosclerosis of the craniofacial bones, most prominent in the skull base
Platyspondyly and sclerosis of the vertebral bodies
Sclerotic pelvic bones most prominent in the iliac bodies, sclerosis of proximal femora
Tubular bones: diaphyseal sclerosis and metaphyseal radiolucency with metaphyseal undermodeling
Progressive bilateral white matter lesions that are hyperintense on T
Calcifications
Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
Cerebral atrophy
Ventriculomegaly
Agenesis or thinning of the corpus callosum
Dandy-Walker malformation
Malformations of cortical development (thinning of the cortex with poor white-gray distinction and underdeveloped gyration)
Progressive neurologic decline beginning at mean age of 40±10 years in women and 47±11 years in men
Neurologic manifestations
Speech disturbances
Cognitive decline
Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
Spasticity
Parkinsonism
Seizures
Progressive bilateral white matter lesions that are hyperintense on T
Cerebral atrophy, including thinning of the corpus callosum
Calcifications are observed in the white matter in up to half of affected individuals, and frequently have a characteristic "stepping-stone appearance" in the frontal pericallosal area and punctate appearance in the frontal white matter (adjacent to the anterior horns of the lateral ventricles) and the parietal subcortical white matter [
Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
In both early- and late-onset
Family history for early- and late-onset
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Several intronic variants outside of the canonical splice junction typically included by standard sequencing have been reported [
Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
To date, a few large intragenic deletions have been reported in individuals with
• Speech disturbances
• Developmental delay and/or cognitive decline
• Spasticity with abnormal reflexes and other pyramidal signs
• Parkinsonism
• Dysphagia
• Seizures
• Diffuse osteosclerosis of the craniofacial bones, most prominent in the skull base
• Platyspondyly and sclerosis of the vertebral bodies
• Sclerotic pelvic bones most prominent in the iliac bodies, sclerosis of proximal femora
• Tubular bones: diaphyseal sclerosis and metaphyseal radiolucency with metaphyseal undermodeling
• Progressive bilateral white matter lesions that are hyperintense on T
• Calcifications
• Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
• Cerebral atrophy
• Ventriculomegaly
• Agenesis or thinning of the corpus callosum
• Dandy-Walker malformation
• Malformations of cortical development (thinning of the cortex with poor white-gray distinction and underdeveloped gyration)
• Progressive neurologic decline beginning at mean age of 40±10 years in women and 47±11 years in men
• Neurologic manifestations
• Speech disturbances
• Cognitive decline
• Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
• Spasticity
• Parkinsonism
• Seizures
• Speech disturbances
• Cognitive decline
• Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
• Spasticity
• Parkinsonism
• Seizures
• Speech disturbances
• Cognitive decline
• Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
• Spasticity
• Parkinsonism
• Seizures
• Progressive bilateral white matter lesions that are hyperintense on T
• Cerebral atrophy, including thinning of the corpus callosum
• Calcifications are observed in the white matter in up to half of affected individuals, and frequently have a characteristic "stepping-stone appearance" in the frontal pericallosal area and punctate appearance in the frontal white matter (adjacent to the anterior horns of the lateral ventricles) and the parietal subcortical white matter [
• Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
## Suggestive Findings
Speech disturbances
Developmental delay and/or cognitive decline
Spasticity with abnormal reflexes and other pyramidal signs
Parkinsonism
Dysphagia
Seizures
Diffuse osteosclerosis of the craniofacial bones, most prominent in the skull base
Platyspondyly and sclerosis of the vertebral bodies
Sclerotic pelvic bones most prominent in the iliac bodies, sclerosis of proximal femora
Tubular bones: diaphyseal sclerosis and metaphyseal radiolucency with metaphyseal undermodeling
Progressive bilateral white matter lesions that are hyperintense on T
Calcifications
Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
Cerebral atrophy
Ventriculomegaly
Agenesis or thinning of the corpus callosum
Dandy-Walker malformation
Malformations of cortical development (thinning of the cortex with poor white-gray distinction and underdeveloped gyration)
Progressive neurologic decline beginning at mean age of 40±10 years in women and 47±11 years in men
Neurologic manifestations
Speech disturbances
Cognitive decline
Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
Spasticity
Parkinsonism
Seizures
Progressive bilateral white matter lesions that are hyperintense on T
Cerebral atrophy, including thinning of the corpus callosum
Calcifications are observed in the white matter in up to half of affected individuals, and frequently have a characteristic "stepping-stone appearance" in the frontal pericallosal area and punctate appearance in the frontal white matter (adjacent to the anterior horns of the lateral ventricles) and the parietal subcortical white matter [
Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
In both early- and late-onset
Family history for early- and late-onset
• Speech disturbances
• Developmental delay and/or cognitive decline
• Spasticity with abnormal reflexes and other pyramidal signs
• Parkinsonism
• Dysphagia
• Seizures
• Diffuse osteosclerosis of the craniofacial bones, most prominent in the skull base
• Platyspondyly and sclerosis of the vertebral bodies
• Sclerotic pelvic bones most prominent in the iliac bodies, sclerosis of proximal femora
• Tubular bones: diaphyseal sclerosis and metaphyseal radiolucency with metaphyseal undermodeling
• Progressive bilateral white matter lesions that are hyperintense on T
• Calcifications
• Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
• Cerebral atrophy
• Ventriculomegaly
• Agenesis or thinning of the corpus callosum
• Dandy-Walker malformation
• Malformations of cortical development (thinning of the cortex with poor white-gray distinction and underdeveloped gyration)
• Progressive neurologic decline beginning at mean age of 40±10 years in women and 47±11 years in men
• Neurologic manifestations
• Speech disturbances
• Cognitive decline
• Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
• Spasticity
• Parkinsonism
• Seizures
• Speech disturbances
• Cognitive decline
• Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
• Spasticity
• Parkinsonism
• Seizures
• Speech disturbances
• Cognitive decline
• Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
• Spasticity
• Parkinsonism
• Seizures
• Progressive bilateral white matter lesions that are hyperintense on T
• Cerebral atrophy, including thinning of the corpus callosum
• Calcifications are observed in the white matter in up to half of affected individuals, and frequently have a characteristic "stepping-stone appearance" in the frontal pericallosal area and punctate appearance in the frontal white matter (adjacent to the anterior horns of the lateral ventricles) and the parietal subcortical white matter [
• Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
## Early Onset (age <18 years)
Speech disturbances
Developmental delay and/or cognitive decline
Spasticity with abnormal reflexes and other pyramidal signs
Parkinsonism
Dysphagia
Seizures
Diffuse osteosclerosis of the craniofacial bones, most prominent in the skull base
Platyspondyly and sclerosis of the vertebral bodies
Sclerotic pelvic bones most prominent in the iliac bodies, sclerosis of proximal femora
Tubular bones: diaphyseal sclerosis and metaphyseal radiolucency with metaphyseal undermodeling
Progressive bilateral white matter lesions that are hyperintense on T
Calcifications
Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
Cerebral atrophy
Ventriculomegaly
Agenesis or thinning of the corpus callosum
Dandy-Walker malformation
Malformations of cortical development (thinning of the cortex with poor white-gray distinction and underdeveloped gyration)
• Speech disturbances
• Developmental delay and/or cognitive decline
• Spasticity with abnormal reflexes and other pyramidal signs
• Parkinsonism
• Dysphagia
• Seizures
• Diffuse osteosclerosis of the craniofacial bones, most prominent in the skull base
• Platyspondyly and sclerosis of the vertebral bodies
• Sclerotic pelvic bones most prominent in the iliac bodies, sclerosis of proximal femora
• Tubular bones: diaphyseal sclerosis and metaphyseal radiolucency with metaphyseal undermodeling
• Progressive bilateral white matter lesions that are hyperintense on T
• Calcifications
• Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
• Cerebral atrophy
• Ventriculomegaly
• Agenesis or thinning of the corpus callosum
• Dandy-Walker malformation
• Malformations of cortical development (thinning of the cortex with poor white-gray distinction and underdeveloped gyration)
## Late Onset (age ≥18 years)
Progressive neurologic decline beginning at mean age of 40±10 years in women and 47±11 years in men
Neurologic manifestations
Speech disturbances
Cognitive decline
Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
Spasticity
Parkinsonism
Seizures
Progressive bilateral white matter lesions that are hyperintense on T
Cerebral atrophy, including thinning of the corpus callosum
Calcifications are observed in the white matter in up to half of affected individuals, and frequently have a characteristic "stepping-stone appearance" in the frontal pericallosal area and punctate appearance in the frontal white matter (adjacent to the anterior horns of the lateral ventricles) and the parietal subcortical white matter [
Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
• Progressive neurologic decline beginning at mean age of 40±10 years in women and 47±11 years in men
• Neurologic manifestations
• Speech disturbances
• Cognitive decline
• Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
• Spasticity
• Parkinsonism
• Seizures
• Speech disturbances
• Cognitive decline
• Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
• Spasticity
• Parkinsonism
• Seizures
• Speech disturbances
• Cognitive decline
• Neurobehavioral/psychiatric manifestations (behavioral and personality changes)
• Spasticity
• Parkinsonism
• Seizures
• Progressive bilateral white matter lesions that are hyperintense on T
• Cerebral atrophy, including thinning of the corpus callosum
• Calcifications are observed in the white matter in up to half of affected individuals, and frequently have a characteristic "stepping-stone appearance" in the frontal pericallosal area and punctate appearance in the frontal white matter (adjacent to the anterior horns of the lateral ventricles) and the parietal subcortical white matter [
• Note: Calcifications are poorly visible or not at all on conventional (1.5- or 3-Tesla) brain MRI; however, they may be appreciated on 7-Tesla brain MRI, which to date has limited availability. Calcifications are also detectable by thin-slice brain computed tomography (CT), which is available in routine clinical settings. Calcifications may be better visualized by 1 mm sections together with sagittal reconstructions.
## Laboratory Findings
In both early- and late-onset
## Family History
Family history for early- and late-onset
## Establishing the Diagnosis
The diagnosis of
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Note: Single-gene testing (sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Several intronic variants outside of the canonical splice junction typically included by standard sequencing have been reported [
Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
To date, a few large intragenic deletions have been reported in individuals with
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Several intronic variants outside of the canonical splice junction typically included by standard sequencing have been reported [
Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
To date, a few large intragenic deletions have been reported in individuals with
## Clinical Characteristics
The spectrum of
Information on about 500 affected individuals has been reported to date. The following description of the phenotypic features associated with
Rigidity; no data on other parkinsonian features
Reported in a few individuals
Brain atrophy was evidenced both on neuroimaging and pathologic examination [
Agenesis
Atrophy [
Arnold-Chiari malformation, another posterior fossa malformation, has been reported [
Dysarthria denotes slurring of speech and affects more than 50% of individuals [
Aphasia refers to disturbances of language production (motor or non-fluent aphasia) or comprehension (sensory or fluent aphasia). Although there are no systematic studies on the subtypes of aphasia in
Parkinsonism (hypomimia, rigidity, bradykinesia, shuffling gait, postural instability, resting and/or kinetic tremor) is common and most often of the non-tremor dominant subtype [
Dystonia may be isolated to one body part, one side of the body, or generalized. It may be a part of a corticobasal syndrome [
Myoclonus may resemble tremor in individuals with polymyoclonus (repetitive low-amplitude myoclonus).
Dyskinesia and chorea may also be observed in some individuals [
Notably, in most individuals motor signs may occur in varying combinations (e.g., pyramidal and extrapyramidal signs). For instance, it is common to observe increased muscle tone of mixed spastic-rigid type.
Pseudobulbar affect (i.e., uncontrolled crying or laughing disproportionate to the individual's emotional state) has been reported occasionally [
Most affected individuals eventually become bedridden with spasticity and rigidity. They lose speech and voluntary movement, and appear to be generally unaware of their surroundings. In the last stage of disease progression, individuals lose their ability to walk and progress to a vegetative state. Primitive reflexes, such as visual and tactile grasp, mouth-opening reflex, and sucking reflex, are present. Death most commonly results from pneumonia or other infections.
No genotype-phenotype correlations have been identified to date.
Penetrance is estimated to be high but not complete [
Based on a few screening studies in cohorts with leukoencephalopathies/leukodystrophies, the total worldwide prevalence of
• Parkinsonism (hypomimia, rigidity, bradykinesia, shuffling gait, postural instability, resting and/or kinetic tremor) is common and most often of the non-tremor dominant subtype [
• Dystonia may be isolated to one body part, one side of the body, or generalized. It may be a part of a corticobasal syndrome [
• Myoclonus may resemble tremor in individuals with polymyoclonus (repetitive low-amplitude myoclonus).
• Dyskinesia and chorea may also be observed in some individuals [
## Clinical Description
The spectrum of
Information on about 500 affected individuals has been reported to date. The following description of the phenotypic features associated with
Rigidity; no data on other parkinsonian features
Reported in a few individuals
Brain atrophy was evidenced both on neuroimaging and pathologic examination [
Agenesis
Atrophy [
Arnold-Chiari malformation, another posterior fossa malformation, has been reported [
Dysarthria denotes slurring of speech and affects more than 50% of individuals [
Aphasia refers to disturbances of language production (motor or non-fluent aphasia) or comprehension (sensory or fluent aphasia). Although there are no systematic studies on the subtypes of aphasia in
Parkinsonism (hypomimia, rigidity, bradykinesia, shuffling gait, postural instability, resting and/or kinetic tremor) is common and most often of the non-tremor dominant subtype [
Dystonia may be isolated to one body part, one side of the body, or generalized. It may be a part of a corticobasal syndrome [
Myoclonus may resemble tremor in individuals with polymyoclonus (repetitive low-amplitude myoclonus).
Dyskinesia and chorea may also be observed in some individuals [
Notably, in most individuals motor signs may occur in varying combinations (e.g., pyramidal and extrapyramidal signs). For instance, it is common to observe increased muscle tone of mixed spastic-rigid type.
Pseudobulbar affect (i.e., uncontrolled crying or laughing disproportionate to the individual's emotional state) has been reported occasionally [
Most affected individuals eventually become bedridden with spasticity and rigidity. They lose speech and voluntary movement, and appear to be generally unaware of their surroundings. In the last stage of disease progression, individuals lose their ability to walk and progress to a vegetative state. Primitive reflexes, such as visual and tactile grasp, mouth-opening reflex, and sucking reflex, are present. Death most commonly results from pneumonia or other infections.
• Parkinsonism (hypomimia, rigidity, bradykinesia, shuffling gait, postural instability, resting and/or kinetic tremor) is common and most often of the non-tremor dominant subtype [
• Dystonia may be isolated to one body part, one side of the body, or generalized. It may be a part of a corticobasal syndrome [
• Myoclonus may resemble tremor in individuals with polymyoclonus (repetitive low-amplitude myoclonus).
• Dyskinesia and chorea may also be observed in some individuals [
## Findings Unique to Early-Onset
## Findings Shared by Early- and Late-Onset
Dysarthria denotes slurring of speech and affects more than 50% of individuals [
Aphasia refers to disturbances of language production (motor or non-fluent aphasia) or comprehension (sensory or fluent aphasia). Although there are no systematic studies on the subtypes of aphasia in
Parkinsonism (hypomimia, rigidity, bradykinesia, shuffling gait, postural instability, resting and/or kinetic tremor) is common and most often of the non-tremor dominant subtype [
Dystonia may be isolated to one body part, one side of the body, or generalized. It may be a part of a corticobasal syndrome [
Myoclonus may resemble tremor in individuals with polymyoclonus (repetitive low-amplitude myoclonus).
Dyskinesia and chorea may also be observed in some individuals [
Notably, in most individuals motor signs may occur in varying combinations (e.g., pyramidal and extrapyramidal signs). For instance, it is common to observe increased muscle tone of mixed spastic-rigid type.
Pseudobulbar affect (i.e., uncontrolled crying or laughing disproportionate to the individual's emotional state) has been reported occasionally [
Most affected individuals eventually become bedridden with spasticity and rigidity. They lose speech and voluntary movement, and appear to be generally unaware of their surroundings. In the last stage of disease progression, individuals lose their ability to walk and progress to a vegetative state. Primitive reflexes, such as visual and tactile grasp, mouth-opening reflex, and sucking reflex, are present. Death most commonly results from pneumonia or other infections.
• Parkinsonism (hypomimia, rigidity, bradykinesia, shuffling gait, postural instability, resting and/or kinetic tremor) is common and most often of the non-tremor dominant subtype [
• Dystonia may be isolated to one body part, one side of the body, or generalized. It may be a part of a corticobasal syndrome [
• Myoclonus may resemble tremor in individuals with polymyoclonus (repetitive low-amplitude myoclonus).
• Dyskinesia and chorea may also be observed in some individuals [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified to date.
## Penetrance
Penetrance is estimated to be high but not complete [
## Nomenclature
## Prevalence
Based on a few screening studies in cohorts with leukoencephalopathies/leukodystrophies, the total worldwide prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Hereditary disorders that primarily affect the central nervous system and manifest with glial and/or myelin abnormalities may mimic early-onset
A
Genetic Disorders to Consider in the Differential Diagnosis of
Cognitive decline, dementia
Spastic paraparesis
Neuropathy & slowly spastic paraparesis
WML are contrast enhancing.
Corticospinal tracts are involved from cranial to medulla.
Executive dysfunction, personality changes, memory issues
Pyramidal signs, seizures
Peripheral neuropathy
Spread of WML into the cerebellar region & WM myelin breakdown w/low-density tigroid stripes
Neurodegeneration
Macrocephaly
Neuropathy
"Occipital horns"
Slowly progressive pyramidal, cerebellar, & dorsal column dysfunction
Deterioration of motor skills
Peripheral neuropathy
WML are either non-homogeneous/spotty or homogeneous & confluent.
Signal abnormalities are evident in the medullary pyramids, dorsal columns, & lateral corticospinal tracts.
Cognitive decline
Spastic paraparesis
Cerebellar ataxia
Stress-induced deterioration w/minor trauma or infections
More widespread & diffuse WM changes & atrophy than in
Cystic breakdown of WM
Peripheral neuropathy
Progressive microcephaly
Peripheral neuropathy
MRI shows predominance in posterior part of WM
MRI detects demyelination in brain stem & cerebellum
T
Progressive macrocephaly
Acute exacerbations of neurologic deficits
Palatal myoclonus
Cognitive function in adults is frequently normal.
Infratentorial atrophy on MRI
Skin & eye changes
Hepatosplenomegaly
Cognitive impairment
Pyramidal & cerebellar signs
Early autonomic dysfunction
Periventricular normal rim on MRI
Frontal lobe syndrome
WML
Stroke-like clinical signs
Multiple cerebral infarcts & WML incl characteristic temporal pools
Neurologic deficits
Abnormal dentition
Endocrine abnormalities
Progressive myopia
Insidious personality changes, frontal lobe syndrome
Motor impairments
Dementia & progression to vegetative state
Pain/tenderness of feet/wrists
Polycystic osseous lesions, pathologic fractures
U-fibers partially affected
Neurodegeneration
Brain calcifications
Skin photosensitivity
Distinct physical appearance
Premature ovarian insufficiency in all females
WM demonstrates rarefaction.
Executive dysfunction, personality changes
Similar age of onset
Episodic memory loss
WM changes are present but much less pronounced.
AD = autosomal dominant; AR = autosomal recessive; CADASIL =
Except for
• A
• Cognitive decline, dementia
• Spastic paraparesis
• Neuropathy & slowly spastic paraparesis
• WML are contrast enhancing.
• Corticospinal tracts are involved from cranial to medulla.
• Executive dysfunction, personality changes, memory issues
• Pyramidal signs, seizures
• Peripheral neuropathy
• Spread of WML into the cerebellar region & WM myelin breakdown w/low-density tigroid stripes
• Neurodegeneration
• Macrocephaly
• Neuropathy
• "Occipital horns"
• Slowly progressive pyramidal, cerebellar, & dorsal column dysfunction
• Deterioration of motor skills
• Peripheral neuropathy
• WML are either non-homogeneous/spotty or homogeneous & confluent.
• Signal abnormalities are evident in the medullary pyramids, dorsal columns, & lateral corticospinal tracts.
• Cognitive decline
• Spastic paraparesis
• Cerebellar ataxia
• Stress-induced deterioration w/minor trauma or infections
• More widespread & diffuse WM changes & atrophy than in
• Cystic breakdown of WM
• Peripheral neuropathy
• Progressive microcephaly
• Peripheral neuropathy
• MRI shows predominance in posterior part of WM
• MRI detects demyelination in brain stem & cerebellum
• T
• Progressive macrocephaly
• Acute exacerbations of neurologic deficits
• Palatal myoclonus
• Cognitive function in adults is frequently normal.
• Infratentorial atrophy on MRI
• Skin & eye changes
• Hepatosplenomegaly
• Cognitive impairment
• Pyramidal & cerebellar signs
• Early autonomic dysfunction
• Periventricular normal rim on MRI
• Frontal lobe syndrome
• WML
• Stroke-like clinical signs
• Multiple cerebral infarcts & WML incl characteristic temporal pools
• Neurologic deficits
• Abnormal dentition
• Endocrine abnormalities
• Progressive myopia
• Insidious personality changes, frontal lobe syndrome
• Motor impairments
• Dementia & progression to vegetative state
• Pain/tenderness of feet/wrists
• Polycystic osseous lesions, pathologic fractures
• U-fibers partially affected
• Neurodegeneration
• Brain calcifications
• Skin photosensitivity
• Distinct physical appearance
• Premature ovarian insufficiency in all females
• WM demonstrates rarefaction.
• Executive dysfunction, personality changes
• Similar age of onset
• Episodic memory loss
• WM changes are present but much less pronounced.
## Early-Onset
Hereditary disorders that primarily affect the central nervous system and manifest with glial and/or myelin abnormalities may mimic early-onset
## Late-Onset
A
Genetic Disorders to Consider in the Differential Diagnosis of
Cognitive decline, dementia
Spastic paraparesis
Neuropathy & slowly spastic paraparesis
WML are contrast enhancing.
Corticospinal tracts are involved from cranial to medulla.
Executive dysfunction, personality changes, memory issues
Pyramidal signs, seizures
Peripheral neuropathy
Spread of WML into the cerebellar region & WM myelin breakdown w/low-density tigroid stripes
Neurodegeneration
Macrocephaly
Neuropathy
"Occipital horns"
Slowly progressive pyramidal, cerebellar, & dorsal column dysfunction
Deterioration of motor skills
Peripheral neuropathy
WML are either non-homogeneous/spotty or homogeneous & confluent.
Signal abnormalities are evident in the medullary pyramids, dorsal columns, & lateral corticospinal tracts.
Cognitive decline
Spastic paraparesis
Cerebellar ataxia
Stress-induced deterioration w/minor trauma or infections
More widespread & diffuse WM changes & atrophy than in
Cystic breakdown of WM
Peripheral neuropathy
Progressive microcephaly
Peripheral neuropathy
MRI shows predominance in posterior part of WM
MRI detects demyelination in brain stem & cerebellum
T
Progressive macrocephaly
Acute exacerbations of neurologic deficits
Palatal myoclonus
Cognitive function in adults is frequently normal.
Infratentorial atrophy on MRI
Skin & eye changes
Hepatosplenomegaly
Cognitive impairment
Pyramidal & cerebellar signs
Early autonomic dysfunction
Periventricular normal rim on MRI
Frontal lobe syndrome
WML
Stroke-like clinical signs
Multiple cerebral infarcts & WML incl characteristic temporal pools
Neurologic deficits
Abnormal dentition
Endocrine abnormalities
Progressive myopia
Insidious personality changes, frontal lobe syndrome
Motor impairments
Dementia & progression to vegetative state
Pain/tenderness of feet/wrists
Polycystic osseous lesions, pathologic fractures
U-fibers partially affected
Neurodegeneration
Brain calcifications
Skin photosensitivity
Distinct physical appearance
Premature ovarian insufficiency in all females
WM demonstrates rarefaction.
Executive dysfunction, personality changes
Similar age of onset
Episodic memory loss
WM changes are present but much less pronounced.
AD = autosomal dominant; AR = autosomal recessive; CADASIL =
Except for
• A
• Cognitive decline, dementia
• Spastic paraparesis
• Neuropathy & slowly spastic paraparesis
• WML are contrast enhancing.
• Corticospinal tracts are involved from cranial to medulla.
• Executive dysfunction, personality changes, memory issues
• Pyramidal signs, seizures
• Peripheral neuropathy
• Spread of WML into the cerebellar region & WM myelin breakdown w/low-density tigroid stripes
• Neurodegeneration
• Macrocephaly
• Neuropathy
• "Occipital horns"
• Slowly progressive pyramidal, cerebellar, & dorsal column dysfunction
• Deterioration of motor skills
• Peripheral neuropathy
• WML are either non-homogeneous/spotty or homogeneous & confluent.
• Signal abnormalities are evident in the medullary pyramids, dorsal columns, & lateral corticospinal tracts.
• Cognitive decline
• Spastic paraparesis
• Cerebellar ataxia
• Stress-induced deterioration w/minor trauma or infections
• More widespread & diffuse WM changes & atrophy than in
• Cystic breakdown of WM
• Peripheral neuropathy
• Progressive microcephaly
• Peripheral neuropathy
• MRI shows predominance in posterior part of WM
• MRI detects demyelination in brain stem & cerebellum
• T
• Progressive macrocephaly
• Acute exacerbations of neurologic deficits
• Palatal myoclonus
• Cognitive function in adults is frequently normal.
• Infratentorial atrophy on MRI
• Skin & eye changes
• Hepatosplenomegaly
• Cognitive impairment
• Pyramidal & cerebellar signs
• Early autonomic dysfunction
• Periventricular normal rim on MRI
• Frontal lobe syndrome
• WML
• Stroke-like clinical signs
• Multiple cerebral infarcts & WML incl characteristic temporal pools
• Neurologic deficits
• Abnormal dentition
• Endocrine abnormalities
• Progressive myopia
• Insidious personality changes, frontal lobe syndrome
• Motor impairments
• Dementia & progression to vegetative state
• Pain/tenderness of feet/wrists
• Polycystic osseous lesions, pathologic fractures
• U-fibers partially affected
• Neurodegeneration
• Brain calcifications
• Skin photosensitivity
• Distinct physical appearance
• Premature ovarian insufficiency in all females
• WM demonstrates rarefaction.
• Executive dysfunction, personality changes
• Similar age of onset
• Episodic memory loss
• WM changes are present but much less pronounced.
## Management
No clinical practice guidelines for
Note that the care of individuals with early-onset
To establish the extent of disease and needs in an individual diagnosed with
Incl screening for cognitive impairment
Assessment for motor impairment incl gait, bradykinesia, rigidity, & tremor; sensory deficits; & bulbar signs
When seizures are suspected, an EEG or video EEG is recommended
Assessment of cognitive function (executive function, language processing, visuospatial/visuoconstructional skills)
Assessment for anxiety, depression, apathy, indifference, abulia, disinhibition, distraction, & other behavioral or personality changes
Assessment of need for speech therapy
Consider need for alternative & augmentative communication.
Incl nutritional assessment, safety of oral feedings
Consider need for gastrostomy tube placement.
Skeletal system (incl radiographs)
Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; & bedsores
Need for adaptive devices
Footwear needs
PT needs
To assess small motor function
To assess ADL
Direct families / affected persons to community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
The limited data available to date suggest that hematopoietic stem cell transplantation (HSCT) could modify disease progression in symptomatic individuals with early neurologic findings of
Supportive treatment is recommended to improve quality of life, maximize function, and reduce complications. This ideally involves multidisciplinary care by specialists in relevant fields (see
Cognitive behavioral therapy
Psychotherapy & psychoeducational interventions
To date, standard treatment for psychiatric manifestations (e.g., depression, suicidal tendencies, anxiety, & psychosis) have not had long-term benefit.
Antipsychotics are not recommended in general due to extrapyramidal side effects but may be used in persons who have issues with aggression.
Transfers (e.g., from bed to wheelchair, wheelchair to car)
Training on fall techniques to minimize risk of injury
To accomplish tasks such as mobility, washing, dressing, eating, cooking, & grooming
To assist w/household modifications to meet special needs
Social issues (unemployment, divorce, financial challenges, &/or alcohol addiction) & suicidal tendencies are often assoc w/progression of disease.
Some of the social consequences may be avoided if family members are informed early re nature of disorder.
ADL = activities of daily living; ASM = anti-seizure medications; OT = occupational therapy; PT = physical therapy
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
ADL = activities of daily living; OT = occupational therapist; PT = physical therapist
Recommended frequency of these evaluations depends on the age of the asymptomatic family member and the average age of disease onset in the family: (a) annually for individuals twenty or more years younger than the average age of disease onset in their family and (b) every six months for individuals approaching the age of expected symptomatic disease onset [Authors, unpublished observations].
As many individuals with
See
In a retrospective cohort study, it was observed that glucocorticoids might protect against symptomatic disease onset in individuals at risk for late-onset
Currently, one interventional clinical trial is in progress, enrolling individuals age 18 years and older with the late-onset
Search
• Incl screening for cognitive impairment
• Assessment for motor impairment incl gait, bradykinesia, rigidity, & tremor; sensory deficits; & bulbar signs
• When seizures are suspected, an EEG or video EEG is recommended
• Assessment of cognitive function (executive function, language processing, visuospatial/visuoconstructional skills)
• Assessment for anxiety, depression, apathy, indifference, abulia, disinhibition, distraction, & other behavioral or personality changes
• Assessment of need for speech therapy
• Consider need for alternative & augmentative communication.
• Incl nutritional assessment, safety of oral feedings
• Consider need for gastrostomy tube placement.
• Skeletal system (incl radiographs)
• Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; & bedsores
• Need for adaptive devices
• Footwear needs
• PT needs
• To assess small motor function
• To assess ADL
• Direct families / affected persons to community or
• Social work involvement for parental support
• Home nursing referral
• Cognitive behavioral therapy
• Psychotherapy & psychoeducational interventions
• To date, standard treatment for psychiatric manifestations (e.g., depression, suicidal tendencies, anxiety, & psychosis) have not had long-term benefit.
• Antipsychotics are not recommended in general due to extrapyramidal side effects but may be used in persons who have issues with aggression.
• Transfers (e.g., from bed to wheelchair, wheelchair to car)
• Training on fall techniques to minimize risk of injury
• To accomplish tasks such as mobility, washing, dressing, eating, cooking, & grooming
• To assist w/household modifications to meet special needs
• Social issues (unemployment, divorce, financial challenges, &/or alcohol addiction) & suicidal tendencies are often assoc w/progression of disease.
• Some of the social consequences may be avoided if family members are informed early re nature of disorder.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Incl screening for cognitive impairment
Assessment for motor impairment incl gait, bradykinesia, rigidity, & tremor; sensory deficits; & bulbar signs
When seizures are suspected, an EEG or video EEG is recommended
Assessment of cognitive function (executive function, language processing, visuospatial/visuoconstructional skills)
Assessment for anxiety, depression, apathy, indifference, abulia, disinhibition, distraction, & other behavioral or personality changes
Assessment of need for speech therapy
Consider need for alternative & augmentative communication.
Incl nutritional assessment, safety of oral feedings
Consider need for gastrostomy tube placement.
Skeletal system (incl radiographs)
Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; & bedsores
Need for adaptive devices
Footwear needs
PT needs
To assess small motor function
To assess ADL
Direct families / affected persons to community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Incl screening for cognitive impairment
• Assessment for motor impairment incl gait, bradykinesia, rigidity, & tremor; sensory deficits; & bulbar signs
• When seizures are suspected, an EEG or video EEG is recommended
• Assessment of cognitive function (executive function, language processing, visuospatial/visuoconstructional skills)
• Assessment for anxiety, depression, apathy, indifference, abulia, disinhibition, distraction, & other behavioral or personality changes
• Assessment of need for speech therapy
• Consider need for alternative & augmentative communication.
• Incl nutritional assessment, safety of oral feedings
• Consider need for gastrostomy tube placement.
• Skeletal system (incl radiographs)
• Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; & bedsores
• Need for adaptive devices
• Footwear needs
• PT needs
• To assess small motor function
• To assess ADL
• Direct families / affected persons to community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
The limited data available to date suggest that hematopoietic stem cell transplantation (HSCT) could modify disease progression in symptomatic individuals with early neurologic findings of
Supportive treatment is recommended to improve quality of life, maximize function, and reduce complications. This ideally involves multidisciplinary care by specialists in relevant fields (see
Cognitive behavioral therapy
Psychotherapy & psychoeducational interventions
To date, standard treatment for psychiatric manifestations (e.g., depression, suicidal tendencies, anxiety, & psychosis) have not had long-term benefit.
Antipsychotics are not recommended in general due to extrapyramidal side effects but may be used in persons who have issues with aggression.
Transfers (e.g., from bed to wheelchair, wheelchair to car)
Training on fall techniques to minimize risk of injury
To accomplish tasks such as mobility, washing, dressing, eating, cooking, & grooming
To assist w/household modifications to meet special needs
Social issues (unemployment, divorce, financial challenges, &/or alcohol addiction) & suicidal tendencies are often assoc w/progression of disease.
Some of the social consequences may be avoided if family members are informed early re nature of disorder.
ADL = activities of daily living; ASM = anti-seizure medications; OT = occupational therapy; PT = physical therapy
• Cognitive behavioral therapy
• Psychotherapy & psychoeducational interventions
• To date, standard treatment for psychiatric manifestations (e.g., depression, suicidal tendencies, anxiety, & psychosis) have not had long-term benefit.
• Antipsychotics are not recommended in general due to extrapyramidal side effects but may be used in persons who have issues with aggression.
• Transfers (e.g., from bed to wheelchair, wheelchair to car)
• Training on fall techniques to minimize risk of injury
• To accomplish tasks such as mobility, washing, dressing, eating, cooking, & grooming
• To assist w/household modifications to meet special needs
• Social issues (unemployment, divorce, financial challenges, &/or alcohol addiction) & suicidal tendencies are often assoc w/progression of disease.
• Some of the social consequences may be avoided if family members are informed early re nature of disorder.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
ADL = activities of daily living; OT = occupational therapist; PT = physical therapist
Recommended frequency of these evaluations depends on the age of the asymptomatic family member and the average age of disease onset in the family: (a) annually for individuals twenty or more years younger than the average age of disease onset in their family and (b) every six months for individuals approaching the age of expected symptomatic disease onset [Authors, unpublished observations].
## Agents/Circumstances to Avoid
As many individuals with
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
In a retrospective cohort study, it was observed that glucocorticoids might protect against symptomatic disease onset in individuals at risk for late-onset
Currently, one interventional clinical trial is in progress, enrolling individuals age 18 years and older with the late-onset
Search
## Genetic Counseling
Early-onset
Late-onset
Note: While biallelic pathogenic variants are typically associated with early-onset disease and heterozygous pathogenic variants are typically associated with late-onset disease, definitive prediction of phenotype based on
The parents of an individual with
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of an individual with early-onset
If both parents are known to be heterozygous for a
Sibs who inherit the same biallelic
The heterozygous sibs of an individual with
Many individuals with
Some individuals with
A pathogenic variant that occurred
A pathogenic variant inherited from a mosaic parent; or
A pathogenic variant inherited from an asymptomatic heterozygous parent. (The penetrance of
If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and provide insight into familial genotype-phenotype correlations.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Somatic and germline mosaicism has been reported in an unaffected mother of four sibs with late-onset
* Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
The family history of some individuals diagnosed with
If a parent of the proband is known to be heterozygous for the
Sibs who are heterozygous for the same
On average, women develop the first manifestations of late-onset
If the
If the parents have not been tested for the
Predictive testing for at-risk relatives is possible once the causative
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Predictive testing of minors for adult-onset disorders for which no treatment exists is not considered appropriate. Such testing negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate.
• The parents of an individual with
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of an individual with early-onset
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Sibs who inherit the same biallelic
• The heterozygous sibs of an individual with
• Many individuals with
• Some individuals with
• A pathogenic variant that occurred
• A pathogenic variant inherited from a mosaic parent; or
• A pathogenic variant inherited from an asymptomatic heterozygous parent. (The penetrance of
• A pathogenic variant that occurred
• A pathogenic variant inherited from a mosaic parent; or
• A pathogenic variant inherited from an asymptomatic heterozygous parent. (The penetrance of
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and provide insight into familial genotype-phenotype correlations.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Somatic and germline mosaicism has been reported in an unaffected mother of four sibs with late-onset
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Somatic and germline mosaicism has been reported in an unaffected mother of four sibs with late-onset
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• The family history of some individuals diagnosed with
• A pathogenic variant that occurred
• A pathogenic variant inherited from a mosaic parent; or
• A pathogenic variant inherited from an asymptomatic heterozygous parent. (The penetrance of
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Somatic and germline mosaicism has been reported in an unaffected mother of four sibs with late-onset
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• If a parent of the proband is known to be heterozygous for the
• Sibs who are heterozygous for the same
• On average, women develop the first manifestations of late-onset
• Sibs who are heterozygous for the same
• On average, women develop the first manifestations of late-onset
• If the
• If the parents have not been tested for the
• Sibs who are heterozygous for the same
• On average, women develop the first manifestations of late-onset
• Predictive testing for at-risk relatives is possible once the causative
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Predictive testing of minors for adult-onset disorders for which no treatment exists is not considered appropriate. Such testing negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Early-onset
Late-onset
Note: While biallelic pathogenic variants are typically associated with early-onset disease and heterozygous pathogenic variants are typically associated with late-onset disease, definitive prediction of phenotype based on
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an individual with
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of an individual with early-onset
If both parents are known to be heterozygous for a
Sibs who inherit the same biallelic
The heterozygous sibs of an individual with
• The parents of an individual with
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of an individual with early-onset
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Sibs who inherit the same biallelic
• The heterozygous sibs of an individual with
## Autosomal Dominant Inheritance – Risk to Family Members
Many individuals with
Some individuals with
A pathogenic variant that occurred
A pathogenic variant inherited from a mosaic parent; or
A pathogenic variant inherited from an asymptomatic heterozygous parent. (The penetrance of
If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and provide insight into familial genotype-phenotype correlations.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Somatic and germline mosaicism has been reported in an unaffected mother of four sibs with late-onset
* Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
The family history of some individuals diagnosed with
If a parent of the proband is known to be heterozygous for the
Sibs who are heterozygous for the same
On average, women develop the first manifestations of late-onset
If the
If the parents have not been tested for the
• Many individuals with
• Some individuals with
• A pathogenic variant that occurred
• A pathogenic variant inherited from a mosaic parent; or
• A pathogenic variant inherited from an asymptomatic heterozygous parent. (The penetrance of
• A pathogenic variant that occurred
• A pathogenic variant inherited from a mosaic parent; or
• A pathogenic variant inherited from an asymptomatic heterozygous parent. (The penetrance of
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and provide insight into familial genotype-phenotype correlations.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Somatic and germline mosaicism has been reported in an unaffected mother of four sibs with late-onset
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Somatic and germline mosaicism has been reported in an unaffected mother of four sibs with late-onset
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• The family history of some individuals diagnosed with
• A pathogenic variant that occurred
• A pathogenic variant inherited from a mosaic parent; or
• A pathogenic variant inherited from an asymptomatic heterozygous parent. (The penetrance of
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Somatic and germline mosaicism has been reported in an unaffected mother of four sibs with late-onset
• * Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.
• If a parent of the proband is known to be heterozygous for the
• Sibs who are heterozygous for the same
• On average, women develop the first manifestations of late-onset
• Sibs who are heterozygous for the same
• On average, women develop the first manifestations of late-onset
• If the
• If the parents have not been tested for the
• Sibs who are heterozygous for the same
• On average, women develop the first manifestations of late-onset
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once the causative
Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Predictive testing of minors for adult-onset disorders for which no treatment exists is not considered appropriate. Such testing negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
For more information, see the National Society of Genetic Counselors
In a family with an established diagnosis of
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Predictive testing for at-risk relatives is possible once the causative
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Predictive testing of minors for adult-onset disorders for which no treatment exists is not considered appropriate. Such testing negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
United Kingdom
Australia
•
•
•
• United Kingdom
•
•
•
•
• Australia
•
•
•
•
•
## Molecular Genetics
CSF1R-Related Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CSF1R-Related Disorder (
To date, most reported
## Molecular Pathogenesis
To date, most reported
## Chapter Notes
Dr Wszolek (
Contact Drs Wszolek and Dulski to inquire about review of
We thank the patients, their families, and the Sisters' Hope and My Complex Genes Foundations for their never-ending support, encouragement, and inspiration.
Jaroslaw Dulski is partially supported by the Haworth Family Professorship in Neurodegenerative Diseases fund (90052067). He serves as an editorial board member of
Zbigniew K Wszolek is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G and Jodi P Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, the Albertson Parkinson's Research Foundation, and the PPND Family Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals, Inc (BHV4157-206) and Vigil Neuroscience, Inc (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc, and as a consultant on neurodegenerative medical research for Eli Lilli & Company.
4 April 2024 (bp) Comprehensive update posted live
5 October 2017 (sw) Comprehensive update posted live
18 December 2014 (me) Comprehensive update posted live
30 August 2012 (me) Review posted live
23 May 2012 (zkw) Original submission
• 4 April 2024 (bp) Comprehensive update posted live
• 5 October 2017 (sw) Comprehensive update posted live
• 18 December 2014 (me) Comprehensive update posted live
• 30 August 2012 (me) Review posted live
• 23 May 2012 (zkw) Original submission
## Author Notes
Dr Wszolek (
Contact Drs Wszolek and Dulski to inquire about review of
## Acknowledgments
We thank the patients, their families, and the Sisters' Hope and My Complex Genes Foundations for their never-ending support, encouragement, and inspiration.
Jaroslaw Dulski is partially supported by the Haworth Family Professorship in Neurodegenerative Diseases fund (90052067). He serves as an editorial board member of
Zbigniew K Wszolek is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G and Jodi P Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, the Albertson Parkinson's Research Foundation, and the PPND Family Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals, Inc (BHV4157-206) and Vigil Neuroscience, Inc (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc, and as a consultant on neurodegenerative medical research for Eli Lilli & Company.
## Revision History
4 April 2024 (bp) Comprehensive update posted live
5 October 2017 (sw) Comprehensive update posted live
18 December 2014 (me) Comprehensive update posted live
30 August 2012 (me) Review posted live
23 May 2012 (zkw) Original submission
• 4 April 2024 (bp) Comprehensive update posted live
• 5 October 2017 (sw) Comprehensive update posted live
• 18 December 2014 (me) Comprehensive update posted live
• 30 August 2012 (me) Review posted live
• 23 May 2012 (zkw) Original submission
## References
## Literature Cited
|
[] |
30/8/2012
|
4/4/2024
|
17/1/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
hemo-a
|
hemo-a
|
[
"Factor VIII Deficiency",
"Factor VIII Deficiency",
"Coagulation factor VIII",
"F8",
"Hemophilia A"
] |
Hemophilia A
|
Barbara A Konkle, Shelley Nakaya Fletcher
|
Summary Hemophilia A is characterized by deficiency in factor VIII clotting activity that results in prolonged bleeding after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor VIII clotting activity. The diagnosis of hemophilia A is established in an individual with low factor VIII clotting activity in the presence of a normal, functional von Willebrand factor level. Identification of a hemizygous Hemophilia A is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother. The risk to sibs of a female proband depends on the genetic status of the mother and father. If the mother of the proband has an
|
## Diagnosis
Hemophilia A
Hemarthrosis, especially with mild or no antecedent trauma
Deep-muscle hematomas
Intracranial bleeding in the absence of major trauma
Neonatal cephalohematoma or intracranial bleeding
Prolonged bleeding or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
Unexplained gastrointestinal bleeding or hematuria *
Heavy menstrual bleeding, especially with onset at menarche
Prolonged nosebleeds, especially recurrent and bilateral *
Excessive bruising, especially with firm, subcutaneous hematomas
* Of any severity, or especially in more severely affected persons
Normal platelet count
Prolonged activated partial thromboplastin time
Normal prothrombin time
Note: Occasionally, in individuals with mild hemophilia A, a standard "one-stage" factor VIII clotting activity assay shows near-normal or low-normal factor VIII clotting activity (40%-80%), whereas in a "two-stage" or chromogenic assay, factor VIII clotting activity is low. Thus, low-normal in vitro clotting activity does not always exclude the presence of mild hemophilia A.
Identification of a hemizygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by prolonged bleeding,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hemophilia A
See
See
Intron 22 and intron 1 inversions can be detected by multiple techniques (e.g., long-range PCR, inverse PCR, PCR-based "inverse shifting" procedure [
An intron 22 inversion is identified in approximately 43%-45% of individuals with severe hemophilia A [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Multiplex ligation-dependent probe amplification (MLPA) is the most commonly used test method to detect
Deletions and duplications detected using MLPA in 2,353 males with severe hemophilia A or 1,709 males with moderate/mild hemophilia A in the
• Hemarthrosis, especially with mild or no antecedent trauma
• Deep-muscle hematomas
• Intracranial bleeding in the absence of major trauma
• Neonatal cephalohematoma or intracranial bleeding
• Prolonged bleeding or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
• Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
• Unexplained gastrointestinal bleeding or hematuria *
• Heavy menstrual bleeding, especially with onset at menarche
• Prolonged nosebleeds, especially recurrent and bilateral *
• Excessive bruising, especially with firm, subcutaneous hematomas
• Normal platelet count
• Prolonged activated partial thromboplastin time
• Normal prothrombin time
## Suggestive Findings
Hemophilia A
Hemarthrosis, especially with mild or no antecedent trauma
Deep-muscle hematomas
Intracranial bleeding in the absence of major trauma
Neonatal cephalohematoma or intracranial bleeding
Prolonged bleeding or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
Unexplained gastrointestinal bleeding or hematuria *
Heavy menstrual bleeding, especially with onset at menarche
Prolonged nosebleeds, especially recurrent and bilateral *
Excessive bruising, especially with firm, subcutaneous hematomas
* Of any severity, or especially in more severely affected persons
Normal platelet count
Prolonged activated partial thromboplastin time
Normal prothrombin time
• Hemarthrosis, especially with mild or no antecedent trauma
• Deep-muscle hematomas
• Intracranial bleeding in the absence of major trauma
• Neonatal cephalohematoma or intracranial bleeding
• Prolonged bleeding or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
• Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
• Unexplained gastrointestinal bleeding or hematuria *
• Heavy menstrual bleeding, especially with onset at menarche
• Prolonged nosebleeds, especially recurrent and bilateral *
• Excessive bruising, especially with firm, subcutaneous hematomas
• Normal platelet count
• Prolonged activated partial thromboplastin time
• Normal prothrombin time
## Establishing the Diagnosis
Note: Occasionally, in individuals with mild hemophilia A, a standard "one-stage" factor VIII clotting activity assay shows near-normal or low-normal factor VIII clotting activity (40%-80%), whereas in a "two-stage" or chromogenic assay, factor VIII clotting activity is low. Thus, low-normal in vitro clotting activity does not always exclude the presence of mild hemophilia A.
Identification of a hemizygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by prolonged bleeding,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hemophilia A
See
See
Intron 22 and intron 1 inversions can be detected by multiple techniques (e.g., long-range PCR, inverse PCR, PCR-based "inverse shifting" procedure [
An intron 22 inversion is identified in approximately 43%-45% of individuals with severe hemophilia A [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Multiplex ligation-dependent probe amplification (MLPA) is the most commonly used test method to detect
Deletions and duplications detected using MLPA in 2,353 males with severe hemophilia A or 1,709 males with moderate/mild hemophilia A in the
## Molecular Genetic Testing
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by prolonged bleeding,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hemophilia A
See
See
Intron 22 and intron 1 inversions can be detected by multiple techniques (e.g., long-range PCR, inverse PCR, PCR-based "inverse shifting" procedure [
An intron 22 inversion is identified in approximately 43%-45% of individuals with severe hemophilia A [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Multiplex ligation-dependent probe amplification (MLPA) is the most commonly used test method to detect
Deletions and duplications detected using MLPA in 2,353 males with severe hemophilia A or 1,709 males with moderate/mild hemophilia A in the
##
For an introduction to multigene panels click
##
When the phenotype is indistinguishable from many other inherited disorders characterized by prolonged bleeding,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hemophilia A
See
See
Intron 22 and intron 1 inversions can be detected by multiple techniques (e.g., long-range PCR, inverse PCR, PCR-based "inverse shifting" procedure [
An intron 22 inversion is identified in approximately 43%-45% of individuals with severe hemophilia A [
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Multiplex ligation-dependent probe amplification (MLPA) is the most commonly used test method to detect
Deletions and duplications detected using MLPA in 2,353 males with severe hemophilia A or 1,709 males with moderate/mild hemophilia A in the
## Clinical Characteristics
Hemophilia A in the untreated individual is characterized by spontaneous hemorrhage; immediate or delayed bleeding or prolonged bleeding after injuries, tooth extractions, or surgery; or renewed bleeding after initial bleeding has stopped [
The age of diagnosis and frequency of bleeding episodes in the untreated individual are related to the factor VIII clotting activity (see
As the child grows and becomes more active, spontaneous joint bleeds occur with increasing frequency unless the child is on a prophylactic treatment program. Spontaneous joint bleeds or deep-muscle hematomas initially cause pain or limping before swelling appears. Children and adults with severe hemophilia A who are not treated prophylactically have an average of two to five spontaneous bleeding episodes each month. While joints are the most common sites of spontaneous bleeding, other sites include muscles, kidneys, gastrointestinal tract, and brain. Without prophylactic treatment, individuals with severe hemophilia A have prolonged bleeding that may result in excessive pain and swelling from minor injuries, surgery, and tooth extractions.
Symptoms Related to Severity of Untreated Hemophilia A
Frequent spontaneous bleeding
Abnormal bleeding after minor injuries, surgery, or tooth extractions
Spontaneous bleeding less common
Abnormal bleeding after minor injuries, surgery, or tooth extractions
Rare spontaneous bleeding
Abnormal bleeding after injuries, surgery, or tooth extractions
Clinical severity does not always correlate with the in vitro assay result.
Hepatitis B transmission from earlier plasma-derived concentrates was eliminated with donor screening and then vaccination in the 1970s. Most individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of hepatitis C virus. Viral inactivation methods implemented in concentrate preparation and donor screening assays developed by 1990 have eliminated this complication.
Approximately 30% of individuals with severe hemophilia A treated with factor VIII concentrates develop alloimmune inhibitors to factor VIII, usually within the first 20 exposures to infused factor VIII [
An inversion between a 1-kb sequence in intron 1 and an inverted repeat 5' to
Single-nucleotide variants leading to new stop codons are essentially all associated with a severe phenotype, as are most frameshift variants. (An exception is the insertion or deletion of adenosine bases resulting in a sequence of eight to ten adenosines, which may result in moderate hemophilia A [
Splice site variants often result in severe disease, but can result in mild or moderate disease depending on the specific change and location.
Missense variants occur in fewer than 20% of individuals with severe hemophilia A but are found in nearly all of those with a diagnosis of mild or moderate disease.
All males with an
Approximately 30% of heterozygous females have factor VIII clotting activity below 40% and are at risk for bleeding. In addition, 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency [
Newly recommended terminology for heterozygous females designates five clinical- and laboratory-based categories [
Severe hemophilia A (<1% factor VIII clotting activity)
Moderate hemophilia A (1%-5% factor VIII clotting activity)
Mild hemophilia A (>5% to <40% factor VIII clotting activity)
For heterozygous females with normal factor VIII clotting activity:
Individuals with a bleeding phenotype: "symptomatic hemophilia carriers"
Individuals who do not have a bleeding phenotype: "asymptomatic hemophilia carriers"
Note: 25% of females with normal factor VIII clotting activity have a bleeding phenotype.
Hemophilia A has also been referred to as "classic hemophilia."
The birth prevalence of hemophilia A has been calculated at 24.6 in 100,000 live male births, and 9.5 in 100,000 for severe hemophilia A [
The birth prevalence is thought to be approximately the same in all countries and all races, presumably because of the high spontaneous mutation rate of
• Frequent spontaneous bleeding
• Abnormal bleeding after minor injuries, surgery, or tooth extractions
• Spontaneous bleeding less common
• Abnormal bleeding after minor injuries, surgery, or tooth extractions
• Rare spontaneous bleeding
• Abnormal bleeding after injuries, surgery, or tooth extractions
• An inversion between a 1-kb sequence in intron 1 and an inverted repeat 5' to
• Single-nucleotide variants leading to new stop codons are essentially all associated with a severe phenotype, as are most frameshift variants. (An exception is the insertion or deletion of adenosine bases resulting in a sequence of eight to ten adenosines, which may result in moderate hemophilia A [
• Splice site variants often result in severe disease, but can result in mild or moderate disease depending on the specific change and location.
• Missense variants occur in fewer than 20% of individuals with severe hemophilia A but are found in nearly all of those with a diagnosis of mild or moderate disease.
• Severe hemophilia A (<1% factor VIII clotting activity)
• Moderate hemophilia A (1%-5% factor VIII clotting activity)
• Mild hemophilia A (>5% to <40% factor VIII clotting activity)
• Individuals with a bleeding phenotype: "symptomatic hemophilia carriers"
• Individuals who do not have a bleeding phenotype: "asymptomatic hemophilia carriers"
## Clinical Description
Hemophilia A in the untreated individual is characterized by spontaneous hemorrhage; immediate or delayed bleeding or prolonged bleeding after injuries, tooth extractions, or surgery; or renewed bleeding after initial bleeding has stopped [
The age of diagnosis and frequency of bleeding episodes in the untreated individual are related to the factor VIII clotting activity (see
As the child grows and becomes more active, spontaneous joint bleeds occur with increasing frequency unless the child is on a prophylactic treatment program. Spontaneous joint bleeds or deep-muscle hematomas initially cause pain or limping before swelling appears. Children and adults with severe hemophilia A who are not treated prophylactically have an average of two to five spontaneous bleeding episodes each month. While joints are the most common sites of spontaneous bleeding, other sites include muscles, kidneys, gastrointestinal tract, and brain. Without prophylactic treatment, individuals with severe hemophilia A have prolonged bleeding that may result in excessive pain and swelling from minor injuries, surgery, and tooth extractions.
Symptoms Related to Severity of Untreated Hemophilia A
Frequent spontaneous bleeding
Abnormal bleeding after minor injuries, surgery, or tooth extractions
Spontaneous bleeding less common
Abnormal bleeding after minor injuries, surgery, or tooth extractions
Rare spontaneous bleeding
Abnormal bleeding after injuries, surgery, or tooth extractions
Clinical severity does not always correlate with the in vitro assay result.
Hepatitis B transmission from earlier plasma-derived concentrates was eliminated with donor screening and then vaccination in the 1970s. Most individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of hepatitis C virus. Viral inactivation methods implemented in concentrate preparation and donor screening assays developed by 1990 have eliminated this complication.
Approximately 30% of individuals with severe hemophilia A treated with factor VIII concentrates develop alloimmune inhibitors to factor VIII, usually within the first 20 exposures to infused factor VIII [
• Frequent spontaneous bleeding
• Abnormal bleeding after minor injuries, surgery, or tooth extractions
• Spontaneous bleeding less common
• Abnormal bleeding after minor injuries, surgery, or tooth extractions
• Rare spontaneous bleeding
• Abnormal bleeding after injuries, surgery, or tooth extractions
## Genotype-Phenotype Correlations
An inversion between a 1-kb sequence in intron 1 and an inverted repeat 5' to
Single-nucleotide variants leading to new stop codons are essentially all associated with a severe phenotype, as are most frameshift variants. (An exception is the insertion or deletion of adenosine bases resulting in a sequence of eight to ten adenosines, which may result in moderate hemophilia A [
Splice site variants often result in severe disease, but can result in mild or moderate disease depending on the specific change and location.
Missense variants occur in fewer than 20% of individuals with severe hemophilia A but are found in nearly all of those with a diagnosis of mild or moderate disease.
• An inversion between a 1-kb sequence in intron 1 and an inverted repeat 5' to
• Single-nucleotide variants leading to new stop codons are essentially all associated with a severe phenotype, as are most frameshift variants. (An exception is the insertion or deletion of adenosine bases resulting in a sequence of eight to ten adenosines, which may result in moderate hemophilia A [
• Splice site variants often result in severe disease, but can result in mild or moderate disease depending on the specific change and location.
• Missense variants occur in fewer than 20% of individuals with severe hemophilia A but are found in nearly all of those with a diagnosis of mild or moderate disease.
## Penetrance
All males with an
Approximately 30% of heterozygous females have factor VIII clotting activity below 40% and are at risk for bleeding. In addition, 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency [
## Nomenclature
Newly recommended terminology for heterozygous females designates five clinical- and laboratory-based categories [
Severe hemophilia A (<1% factor VIII clotting activity)
Moderate hemophilia A (1%-5% factor VIII clotting activity)
Mild hemophilia A (>5% to <40% factor VIII clotting activity)
For heterozygous females with normal factor VIII clotting activity:
Individuals with a bleeding phenotype: "symptomatic hemophilia carriers"
Individuals who do not have a bleeding phenotype: "asymptomatic hemophilia carriers"
Note: 25% of females with normal factor VIII clotting activity have a bleeding phenotype.
Hemophilia A has also been referred to as "classic hemophilia."
• Severe hemophilia A (<1% factor VIII clotting activity)
• Moderate hemophilia A (1%-5% factor VIII clotting activity)
• Mild hemophilia A (>5% to <40% factor VIII clotting activity)
• Individuals with a bleeding phenotype: "symptomatic hemophilia carriers"
• Individuals who do not have a bleeding phenotype: "asymptomatic hemophilia carriers"
## Prevalence
The birth prevalence of hemophilia A has been calculated at 24.6 in 100,000 live male births, and 9.5 in 100,000 for severe hemophilia A [
The birth prevalence is thought to be approximately the same in all countries and all races, presumably because of the high spontaneous mutation rate of
## Genetically Related (Allelic) Disorders
A partial
## Differential Diagnosis
A detailed history of bleeding episodes can help determine if an individual has a lifelong, inherited bleeding disorder or an acquired (often transient) bleeding disorder. Increased bleeding with trauma, tonsillectomy, or for a few hours following tooth extraction may be seen in individuals without a bleeding disorder. In contrast, prolonged or intermittent bleeding that lasts several days following tooth extraction or mouth injury, renewed bleeding or increased pain and swelling several days after an injury, or development of a wound hematoma several days after surgery almost always indicates a coagulation problem. An older individual with severe or moderate hemophilia A may have joint deformities and muscle contractures. Large bruises and subcutaneous hematomas for which no trauma can be identified may be present. Individuals with a mild bleeding disorder have no outward signs except during an acute bleeding episode.
Note: Petechial hemorrhages indicate severe thrombocytopenia and are not a feature of hemophilia A.
Inherited Bleeding Disorders with Low Factor VIII Clotting Activity
AD = autosomal dominant; aPTT = activated partial thromboplastin time; AR = autosomal recessive; ELISA = enzyme-linked immunosorbent assay; MOI = mode of inheritance; PT = prothrombin time; VWF = von Willebrand factor
Inherited Bleeding Disorders with Normal Factor VIII Clotting Activity
AD = autosomal dominant; aPTT = activated partial thromboplastin time; AR = autosomal recessive; GI = gastrointestinal; MOI = mode of inheritance; PT = prothrombin time
Combined (multiple) deficiencies are usually acquired disorders, although a few families have hereditary deficits of the vitamin K-dependent factors, often resulting from deficiency of gamma-carboxylase.
Afibrinogenemia is inherited in an autosomal recessive manner. Hypofibrinogenemia can be inherited in either an autosomal dominant or an autosomal recessive manner. Dysfibrinogenemia is inherited in an autosomal dominant manner.
## Management
Clinical practice
To establish the extent of disease and needs in an individual diagnosed with hemophilia A, the evaluations summarized in
Hemophilia A: Recommended Evaluations Following Initial Diagnosis
Personal & family history of bleeding to help predict disease severity
CBC w/platelet count, esp if history of nose bleeds, GI bleeding, mouth bleeding, or (in females) heavy menstrual bleeding or postpartum hemorrhage
Referral to HTC
CBC = complete blood count; GI = gastrointestinal; HTC = hemophilia treatment center; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
The World Federation of Hemophilia has published
Low-dose prophylaxis regimens have been used to successfully prevent bleeding in young boys in resource-constrained countries [
Factor VIII concentrate infusions are also used for bleeding episodes with treatment ideally within an hour of noticing symptoms. Dosing is weight based, and target levels and duration of treatment vary by the severity of bleeding. Laboratory expertise in assessment of factor VIII activity is needed to monitor for under- and overdosing in treatment for major surgery and severe bleeds.
Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure with consideration of the risks versus benefit of factor VIII exposure.
Immunizations should be administered preferably subcutaneously, but when required, intramuscular injections can be given in those treated with factor VIII concentrate; in some individuals prolonged pressure on the vaccination site may successfully prevent excessive bleeding.
Effective dosing of factor VIII requires an understanding of different pharmacokinetics in young children.
Note: Hemophilia A genotype influences DDAVP
Persons with hemophilia who are followed at an HTC (see
Young children with severe or moderate hemophilia A should be evaluated at an HTC (accompanied by their parents/guardians) every six to 12 months and as needed to review their history of bleeding episodes and adjust treatment plans. Early signs and symptoms of possible bleeding episodes are reviewed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, a discussion of any other problems related to the individual's hemophilia A, and family and community support.
Screening for alloimmune inhibitors is indicated at least once during the first ten to 20 treatment days in children with severe hemophilia, and then every three to six months after treatment with factor VIII concentrate has been initiated either for bleeding or prophylaxis. After 50 to 100 exposure days, annual screening and screening prior to elective surgical procedures is sufficient. Testing for inhibitors should be performed in any individual with hemophilia A whenever a suboptimal clinical response to treatment is suspected, regardless of disease severity. Use of emicizumab for prophylaxis in young children usually alters exposure to factor VIII and may change the approach to monitoring for inhibitors.
Older children and adults with severe or moderate hemophilia A benefit from at least annual assessment at an HTC to review bleeding episodes and treatment plans, evaluate joints and muscles, screen for inhibitors, perform viral testing if indicated, provide education, and discuss other issues relevant to the individual's hemophilia A.
Individuals with mild hemophilia A can benefit from an assessment at an HTC every one to two years. Affected individuals with comorbidities and other complications or treatment challenges may require more frequent visits.
The following agents/circumstances should be avoided:
Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure. The benefit versus the risk of factor VIII exposure in early life should be considered.
Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as in individuals with a cardiovascular indication. Individuals with severe hemophilia usually require prophylaxis to allow aspirin and other platelet-inhibitory drugs to be used safely [
Intramuscular injections without factor treatment should be avoided. Pressure on the site after intramuscular injection in children has been reported without factor VIII coverage. Individuals on prophylactic therapy may be given intramuscular injections.
Activities that involve a high risk of trauma, particularly of head injury, should be avoided.
It is appropriate to evaluate asymptomatic male and female at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment, preventive measures, and surveillance. A thorough family history may identify relatives who are at risk but have not been tested (particularly in families with mild hemophilia A).
Assay of factor VIII clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue), assessment of factor VIII clotting activity in the neonatal period, or molecular genetic testing for the family-specific
Note: Ideally, the cord blood for factor VIII clotting activity assay should be drawn into a syringe containing one tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. If not available, a standard blue top tube can be used.
Infants with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, factor VIII concentrate is administered immediately before and after the procedure to prevent delayed bleeding and poor wound healing. The benefit versus the risk of exposure to factor VIII in early childhood should be considered.
All daughters and mothers of an affected male and other at-risk females should have molecular genetic testing for the family-specific
It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible.
See
If the heterozygous female has hemophilia A (factor VIII clotting activity 100% for delivery and >50% for neuroaxial anesthesia), delivery can proceed as clinically indicated if the fetus is confirmed not to be affected by hemophilia. Postpartum factor VIII clotting activity may decrease soon after delivery, and postpartum hemorrhage may ensue [
Clinical trials for gene therapy for hemophilia A are under way; one product, valoctocogene roxaparvovec, received conditional marketing authorization by the European Medicines Agency in 2022 and approval by the FDA in 2023. The gene therapies currently in or having recently completed Phase III trials use liver-targeted adeno-associated (AAV) vectors. Therapeutic levels have been achieved in many (although not all) individuals in studies to date, and short-term steroids are often needed for elevated transaminases. Long-term durability as well as safety need further study [
Drugs that "rebalance" coagulation are under study, including completed Phase III or late-phase trials for inhibitors of tissue pathways (concizumab and marstacimab) in individuals with hemophilia A with and without inhibitors [
Search
Vitamin K does not prevent or control bleeding in hemophilia A.
Cryoprecipitate is no longer recommended to treat hemophilia A because it is not treated with a virucidal agent and contains a lower concentration of factor VIII than concentrates. However, it can be used in emergencies if no factor products are available.
• Personal & family history of bleeding to help predict disease severity
• CBC w/platelet count, esp if history of nose bleeds, GI bleeding, mouth bleeding, or (in females) heavy menstrual bleeding or postpartum hemorrhage
• Referral to HTC
• Low-dose prophylaxis regimens have been used to successfully prevent bleeding in young boys in resource-constrained countries [
• Factor VIII concentrate infusions are also used for bleeding episodes with treatment ideally within an hour of noticing symptoms. Dosing is weight based, and target levels and duration of treatment vary by the severity of bleeding. Laboratory expertise in assessment of factor VIII activity is needed to monitor for under- and overdosing in treatment for major surgery and severe bleeds.
• Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure with consideration of the risks versus benefit of factor VIII exposure.
• Immunizations should be administered preferably subcutaneously, but when required, intramuscular injections can be given in those treated with factor VIII concentrate; in some individuals prolonged pressure on the vaccination site may successfully prevent excessive bleeding.
• Effective dosing of factor VIII requires an understanding of different pharmacokinetics in young children.
• Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure. The benefit versus the risk of factor VIII exposure in early life should be considered.
• Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as in individuals with a cardiovascular indication. Individuals with severe hemophilia usually require prophylaxis to allow aspirin and other platelet-inhibitory drugs to be used safely [
• Intramuscular injections without factor treatment should be avoided. Pressure on the site after intramuscular injection in children has been reported without factor VIII coverage. Individuals on prophylactic therapy may be given intramuscular injections.
• Activities that involve a high risk of trauma, particularly of head injury, should be avoided.
• Assay of factor VIII clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue), assessment of factor VIII clotting activity in the neonatal period, or molecular genetic testing for the family-specific
• Note: Ideally, the cord blood for factor VIII clotting activity assay should be drawn into a syringe containing one tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. If not available, a standard blue top tube can be used.
• Infants with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, factor VIII concentrate is administered immediately before and after the procedure to prevent delayed bleeding and poor wound healing. The benefit versus the risk of exposure to factor VIII in early childhood should be considered.
• All daughters and mothers of an affected male and other at-risk females should have molecular genetic testing for the family-specific
• It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hemophilia A, the evaluations summarized in
Hemophilia A: Recommended Evaluations Following Initial Diagnosis
Personal & family history of bleeding to help predict disease severity
CBC w/platelet count, esp if history of nose bleeds, GI bleeding, mouth bleeding, or (in females) heavy menstrual bleeding or postpartum hemorrhage
Referral to HTC
CBC = complete blood count; GI = gastrointestinal; HTC = hemophilia treatment center; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Personal & family history of bleeding to help predict disease severity
• CBC w/platelet count, esp if history of nose bleeds, GI bleeding, mouth bleeding, or (in females) heavy menstrual bleeding or postpartum hemorrhage
• Referral to HTC
## Treatment of Manifestations
The World Federation of Hemophilia has published
Low-dose prophylaxis regimens have been used to successfully prevent bleeding in young boys in resource-constrained countries [
Factor VIII concentrate infusions are also used for bleeding episodes with treatment ideally within an hour of noticing symptoms. Dosing is weight based, and target levels and duration of treatment vary by the severity of bleeding. Laboratory expertise in assessment of factor VIII activity is needed to monitor for under- and overdosing in treatment for major surgery and severe bleeds.
Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure with consideration of the risks versus benefit of factor VIII exposure.
Immunizations should be administered preferably subcutaneously, but when required, intramuscular injections can be given in those treated with factor VIII concentrate; in some individuals prolonged pressure on the vaccination site may successfully prevent excessive bleeding.
Effective dosing of factor VIII requires an understanding of different pharmacokinetics in young children.
Note: Hemophilia A genotype influences DDAVP
• Low-dose prophylaxis regimens have been used to successfully prevent bleeding in young boys in resource-constrained countries [
• Factor VIII concentrate infusions are also used for bleeding episodes with treatment ideally within an hour of noticing symptoms. Dosing is weight based, and target levels and duration of treatment vary by the severity of bleeding. Laboratory expertise in assessment of factor VIII activity is needed to monitor for under- and overdosing in treatment for major surgery and severe bleeds.
• Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure with consideration of the risks versus benefit of factor VIII exposure.
• Immunizations should be administered preferably subcutaneously, but when required, intramuscular injections can be given in those treated with factor VIII concentrate; in some individuals prolonged pressure on the vaccination site may successfully prevent excessive bleeding.
• Effective dosing of factor VIII requires an understanding of different pharmacokinetics in young children.
## Targeted Therapies
Low-dose prophylaxis regimens have been used to successfully prevent bleeding in young boys in resource-constrained countries [
Factor VIII concentrate infusions are also used for bleeding episodes with treatment ideally within an hour of noticing symptoms. Dosing is weight based, and target levels and duration of treatment vary by the severity of bleeding. Laboratory expertise in assessment of factor VIII activity is needed to monitor for under- and overdosing in treatment for major surgery and severe bleeds.
Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure with consideration of the risks versus benefit of factor VIII exposure.
Immunizations should be administered preferably subcutaneously, but when required, intramuscular injections can be given in those treated with factor VIII concentrate; in some individuals prolonged pressure on the vaccination site may successfully prevent excessive bleeding.
Effective dosing of factor VIII requires an understanding of different pharmacokinetics in young children.
Note: Hemophilia A genotype influences DDAVP
• Low-dose prophylaxis regimens have been used to successfully prevent bleeding in young boys in resource-constrained countries [
• Factor VIII concentrate infusions are also used for bleeding episodes with treatment ideally within an hour of noticing symptoms. Dosing is weight based, and target levels and duration of treatment vary by the severity of bleeding. Laboratory expertise in assessment of factor VIII activity is needed to monitor for under- and overdosing in treatment for major surgery and severe bleeds.
• Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure with consideration of the risks versus benefit of factor VIII exposure.
• Immunizations should be administered preferably subcutaneously, but when required, intramuscular injections can be given in those treated with factor VIII concentrate; in some individuals prolonged pressure on the vaccination site may successfully prevent excessive bleeding.
• Effective dosing of factor VIII requires an understanding of different pharmacokinetics in young children.
## Supportive Care
## Surveillance
Persons with hemophilia who are followed at an HTC (see
Young children with severe or moderate hemophilia A should be evaluated at an HTC (accompanied by their parents/guardians) every six to 12 months and as needed to review their history of bleeding episodes and adjust treatment plans. Early signs and symptoms of possible bleeding episodes are reviewed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, a discussion of any other problems related to the individual's hemophilia A, and family and community support.
Screening for alloimmune inhibitors is indicated at least once during the first ten to 20 treatment days in children with severe hemophilia, and then every three to six months after treatment with factor VIII concentrate has been initiated either for bleeding or prophylaxis. After 50 to 100 exposure days, annual screening and screening prior to elective surgical procedures is sufficient. Testing for inhibitors should be performed in any individual with hemophilia A whenever a suboptimal clinical response to treatment is suspected, regardless of disease severity. Use of emicizumab for prophylaxis in young children usually alters exposure to factor VIII and may change the approach to monitoring for inhibitors.
Older children and adults with severe or moderate hemophilia A benefit from at least annual assessment at an HTC to review bleeding episodes and treatment plans, evaluate joints and muscles, screen for inhibitors, perform viral testing if indicated, provide education, and discuss other issues relevant to the individual's hemophilia A.
Individuals with mild hemophilia A can benefit from an assessment at an HTC every one to two years. Affected individuals with comorbidities and other complications or treatment challenges may require more frequent visits.
## Agents/Circumstances to Avoid
The following agents/circumstances should be avoided:
Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure. The benefit versus the risk of factor VIII exposure in early life should be considered.
Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as in individuals with a cardiovascular indication. Individuals with severe hemophilia usually require prophylaxis to allow aspirin and other platelet-inhibitory drugs to be used safely [
Intramuscular injections without factor treatment should be avoided. Pressure on the site after intramuscular injection in children has been reported without factor VIII coverage. Individuals on prophylactic therapy may be given intramuscular injections.
Activities that involve a high risk of trauma, particularly of head injury, should be avoided.
• Infant males with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, treated with factor VIII concentrate directly before and after the procedure. The benefit versus the risk of factor VIII exposure in early life should be considered.
• Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as in individuals with a cardiovascular indication. Individuals with severe hemophilia usually require prophylaxis to allow aspirin and other platelet-inhibitory drugs to be used safely [
• Intramuscular injections without factor treatment should be avoided. Pressure on the site after intramuscular injection in children has been reported without factor VIII coverage. Individuals on prophylactic therapy may be given intramuscular injections.
• Activities that involve a high risk of trauma, particularly of head injury, should be avoided.
## Evaluation of Relatives at Risk
It is appropriate to evaluate asymptomatic male and female at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment, preventive measures, and surveillance. A thorough family history may identify relatives who are at risk but have not been tested (particularly in families with mild hemophilia A).
Assay of factor VIII clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue), assessment of factor VIII clotting activity in the neonatal period, or molecular genetic testing for the family-specific
Note: Ideally, the cord blood for factor VIII clotting activity assay should be drawn into a syringe containing one tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. If not available, a standard blue top tube can be used.
Infants with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, factor VIII concentrate is administered immediately before and after the procedure to prevent delayed bleeding and poor wound healing. The benefit versus the risk of exposure to factor VIII in early childhood should be considered.
All daughters and mothers of an affected male and other at-risk females should have molecular genetic testing for the family-specific
It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible.
See
• Assay of factor VIII clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue), assessment of factor VIII clotting activity in the neonatal period, or molecular genetic testing for the family-specific
• Note: Ideally, the cord blood for factor VIII clotting activity assay should be drawn into a syringe containing one tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. If not available, a standard blue top tube can be used.
• Infants with a family history of hemophilia A should not be circumcised unless hemophilia A is either excluded or, if present, factor VIII concentrate is administered immediately before and after the procedure to prevent delayed bleeding and poor wound healing. The benefit versus the risk of exposure to factor VIII in early childhood should be considered.
• All daughters and mothers of an affected male and other at-risk females should have molecular genetic testing for the family-specific
• It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible.
## Pregnancy Management
If the heterozygous female has hemophilia A (factor VIII clotting activity 100% for delivery and >50% for neuroaxial anesthesia), delivery can proceed as clinically indicated if the fetus is confirmed not to be affected by hemophilia. Postpartum factor VIII clotting activity may decrease soon after delivery, and postpartum hemorrhage may ensue [
## Therapies Under Investigation
Clinical trials for gene therapy for hemophilia A are under way; one product, valoctocogene roxaparvovec, received conditional marketing authorization by the European Medicines Agency in 2022 and approval by the FDA in 2023. The gene therapies currently in or having recently completed Phase III trials use liver-targeted adeno-associated (AAV) vectors. Therapeutic levels have been achieved in many (although not all) individuals in studies to date, and short-term steroids are often needed for elevated transaminases. Long-term durability as well as safety need further study [
Drugs that "rebalance" coagulation are under study, including completed Phase III or late-phase trials for inhibitors of tissue pathways (concizumab and marstacimab) in individuals with hemophilia A with and without inhibitors [
Search
## Other
Vitamin K does not prevent or control bleeding in hemophilia A.
Cryoprecipitate is no longer recommended to treat hemophilia A because it is not treated with a virucidal agent and contains a lower concentration of factor VIII than concentrates. However, it can be used in emergencies if no factor products are available.
## Genetic Counseling
Hemophilia A is inherited in an X-linked manner.
The father of an affected male will not have the disorder, nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
Approximately 30% of affected males have no family history of hemophilia A. If a male is the only affected family member (i.e., a simplex case), it is possible that:
The mother is heterozygous for an
Note: In a Swedish study of individuals with severe hemophilia A who represented simplex cases, the mother of the proband was heterozygous in 28 out of 45 families [
The mother has somatic/germline mosaicism. Studies have shown varying frequencies of mosaicism ranging from 13% to 22.5% in the mothers of apparent simplex cases [
Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Specialized testing approaches designed to detect low-level mosaicism have been developed [
The mother is not heterozygous for an
Molecular genetic testing of the mother is recommended to assess her genetic status and to allow reliable recurrence risk assessment.
A heterozygous female proband may have inherited the
On rare occasion, biallelic
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes. Approximately 30% of heterozygous females have a factor VIII clotting activity lower than 40% and are at risk for bleeding; 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency (see
All sibs should have factor VIII clotting activity assayed unless molecular genetic testing confirms that they have not inherited the
If the mother of the proband has an
If the father of the proband has an
The maternal aunts and maternal cousins of a male proband may be at risk of having an
The risk to other family members of a female proband depends on the status of the proband's mother and father: if a parent has the
Note: Molecular genetic testing can often determine the point of origin of a
Molecular genetic testing for identification of female heterozygotes is most informative if the
See Management,
Factor VIII clotting activity, or its ratio to von Willebrand factor level, is not a reliable test for determining genetic status: it can only be suggestive if low. Only an estimated 30% of heterozygous females have factor VIII clotting activity lower than 40% [
See Management,
See the World Federation of Hemophilia
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is recommended that the genetic status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible (see
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disorder, nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• Approximately 30% of affected males have no family history of hemophilia A. If a male is the only affected family member (i.e., a simplex case), it is possible that:
• The mother is heterozygous for an
• Note: In a Swedish study of individuals with severe hemophilia A who represented simplex cases, the mother of the proband was heterozygous in 28 out of 45 families [
• The mother has somatic/germline mosaicism. Studies have shown varying frequencies of mosaicism ranging from 13% to 22.5% in the mothers of apparent simplex cases [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Specialized testing approaches designed to detect low-level mosaicism have been developed [
• The mother is not heterozygous for an
• The mother is heterozygous for an
• Note: In a Swedish study of individuals with severe hemophilia A who represented simplex cases, the mother of the proband was heterozygous in 28 out of 45 families [
• The mother has somatic/germline mosaicism. Studies have shown varying frequencies of mosaicism ranging from 13% to 22.5% in the mothers of apparent simplex cases [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Specialized testing approaches designed to detect low-level mosaicism have been developed [
• The mother is not heterozygous for an
• Molecular genetic testing of the mother is recommended to assess her genetic status and to allow reliable recurrence risk assessment.
• The mother is heterozygous for an
• Note: In a Swedish study of individuals with severe hemophilia A who represented simplex cases, the mother of the proband was heterozygous in 28 out of 45 families [
• The mother has somatic/germline mosaicism. Studies have shown varying frequencies of mosaicism ranging from 13% to 22.5% in the mothers of apparent simplex cases [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Specialized testing approaches designed to detect low-level mosaicism have been developed [
• The mother is not heterozygous for an
• A heterozygous female proband may have inherited the
• On rare occasion, biallelic
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Approximately 30% of heterozygous females have a factor VIII clotting activity lower than 40% and are at risk for bleeding; 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency (see
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Approximately 30% of heterozygous females have a factor VIII clotting activity lower than 40% and are at risk for bleeding; 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency (see
• All sibs should have factor VIII clotting activity assayed unless molecular genetic testing confirms that they have not inherited the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Approximately 30% of heterozygous females have a factor VIII clotting activity lower than 40% and are at risk for bleeding; 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency (see
• If the mother of the proband has an
• If the father of the proband has an
• The maternal aunts and maternal cousins of a male proband may be at risk of having an
• The risk to other family members of a female proband depends on the status of the proband's mother and father: if a parent has the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is recommended that the genetic status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible (see
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Mode of Inheritance
Hemophilia A is inherited in an X-linked manner.
## Risk to Family Members
The father of an affected male will not have the disorder, nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
Approximately 30% of affected males have no family history of hemophilia A. If a male is the only affected family member (i.e., a simplex case), it is possible that:
The mother is heterozygous for an
Note: In a Swedish study of individuals with severe hemophilia A who represented simplex cases, the mother of the proband was heterozygous in 28 out of 45 families [
The mother has somatic/germline mosaicism. Studies have shown varying frequencies of mosaicism ranging from 13% to 22.5% in the mothers of apparent simplex cases [
Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Specialized testing approaches designed to detect low-level mosaicism have been developed [
The mother is not heterozygous for an
Molecular genetic testing of the mother is recommended to assess her genetic status and to allow reliable recurrence risk assessment.
A heterozygous female proband may have inherited the
On rare occasion, biallelic
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes. Approximately 30% of heterozygous females have a factor VIII clotting activity lower than 40% and are at risk for bleeding; 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency (see
All sibs should have factor VIII clotting activity assayed unless molecular genetic testing confirms that they have not inherited the
If the mother of the proband has an
If the father of the proband has an
The maternal aunts and maternal cousins of a male proband may be at risk of having an
The risk to other family members of a female proband depends on the status of the proband's mother and father: if a parent has the
Note: Molecular genetic testing can often determine the point of origin of a
• The father of an affected male will not have the disorder, nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• Approximately 30% of affected males have no family history of hemophilia A. If a male is the only affected family member (i.e., a simplex case), it is possible that:
• The mother is heterozygous for an
• Note: In a Swedish study of individuals with severe hemophilia A who represented simplex cases, the mother of the proband was heterozygous in 28 out of 45 families [
• The mother has somatic/germline mosaicism. Studies have shown varying frequencies of mosaicism ranging from 13% to 22.5% in the mothers of apparent simplex cases [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Specialized testing approaches designed to detect low-level mosaicism have been developed [
• The mother is not heterozygous for an
• The mother is heterozygous for an
• Note: In a Swedish study of individuals with severe hemophilia A who represented simplex cases, the mother of the proband was heterozygous in 28 out of 45 families [
• The mother has somatic/germline mosaicism. Studies have shown varying frequencies of mosaicism ranging from 13% to 22.5% in the mothers of apparent simplex cases [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Specialized testing approaches designed to detect low-level mosaicism have been developed [
• The mother is not heterozygous for an
• Molecular genetic testing of the mother is recommended to assess her genetic status and to allow reliable recurrence risk assessment.
• The mother is heterozygous for an
• Note: In a Swedish study of individuals with severe hemophilia A who represented simplex cases, the mother of the proband was heterozygous in 28 out of 45 families [
• The mother has somatic/germline mosaicism. Studies have shown varying frequencies of mosaicism ranging from 13% to 22.5% in the mothers of apparent simplex cases [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Specialized testing approaches designed to detect low-level mosaicism have been developed [
• The mother is not heterozygous for an
• A heterozygous female proband may have inherited the
• On rare occasion, biallelic
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Approximately 30% of heterozygous females have a factor VIII clotting activity lower than 40% and are at risk for bleeding; 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency (see
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Approximately 30% of heterozygous females have a factor VIII clotting activity lower than 40% and are at risk for bleeding; 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency (see
• All sibs should have factor VIII clotting activity assayed unless molecular genetic testing confirms that they have not inherited the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Approximately 30% of heterozygous females have a factor VIII clotting activity lower than 40% and are at risk for bleeding; 25% of heterozygous females with normal factor VIII clotting activity report an increased bleeding tendency (see
• If the mother of the proband has an
• If the father of the proband has an
• The maternal aunts and maternal cousins of a male proband may be at risk of having an
• The risk to other family members of a female proband depends on the status of the proband's mother and father: if a parent has the
## Heterozygote Detection
Molecular genetic testing for identification of female heterozygotes is most informative if the
See Management,
Factor VIII clotting activity, or its ratio to von Willebrand factor level, is not a reliable test for determining genetic status: it can only be suggestive if low. Only an estimated 30% of heterozygous females have factor VIII clotting activity lower than 40% [
## Related Genetic Counseling Issues
See Management,
See the World Federation of Hemophilia
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is recommended that the genetic status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible (see
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is recommended that the genetic status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible (see
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
United Kingdom
Canada
Centers for Disease Control and Prevention
•
• Canada
•
•
•
•
•
•
•
•
• United Kingdom
•
•
• Canada
•
•
• Centers for Disease Control and Prevention
•
## Molecular Genetics
Hemophilia A: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hemophilia A (
Factor VIII is synthesized primarily in the liver sinusoidal endothelial cells and circulates as an inactive clotting cofactor that has been cleaved in the B domain prior to secretion. In circulation, factor VIII is stabilized by binding to von Willebrand factor (VWF). Once activated by trace amounts of thrombin, it is released from VWF and binds to phospholipid membrane surfaces such as those provided by activated platelets. There it interacts with factor IXa to become the "intrinsic system" factor X activator [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Factor VIII is synthesized primarily in the liver sinusoidal endothelial cells and circulates as an inactive clotting cofactor that has been cleaved in the B domain prior to secretion. In circulation, factor VIII is stabilized by binding to von Willebrand factor (VWF). Once activated by trace amounts of thrombin, it is released from VWF and binds to phospholipid membrane surfaces such as those provided by activated platelets. There it interacts with factor IXa to become the "intrinsic system" factor X activator [
Variants listed in the table have been provided by the authors.
## Chapter Notes
Barbara A Konkle (
Cheryl L Brower, RN, MSPH; Bloodworks Northwest (2008-2011) Frank K Fujimura, PhD, FACMG; GMP Genetics, Inc (2000-2003)Haley Huston, BS; Bloodworks Northwest (2017-2022)Maribel J Johnson, RN, MA; Bloodworks Northwest (2000-2008)Neil C Josephson, MD; Bloodworks Northwest (2011-2017)Barbara A Konkle, MD (2011-present)Shelley Nakaya Fletcher, BS (2011-present)Arthur R Thompson, MD, PhD; University of Washington (2000-2014)
7 August 2025 (sw) Comprehensive update posted live
27 October 2022 (sw) Comprehensive update posted live
2 February 2017 (sw) Comprehensive update posted live
5 June 2014 (me) Comprehensive update posted live
22 September 2011 (me) Comprehensive update posted live
25 March 2008 (me) Comprehensive update posted live
17 August 2005 (me) Comprehensive update posted live
8 May 2003 (me) Comprehensive update posted live
21 September 2000 (me) Review posted live
April 2000 (art) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 27 October 2022 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 5 June 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Comprehensive update posted live
• 25 March 2008 (me) Comprehensive update posted live
• 17 August 2005 (me) Comprehensive update posted live
• 8 May 2003 (me) Comprehensive update posted live
• 21 September 2000 (me) Review posted live
• April 2000 (art) Original submission
## Author Notes
Barbara A Konkle (
## Author History
Cheryl L Brower, RN, MSPH; Bloodworks Northwest (2008-2011) Frank K Fujimura, PhD, FACMG; GMP Genetics, Inc (2000-2003)Haley Huston, BS; Bloodworks Northwest (2017-2022)Maribel J Johnson, RN, MA; Bloodworks Northwest (2000-2008)Neil C Josephson, MD; Bloodworks Northwest (2011-2017)Barbara A Konkle, MD (2011-present)Shelley Nakaya Fletcher, BS (2011-present)Arthur R Thompson, MD, PhD; University of Washington (2000-2014)
## Revision History
7 August 2025 (sw) Comprehensive update posted live
27 October 2022 (sw) Comprehensive update posted live
2 February 2017 (sw) Comprehensive update posted live
5 June 2014 (me) Comprehensive update posted live
22 September 2011 (me) Comprehensive update posted live
25 March 2008 (me) Comprehensive update posted live
17 August 2005 (me) Comprehensive update posted live
8 May 2003 (me) Comprehensive update posted live
21 September 2000 (me) Review posted live
April 2000 (art) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 27 October 2022 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 5 June 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Comprehensive update posted live
• 25 March 2008 (me) Comprehensive update posted live
• 17 August 2005 (me) Comprehensive update posted live
• 8 May 2003 (me) Comprehensive update posted live
• 21 September 2000 (me) Review posted live
• April 2000 (art) Original submission
## Key Sections in This
## References
Keeney S, Mitchell M, Goodeve A. Practice guidelines for the molecular diagnosis of haemophilia A. UK Haemophilia Centre, Doctors' Organisation (UKHCDO), Haemophilia Genetics Laboratory Network, and Clinical Molecular Genetics Society. Available
Sutherland M, de Brasi C, Konkle BA, Shetty S, Pierce GF, Srivastava A. Chapter 4: genetic assessment. In: Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF, et al. WFH guidelines for the management of hemophilia, 3rd ed. Haemophilia. 2020;26:49-58. [
Pai M, Key NS, Skinner M, Curtis R, Feinstein M, Kessler C, Lane SJ, Makris M, Riker E, Santesso N, Soucie JM, Yeung CHT, Iorio A, Schünemann HJ. NHF-McMaster guideline on care models for haemophilia management. Haemophilia. 2016;22:6-16. [
Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF, et al. WFH guidelines for the management of hemophilia, 3rd ed. Haemophilia. 2020;26:1-158. [
• Keeney S, Mitchell M, Goodeve A. Practice guidelines for the molecular diagnosis of haemophilia A. UK Haemophilia Centre, Doctors' Organisation (UKHCDO), Haemophilia Genetics Laboratory Network, and Clinical Molecular Genetics Society. Available
• Sutherland M, de Brasi C, Konkle BA, Shetty S, Pierce GF, Srivastava A. Chapter 4: genetic assessment. In: Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF, et al. WFH guidelines for the management of hemophilia, 3rd ed. Haemophilia. 2020;26:49-58. [
• Pai M, Key NS, Skinner M, Curtis R, Feinstein M, Kessler C, Lane SJ, Makris M, Riker E, Santesso N, Soucie JM, Yeung CHT, Iorio A, Schünemann HJ. NHF-McMaster guideline on care models for haemophilia management. Haemophilia. 2016;22:6-16. [
• Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF, et al. WFH guidelines for the management of hemophilia, 3rd ed. Haemophilia. 2020;26:1-158. [
## Genetic Testing Guidelines
Keeney S, Mitchell M, Goodeve A. Practice guidelines for the molecular diagnosis of haemophilia A. UK Haemophilia Centre, Doctors' Organisation (UKHCDO), Haemophilia Genetics Laboratory Network, and Clinical Molecular Genetics Society. Available
Sutherland M, de Brasi C, Konkle BA, Shetty S, Pierce GF, Srivastava A. Chapter 4: genetic assessment. In: Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF, et al. WFH guidelines for the management of hemophilia, 3rd ed. Haemophilia. 2020;26:49-58. [
• Keeney S, Mitchell M, Goodeve A. Practice guidelines for the molecular diagnosis of haemophilia A. UK Haemophilia Centre, Doctors' Organisation (UKHCDO), Haemophilia Genetics Laboratory Network, and Clinical Molecular Genetics Society. Available
• Sutherland M, de Brasi C, Konkle BA, Shetty S, Pierce GF, Srivastava A. Chapter 4: genetic assessment. In: Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF, et al. WFH guidelines for the management of hemophilia, 3rd ed. Haemophilia. 2020;26:49-58. [
## Treatment Guidelines
Pai M, Key NS, Skinner M, Curtis R, Feinstein M, Kessler C, Lane SJ, Makris M, Riker E, Santesso N, Soucie JM, Yeung CHT, Iorio A, Schünemann HJ. NHF-McMaster guideline on care models for haemophilia management. Haemophilia. 2016;22:6-16. [
Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF, et al. WFH guidelines for the management of hemophilia, 3rd ed. Haemophilia. 2020;26:1-158. [
• Pai M, Key NS, Skinner M, Curtis R, Feinstein M, Kessler C, Lane SJ, Makris M, Riker E, Santesso N, Soucie JM, Yeung CHT, Iorio A, Schünemann HJ. NHF-McMaster guideline on care models for haemophilia management. Haemophilia. 2016;22:6-16. [
• Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinás A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF, et al. WFH guidelines for the management of hemophilia, 3rd ed. Haemophilia. 2020;26:1-158. [
## Literature Cited
|
[] |
21/9/2000
|
7/8/2025
|
27/7/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
hemo-b
|
hemo-b
|
[
"Christmas Disease",
"Factor IX Deficiency",
"Christmas Disease",
"Factor IX Deficiency",
"Coagulation factor IX",
"F9",
"Hemophilia B"
] |
Hemophilia B
|
Barbara A Konkle, Shelley Nakaya Fletcher
|
Summary Hemophilia B is characterized by deficiency in factor IX clotting activity that results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor IX clotting activity. In any individual with hemophilia B, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. The diagnosis of hemophilia B is established in individuals with low factor IX clotting activity. Identification of a hemizygous Hemophilia B is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother. The risk to sibs of a female proband depends on the genetic status of the mother and father. If the mother of the proband has an
|
## Diagnosis
For the purposes of this
Hemophilia B
Hemarthrosis, especially with mild or no antecedent trauma
Deep-muscle hematomas
Intracranial bleeding in the absence of major trauma
Neonatal cephalohematoma or intracranial bleeding
Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
Unexplained gastrointestinal bleeding or hematuria *
Heavy menstrual bleeding, especially with onset at menarche
Prolonged nosebleeds, especially recurrent and bilateral *
Excessive bruising, especially with firm, subcutaneous hematomas
* Of any severity, or especially in more severely affected persons
Normal platelet count
Prolonged activated partial thromboplastin time (aPTT) in severe and moderate hemophilia B; normal or mildly prolonged aPTT in mild hemophilia B
Normal prothrombin time
Note: (1) The normal range for factor IX clotting activity is approximately 50%-150% [
Identification of a hemizygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMG variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by prolonged bleeding,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hemophilia B
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Routine sequence analysis should detect pathogenic variants in the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Hemarthrosis, especially with mild or no antecedent trauma
• Deep-muscle hematomas
• Intracranial bleeding in the absence of major trauma
• Neonatal cephalohematoma or intracranial bleeding
• Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
• Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
• Unexplained gastrointestinal bleeding or hematuria *
• Heavy menstrual bleeding, especially with onset at menarche
• Prolonged nosebleeds, especially recurrent and bilateral *
• Excessive bruising, especially with firm, subcutaneous hematomas
• Normal platelet count
• Prolonged activated partial thromboplastin time (aPTT) in severe and moderate hemophilia B; normal or mildly prolonged aPTT in mild hemophilia B
• Normal prothrombin time
## Suggestive Findings
Hemophilia B
Hemarthrosis, especially with mild or no antecedent trauma
Deep-muscle hematomas
Intracranial bleeding in the absence of major trauma
Neonatal cephalohematoma or intracranial bleeding
Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
Unexplained gastrointestinal bleeding or hematuria *
Heavy menstrual bleeding, especially with onset at menarche
Prolonged nosebleeds, especially recurrent and bilateral *
Excessive bruising, especially with firm, subcutaneous hematomas
* Of any severity, or especially in more severely affected persons
Normal platelet count
Prolonged activated partial thromboplastin time (aPTT) in severe and moderate hemophilia B; normal or mildly prolonged aPTT in mild hemophilia B
Normal prothrombin time
• Hemarthrosis, especially with mild or no antecedent trauma
• Deep-muscle hematomas
• Intracranial bleeding in the absence of major trauma
• Neonatal cephalohematoma or intracranial bleeding
• Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision *
• Prolonged or delayed bleeding or poor wound healing following surgery or trauma *
• Unexplained gastrointestinal bleeding or hematuria *
• Heavy menstrual bleeding, especially with onset at menarche
• Prolonged nosebleeds, especially recurrent and bilateral *
• Excessive bruising, especially with firm, subcutaneous hematomas
• Normal platelet count
• Prolonged activated partial thromboplastin time (aPTT) in severe and moderate hemophilia B; normal or mildly prolonged aPTT in mild hemophilia B
• Normal prothrombin time
## Establishing the Diagnosis
Note: (1) The normal range for factor IX clotting activity is approximately 50%-150% [
Identification of a hemizygous pathogenic (or likely pathogenic) variant in
Note: (1) Per ACMG/AMG variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by prolonged bleeding,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hemophilia B
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Routine sequence analysis should detect pathogenic variants in the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Molecular Genetic Testing
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by prolonged bleeding,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hemophilia B
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Routine sequence analysis should detect pathogenic variants in the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
##
For an introduction to multigene panels click
##
When the phenotype is indistinguishable from many other inherited disorders characterized by prolonged bleeding,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hemophilia B
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Routine sequence analysis should detect pathogenic variants in the
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Hemophilia B in the untreated individual is characterized by spontaneous bleeding including intracranial bleeding, muscle and joint bleeding (usually in severe disease), immediate or delayed bleeding or prolonged oozing after injuries, tooth extractions, or surgery, or renewed bleeding after initial bleeding has stopped [
The age of diagnosis and frequency of bleeding episodes are generally related to the factor IX clotting activity (see Table 2). In any affected individual, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. To some extent, this greater frequency is a function of both physical activity levels and vulnerability during more rapid growth.
As the child grows and becomes more active, spontaneous joint bleeds occur with increasing frequency unless the child is on a prophylactic treatment program. Spontaneous joint bleeds or deep-muscle hematomas initially cause pain or limping before swelling appears. Children and young adults with severe hemophilia B who are not treated have an average of two to five spontaneous bleeding episodes each month. Joints are the most common sites of spontaneous bleeding; other sites include the muscles, kidneys, gastrointestinal tract, brain, and nose. Without prophylactic treatment, individuals with hemophilia B have prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.
Symptoms Related to Severity of Untreated Hemophilia B
Frequent spontaneous bleeding
Excessive &/or prolonged bleeding after minor injuries, surgery, or tooth extractions
Spontaneous bleeding less common
Excessive &/or prolonged bleeding after minor injuries, surgery, or tooth extractions
Rare spontaneous bleeding
Excessive &/or prolonged bleeding after major injuries, surgery, or tooth extractions
Clinical severity does not always correlate with the in vitro assay result.
Viral inactivation methods and donor screening of plasmas were introduced by 1990 and a recombinant factor IX concentrate became available shortly thereafter [
Hepatitis B transmission from earlier plasma-derived concentrates was eliminated with donor screening and then vaccination introduced in the 1970s. Most individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of hepatitis C. Viral inactivation methods implemented in concentrate preparation and donor screening assays developed by 1990 have essentially eliminated hepatitis C transmission from plasma-derived concentrates.
Alloimmune inhibitors occur much less frequently in hemophilia B than in hemophilia A, although they are more common than previously appreciated. Earlier data suggested a rate of 3%-5%, but more recent data suggests that it may be closer to 10%, almost exclusively in individuals with severe disease. The incidence appears to vary by population and underlying genetic variant [
Large deletions, nonsense variants, and most frameshift variants cause severe disease.
Missense variants can cause severe, moderate, or mild disease depending on their location and the specific substitutions involved.
Alloimmune inhibitors occur with the greatest frequency (40%-60%) in individuals with large partial (>50 bp) deletions, whole-gene deletions, or early-termination variants (<100 predicted amino acids) [
Missense variants are rarely associated with inhibitors.
Unlike hemophilia A, severe hemophilia B is often caused by a missense variant, and several of these are associated with normal cross-reacting material (factor IX antigen) levels (see
Uncommon variants within the carboxylase-binding domain of the propeptide cause increased sensitivity to warfarin anticoagulation in individuals without any baseline bleeding tendency [
In hemophilia B Leyden, more than 20 different causative variants in the proximal
All males with an
Approximately 30% of heterozygous females have factor IX clotting activity below 40% and are at risk for bleeding; mild bleeding can occur in carriers with low-normal factor IX activity [
Newly recommended terminology for heterozygous females designates five clinical- and laboratory-based categories [
Severe hemophilia B (<1% factor IX clotting activity)
Moderate hemophilia B (1%-5% factor IX clotting activity)
Mild hemophilia B (>5% to <40% factor IX clotting activity)
For heterozygous females with normal factor IX clotting activity:
Individuals with a bleeding phenotype: "symptomatic hemophilia carriers"
Individuals who do not have a bleeding phenotype: "asymptomatic hemophilia carriers"
The birth prevalence of hemophilia B has been calculated to be five in 100,000 live male births, and 1.5 in 100,000 for severe hemophilia B [
The birth prevalence is thought to be approximately the same in all countries and all ethnicities, presumably because of the high spontaneous mutation rate of
Hemophilia B is about one fifth as prevalent as
• Frequent spontaneous bleeding
• Excessive &/or prolonged bleeding after minor injuries, surgery, or tooth extractions
• Spontaneous bleeding less common
• Excessive &/or prolonged bleeding after minor injuries, surgery, or tooth extractions
• Rare spontaneous bleeding
• Excessive &/or prolonged bleeding after major injuries, surgery, or tooth extractions
• Large deletions, nonsense variants, and most frameshift variants cause severe disease.
• Missense variants can cause severe, moderate, or mild disease depending on their location and the specific substitutions involved.
• Alloimmune inhibitors occur with the greatest frequency (40%-60%) in individuals with large partial (>50 bp) deletions, whole-gene deletions, or early-termination variants (<100 predicted amino acids) [
• Missense variants are rarely associated with inhibitors.
• Severe hemophilia B (<1% factor IX clotting activity)
• Moderate hemophilia B (1%-5% factor IX clotting activity)
• Mild hemophilia B (>5% to <40% factor IX clotting activity)
• Individuals with a bleeding phenotype: "symptomatic hemophilia carriers"
• Individuals who do not have a bleeding phenotype: "asymptomatic hemophilia carriers"
## Clinical Description
Hemophilia B in the untreated individual is characterized by spontaneous bleeding including intracranial bleeding, muscle and joint bleeding (usually in severe disease), immediate or delayed bleeding or prolonged oozing after injuries, tooth extractions, or surgery, or renewed bleeding after initial bleeding has stopped [
The age of diagnosis and frequency of bleeding episodes are generally related to the factor IX clotting activity (see Table 2). In any affected individual, bleeding episodes may be more frequent in childhood and adolescence than in adulthood. To some extent, this greater frequency is a function of both physical activity levels and vulnerability during more rapid growth.
As the child grows and becomes more active, spontaneous joint bleeds occur with increasing frequency unless the child is on a prophylactic treatment program. Spontaneous joint bleeds or deep-muscle hematomas initially cause pain or limping before swelling appears. Children and young adults with severe hemophilia B who are not treated have an average of two to five spontaneous bleeding episodes each month. Joints are the most common sites of spontaneous bleeding; other sites include the muscles, kidneys, gastrointestinal tract, brain, and nose. Without prophylactic treatment, individuals with hemophilia B have prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions.
Symptoms Related to Severity of Untreated Hemophilia B
Frequent spontaneous bleeding
Excessive &/or prolonged bleeding after minor injuries, surgery, or tooth extractions
Spontaneous bleeding less common
Excessive &/or prolonged bleeding after minor injuries, surgery, or tooth extractions
Rare spontaneous bleeding
Excessive &/or prolonged bleeding after major injuries, surgery, or tooth extractions
Clinical severity does not always correlate with the in vitro assay result.
Viral inactivation methods and donor screening of plasmas were introduced by 1990 and a recombinant factor IX concentrate became available shortly thereafter [
Hepatitis B transmission from earlier plasma-derived concentrates was eliminated with donor screening and then vaccination introduced in the 1970s. Most individuals exposed to plasma-derived concentrates prior to the late 1980s became chronic carriers of hepatitis C. Viral inactivation methods implemented in concentrate preparation and donor screening assays developed by 1990 have essentially eliminated hepatitis C transmission from plasma-derived concentrates.
Alloimmune inhibitors occur much less frequently in hemophilia B than in hemophilia A, although they are more common than previously appreciated. Earlier data suggested a rate of 3%-5%, but more recent data suggests that it may be closer to 10%, almost exclusively in individuals with severe disease. The incidence appears to vary by population and underlying genetic variant [
• Frequent spontaneous bleeding
• Excessive &/or prolonged bleeding after minor injuries, surgery, or tooth extractions
• Spontaneous bleeding less common
• Excessive &/or prolonged bleeding after minor injuries, surgery, or tooth extractions
• Rare spontaneous bleeding
• Excessive &/or prolonged bleeding after major injuries, surgery, or tooth extractions
## Genotype-Phenotype Correlations
Large deletions, nonsense variants, and most frameshift variants cause severe disease.
Missense variants can cause severe, moderate, or mild disease depending on their location and the specific substitutions involved.
Alloimmune inhibitors occur with the greatest frequency (40%-60%) in individuals with large partial (>50 bp) deletions, whole-gene deletions, or early-termination variants (<100 predicted amino acids) [
Missense variants are rarely associated with inhibitors.
Unlike hemophilia A, severe hemophilia B is often caused by a missense variant, and several of these are associated with normal cross-reacting material (factor IX antigen) levels (see
Uncommon variants within the carboxylase-binding domain of the propeptide cause increased sensitivity to warfarin anticoagulation in individuals without any baseline bleeding tendency [
In hemophilia B Leyden, more than 20 different causative variants in the proximal
• Large deletions, nonsense variants, and most frameshift variants cause severe disease.
• Missense variants can cause severe, moderate, or mild disease depending on their location and the specific substitutions involved.
• Alloimmune inhibitors occur with the greatest frequency (40%-60%) in individuals with large partial (>50 bp) deletions, whole-gene deletions, or early-termination variants (<100 predicted amino acids) [
• Missense variants are rarely associated with inhibitors.
## Penetrance
All males with an
Approximately 30% of heterozygous females have factor IX clotting activity below 40% and are at risk for bleeding; mild bleeding can occur in carriers with low-normal factor IX activity [
## Nomenclature
Newly recommended terminology for heterozygous females designates five clinical- and laboratory-based categories [
Severe hemophilia B (<1% factor IX clotting activity)
Moderate hemophilia B (1%-5% factor IX clotting activity)
Mild hemophilia B (>5% to <40% factor IX clotting activity)
For heterozygous females with normal factor IX clotting activity:
Individuals with a bleeding phenotype: "symptomatic hemophilia carriers"
Individuals who do not have a bleeding phenotype: "asymptomatic hemophilia carriers"
• Severe hemophilia B (<1% factor IX clotting activity)
• Moderate hemophilia B (1%-5% factor IX clotting activity)
• Mild hemophilia B (>5% to <40% factor IX clotting activity)
• Individuals with a bleeding phenotype: "symptomatic hemophilia carriers"
• Individuals who do not have a bleeding phenotype: "asymptomatic hemophilia carriers"
## Prevalence
The birth prevalence of hemophilia B has been calculated to be five in 100,000 live male births, and 1.5 in 100,000 for severe hemophilia B [
The birth prevalence is thought to be approximately the same in all countries and all ethnicities, presumably because of the high spontaneous mutation rate of
Hemophilia B is about one fifth as prevalent as
## Genetically Related (Allelic) Disorders
Certain missense variants within the propeptide portion of factor IX enhance sensitivity to warfarin by altering the binding of a gamma-carboxylase responsible for post-translational Gla residue formation [
The pathogenic variant
## Differential Diagnosis
A detailed history of bleeding episodes can help determine if an individual has a lifelong inherited bleeding disorder or an acquired (often transient) bleeding disorder. Increased bleeding with trauma, tonsillectomy, or for a few hours following tooth extraction may be seen in individuals without a bleeding disorder. In contrast, prolonged or intermittent oozing that lasts several days following tooth extraction or mouth injury, renewed bleeding or increased pain and swelling several days after an injury, or development of a wound hematoma several days after surgery almost always indicates a coagulation problem. An older individual with severe or moderate hemophilia B may have joint deformities and muscle contractures. Large bruises and subcutaneous hematomas for which no trauma can be identified may be present. Individuals with a mild bleeding disorder usually have no outward signs except during an acute bleeding episode.
Note: Petechial hemorrhages indicate severe thrombocytopenia and are not a feature of hemophilia B.
Common acquired deficiencies of vitamin K-dependent factors occur in individuals receiving
Inherited Bleeding Disorders with Normal Factor IX Clotting Activity
AD = autosomal dominant; aPTT = activated partial thromboplastin time; AR = autosomal recessive; GI = gastrointestinal; MOI = mode of inheritance; PT = prothrombin time; VWF = von Willebrand factor; XL = X-linked
Afibrinogenemia is inherited in an autosomal recessive manner. Hypofibrinogenemia can be inherited in either an autosomal dominant or an autosomal recessive manner. Dysfibrinogenemia is inherited in an autosomal dominant manner.
• Common acquired deficiencies of vitamin K-dependent factors occur in individuals receiving
## Management
To establish the extent of disease and needs in an individual diagnosed with hemophilia B, the evaluations summarized in
Hemophilia B: Recommended Evaluations Following Initial Diagnosis
Personal & family history of bleeding to help predict disease severity
CBC w/platelet count, esp if history of nose bleeds, GI bleeding, mouth bleeding, or (in females) heavy menstrual bleeding or postpartum hemorrhage
Referral to HTC
CBC = complete blood count; GI = gastrointestinal; HTC = hemophilia treatment center; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
The World Federation of Hemophilia has published
Experience, primarily in hemophilia A, has shown that lower-dose prophylaxis used in countries with fewer resources can decrease bleeding and improve outcomes [
In addition, factor IX concentrates are used to
Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
Immunizations should be administered subcutaneously if known to be an effective route; intramuscular injections may be managed with pressure and ice and, if possible, under factor IX coverage.
Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children.
Persons with hemophilia followed at an HTC (see
Young children with severe or moderate hemophilia B should be evaluated at an HTC (accompanied by their parents/guardians) every six to 12 months and as needed to review their history of bleeding episodes and adjust treatment plans. Early signs and symptoms of possible bleeding episodes are reviewed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, a discussion of any other issues related to the individual's hemophilia B, and family and community support.
Because of the risk of severe allergic reactions with development of alloantibodies, it is recommended that the first 20 factor replacement treatments be given in a medical setting where resuscitation medications and equipment are available. Risk can be stratified if the genetic variant is known. Those with large partial deletions, complete gene deletions, and early termination variants (<100 predicted amino acids) are at highest risk [
Older children and adults with severe or moderate hemophilia B benefit from at least annual assessment at an HTC to review bleeding episodes and treatment plans, evaluate joints and muscles, screen for inhibitors, perform viral testing if indicated, provide education, and discuss other issues relevant to the individual's hemophilia B.
Individuals with mild hemophilia B can benefit from an assessment at an HTC every one to two years. Affected individuals with comorbidities and other complications or treatment challenges may require more frequent visits.
The following agents/circumstances should be avoided:
Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
Use precaution with intramuscular injections without factor IX treatment. Pressure on the site after intramuscular injection in children has been reported to be effective without factor IX coverage. Individuals on prophylaxis may be given intramuscular injections.
Activities that involve a high risk of trauma, particularly of head injury, should be avoided.
Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as individuals with a cardiovascular indication. Individuals with severe hemophilia usually require prophylaxis to allow aspirin and other platelet-inhibitory drugs to be used safely [
Older, intermediate-purity plasma-derived "prothrombin complex" concentrates should be used cautiously (if at all) in hemophilia B because of their thrombogenic potential.
It is appropriate to evaluate asymptomatic male and female at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted therapies, supportive care, and surveillance. A thorough family history may identify relatives who are at risk but have not been tested (particularly in families with mild hemophilia B).
Assay of factor IX clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue), assessment of factor IX clotting activity in the neonatal period, or molecular genetic testing for the family-specific
Note: (1) The cord blood for factor IX clotting activity assay should be drawn into a syringe containing one tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. (2) Factor IX clotting activity in cord blood in a normal-term newborn is lower than in adults (mean: ~30%; range: 15%-50%); thus, the diagnosis of hemophilia B can be established in an infant with activity lower than 1% but is equivocal in an infant with moderately low (15%-20%) activity.
Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is excluded or, if present, factor IX concentrate is administered immediately before and after the procedure to prevent delayed oozing and poor wound healing. The benefit versus the risk of exposure to factor IX concentrate in early childhood should be considered.
All daughters and mothers of an affected male and other at-risk females should have molecular genetic testing for the family-specific
It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible.
See
Unlike for factor VIII, maternal factor IX levels do not generally increase during pregnancy, and heterozygous females are more likely to need factor IX infusion support for delivery and/or to treat or prevent postpartum hemorrhage. In females with hemophilia B, postpartum hemorrhage has been a prominent feature, even in women without heavy menstrual bleeding [
If the female has a baseline factor IX clotting activity below approximately 40%, she by definition has hemophilia B and is at risk for excessive bleeding, particularly post partum, and may require therapy with factor IX concentrate [
Search
Vitamin K does not prevent or control bleeding in hemophilia B.
Fresh frozen plasma is no longer recommended to treat hemophilia B because it is not treated with a virucidal agent.
• Personal & family history of bleeding to help predict disease severity
• CBC w/platelet count, esp if history of nose bleeds, GI bleeding, mouth bleeding, or (in females) heavy menstrual bleeding or postpartum hemorrhage
• Referral to HTC
• Experience, primarily in hemophilia A, has shown that lower-dose prophylaxis used in countries with fewer resources can decrease bleeding and improve outcomes [
• In addition, factor IX concentrates are used to
• Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
• Immunizations should be administered subcutaneously if known to be an effective route; intramuscular injections may be managed with pressure and ice and, if possible, under factor IX coverage.
• Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children.
• Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
• Use precaution with intramuscular injections without factor IX treatment. Pressure on the site after intramuscular injection in children has been reported to be effective without factor IX coverage. Individuals on prophylaxis may be given intramuscular injections.
• Activities that involve a high risk of trauma, particularly of head injury, should be avoided.
• Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as individuals with a cardiovascular indication. Individuals with severe hemophilia usually require prophylaxis to allow aspirin and other platelet-inhibitory drugs to be used safely [
• Assay of factor IX clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue), assessment of factor IX clotting activity in the neonatal period, or molecular genetic testing for the family-specific
• Note: (1) The cord blood for factor IX clotting activity assay should be drawn into a syringe containing one tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. (2) Factor IX clotting activity in cord blood in a normal-term newborn is lower than in adults (mean: ~30%; range: 15%-50%); thus, the diagnosis of hemophilia B can be established in an infant with activity lower than 1% but is equivocal in an infant with moderately low (15%-20%) activity.
• Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is excluded or, if present, factor IX concentrate is administered immediately before and after the procedure to prevent delayed oozing and poor wound healing. The benefit versus the risk of exposure to factor IX concentrate in early childhood should be considered.
• All daughters and mothers of an affected male and other at-risk females should have molecular genetic testing for the family-specific
• It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hemophilia B, the evaluations summarized in
Hemophilia B: Recommended Evaluations Following Initial Diagnosis
Personal & family history of bleeding to help predict disease severity
CBC w/platelet count, esp if history of nose bleeds, GI bleeding, mouth bleeding, or (in females) heavy menstrual bleeding or postpartum hemorrhage
Referral to HTC
CBC = complete blood count; GI = gastrointestinal; HTC = hemophilia treatment center; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Personal & family history of bleeding to help predict disease severity
• CBC w/platelet count, esp if history of nose bleeds, GI bleeding, mouth bleeding, or (in females) heavy menstrual bleeding or postpartum hemorrhage
• Referral to HTC
## Treatment of Manifestations
The World Federation of Hemophilia has published
Experience, primarily in hemophilia A, has shown that lower-dose prophylaxis used in countries with fewer resources can decrease bleeding and improve outcomes [
In addition, factor IX concentrates are used to
Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
Immunizations should be administered subcutaneously if known to be an effective route; intramuscular injections may be managed with pressure and ice and, if possible, under factor IX coverage.
Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children.
• Experience, primarily in hemophilia A, has shown that lower-dose prophylaxis used in countries with fewer resources can decrease bleeding and improve outcomes [
• In addition, factor IX concentrates are used to
• Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
• Immunizations should be administered subcutaneously if known to be an effective route; intramuscular injections may be managed with pressure and ice and, if possible, under factor IX coverage.
• Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children.
## Targeted Therapies
Experience, primarily in hemophilia A, has shown that lower-dose prophylaxis used in countries with fewer resources can decrease bleeding and improve outcomes [
In addition, factor IX concentrates are used to
Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
Immunizations should be administered subcutaneously if known to be an effective route; intramuscular injections may be managed with pressure and ice and, if possible, under factor IX coverage.
Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children.
• Experience, primarily in hemophilia A, has shown that lower-dose prophylaxis used in countries with fewer resources can decrease bleeding and improve outcomes [
• In addition, factor IX concentrates are used to
• Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
• Immunizations should be administered subcutaneously if known to be an effective route; intramuscular injections may be managed with pressure and ice and, if possible, under factor IX coverage.
• Effective dosing of factor IX requires an understanding of different pharmacokinetics in young children.
## Supportive Care
## Surveillance
Persons with hemophilia followed at an HTC (see
Young children with severe or moderate hemophilia B should be evaluated at an HTC (accompanied by their parents/guardians) every six to 12 months and as needed to review their history of bleeding episodes and adjust treatment plans. Early signs and symptoms of possible bleeding episodes are reviewed. The assessment should also include a joint and muscle evaluation, an inhibitor screen, viral testing if indicated, a discussion of any other issues related to the individual's hemophilia B, and family and community support.
Because of the risk of severe allergic reactions with development of alloantibodies, it is recommended that the first 20 factor replacement treatments be given in a medical setting where resuscitation medications and equipment are available. Risk can be stratified if the genetic variant is known. Those with large partial deletions, complete gene deletions, and early termination variants (<100 predicted amino acids) are at highest risk [
Older children and adults with severe or moderate hemophilia B benefit from at least annual assessment at an HTC to review bleeding episodes and treatment plans, evaluate joints and muscles, screen for inhibitors, perform viral testing if indicated, provide education, and discuss other issues relevant to the individual's hemophilia B.
Individuals with mild hemophilia B can benefit from an assessment at an HTC every one to two years. Affected individuals with comorbidities and other complications or treatment challenges may require more frequent visits.
## Agents/Circumstances to Avoid
The following agents/circumstances should be avoided:
Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
Use precaution with intramuscular injections without factor IX treatment. Pressure on the site after intramuscular injection in children has been reported to be effective without factor IX coverage. Individuals on prophylaxis may be given intramuscular injections.
Activities that involve a high risk of trauma, particularly of head injury, should be avoided.
Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as individuals with a cardiovascular indication. Individuals with severe hemophilia usually require prophylaxis to allow aspirin and other platelet-inhibitory drugs to be used safely [
Older, intermediate-purity plasma-derived "prothrombin complex" concentrates should be used cautiously (if at all) in hemophilia B because of their thrombogenic potential.
• Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is either excluded or, if present, treated with factor IX concentrate directly before and after the procedure.
• Use precaution with intramuscular injections without factor IX treatment. Pressure on the site after intramuscular injection in children has been reported to be effective without factor IX coverage. Individuals on prophylaxis may be given intramuscular injections.
• Activities that involve a high risk of trauma, particularly of head injury, should be avoided.
• Medications and herbal remedies that affect platelet function, including aspirin, should be avoided unless there is strong medical indication, such as individuals with a cardiovascular indication. Individuals with severe hemophilia usually require prophylaxis to allow aspirin and other platelet-inhibitory drugs to be used safely [
## Evaluation of Relatives at Risk
It is appropriate to evaluate asymptomatic male and female at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted therapies, supportive care, and surveillance. A thorough family history may identify relatives who are at risk but have not been tested (particularly in families with mild hemophilia B).
Assay of factor IX clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue), assessment of factor IX clotting activity in the neonatal period, or molecular genetic testing for the family-specific
Note: (1) The cord blood for factor IX clotting activity assay should be drawn into a syringe containing one tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. (2) Factor IX clotting activity in cord blood in a normal-term newborn is lower than in adults (mean: ~30%; range: 15%-50%); thus, the diagnosis of hemophilia B can be established in an infant with activity lower than 1% but is equivocal in an infant with moderately low (15%-20%) activity.
Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is excluded or, if present, factor IX concentrate is administered immediately before and after the procedure to prevent delayed oozing and poor wound healing. The benefit versus the risk of exposure to factor IX concentrate in early childhood should be considered.
All daughters and mothers of an affected male and other at-risk females should have molecular genetic testing for the family-specific
It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible.
See
• Assay of factor IX clotting activity from a cord blood sample obtained by venipuncture of the umbilical vein (to avoid contamination by amniotic fluid or placenta tissue), assessment of factor IX clotting activity in the neonatal period, or molecular genetic testing for the family-specific
• Note: (1) The cord blood for factor IX clotting activity assay should be drawn into a syringe containing one tenth volume of sodium citrate to avoid clotting and to provide an optimal mixing of the sample with the anticoagulant. (2) Factor IX clotting activity in cord blood in a normal-term newborn is lower than in adults (mean: ~30%; range: 15%-50%); thus, the diagnosis of hemophilia B can be established in an infant with activity lower than 1% but is equivocal in an infant with moderately low (15%-20%) activity.
• Infant males with a family history of hemophilia B should not be circumcised unless hemophilia B is excluded or, if present, factor IX concentrate is administered immediately before and after the procedure to prevent delayed oozing and poor wound healing. The benefit versus the risk of exposure to factor IX concentrate in early childhood should be considered.
• All daughters and mothers of an affected male and other at-risk females should have molecular genetic testing for the family-specific
• It is recommended that the genetic status of at-risk females be established prior to pregnancy or as early in a pregnancy as possible.
## Pregnancy Management
Unlike for factor VIII, maternal factor IX levels do not generally increase during pregnancy, and heterozygous females are more likely to need factor IX infusion support for delivery and/or to treat or prevent postpartum hemorrhage. In females with hemophilia B, postpartum hemorrhage has been a prominent feature, even in women without heavy menstrual bleeding [
If the female has a baseline factor IX clotting activity below approximately 40%, she by definition has hemophilia B and is at risk for excessive bleeding, particularly post partum, and may require therapy with factor IX concentrate [
## Therapies Under Investigation
Search
## Other
Vitamin K does not prevent or control bleeding in hemophilia B.
Fresh frozen plasma is no longer recommended to treat hemophilia B because it is not treated with a virucidal agent.
## Genetic Counseling
Hemophilia B is inherited in an X-linked manner.
The father of an affected male will not have the disease, nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
Approximately 30% of affected males have no family history of hemophilia B. If a male is the only affected family member (i.e., a simplex case), it is possible that:
The mother is heterozygous for an
The mother has somatic/germline mosaicism. Somatic mosaicism is reported in ≤11% of families [
Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The mother is not heterozygous for an
Molecular genetic testing of the mother is recommended to assess her genetic status and to allow reliable recurrence risk assessment.
A heterozygous female proband may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [
All sibs should have factor IX clotting activity assayed unless molecular genetic testing confirms that they have not inherited the
If the mother of the proband has an
If the father of the proband has an
The maternal aunts and maternal cousins of a male proband may be at risk of having an
The risk to other family members of a female proband depends on the status of the proband's mother and father: if a parent has the
Note: Molecular genetic testing can often determine the point of origin of a
Molecular genetic testing for identification of female heterozygotes is most informative if the
See Management,
Note: Factor IX clotting activity does not reliably identify heterozygous females, as only approximately 30% of females heterozygous for an
See Management,
See the World Federation of Hemophilia
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is recommended that the genetic status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible (see Management,
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The father of an affected male will not have the disease, nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• Approximately 30% of affected males have no family history of hemophilia B. If a male is the only affected family member (i.e., a simplex case), it is possible that:
• The mother is heterozygous for an
• The mother has somatic/germline mosaicism. Somatic mosaicism is reported in ≤11% of families [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The mother is not heterozygous for an
• The mother is heterozygous for an
• The mother has somatic/germline mosaicism. Somatic mosaicism is reported in ≤11% of families [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The mother is not heterozygous for an
• Molecular genetic testing of the mother is recommended to assess her genetic status and to allow reliable recurrence risk assessment.
• The mother is heterozygous for an
• The mother has somatic/germline mosaicism. Somatic mosaicism is reported in ≤11% of families [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The mother is not heterozygous for an
• A heterozygous female proband may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [
• All sibs should have factor IX clotting activity assayed unless molecular genetic testing confirms that they have not inherited the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [
• If the mother of the proband has an
• If the father of the proband has an
• The maternal aunts and maternal cousins of a male proband may be at risk of having an
• The risk to other family members of a female proband depends on the status of the proband's mother and father: if a parent has the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is recommended that the genetic status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible (see Management,
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Mode of Inheritance
Hemophilia B is inherited in an X-linked manner.
## Risk to Family Members
The father of an affected male will not have the disease, nor will he be hemizygous for the
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
Approximately 30% of affected males have no family history of hemophilia B. If a male is the only affected family member (i.e., a simplex case), it is possible that:
The mother is heterozygous for an
The mother has somatic/germline mosaicism. Somatic mosaicism is reported in ≤11% of families [
Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The mother is not heterozygous for an
Molecular genetic testing of the mother is recommended to assess her genetic status and to allow reliable recurrence risk assessment.
A heterozygous female proband may have inherited the
Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected.
Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [
All sibs should have factor IX clotting activity assayed unless molecular genetic testing confirms that they have not inherited the
If the mother of the proband has an
If the father of the proband has an
The maternal aunts and maternal cousins of a male proband may be at risk of having an
The risk to other family members of a female proband depends on the status of the proband's mother and father: if a parent has the
Note: Molecular genetic testing can often determine the point of origin of a
• The father of an affected male will not have the disease, nor will he be hemizygous for the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• Approximately 30% of affected males have no family history of hemophilia B. If a male is the only affected family member (i.e., a simplex case), it is possible that:
• The mother is heterozygous for an
• The mother has somatic/germline mosaicism. Somatic mosaicism is reported in ≤11% of families [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The mother is not heterozygous for an
• The mother is heterozygous for an
• The mother has somatic/germline mosaicism. Somatic mosaicism is reported in ≤11% of families [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The mother is not heterozygous for an
• Molecular genetic testing of the mother is recommended to assess her genetic status and to allow reliable recurrence risk assessment.
• The mother is heterozygous for an
• The mother has somatic/germline mosaicism. Somatic mosaicism is reported in ≤11% of families [
• Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The mother is not heterozygous for an
• A heterozygous female proband may have inherited the
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [
• All sibs should have factor IX clotting activity assayed unless molecular genetic testing confirms that they have not inherited the
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes. Heterozygous females with a factor IX clotting activity level lower than 40% are at risk for bleeding that is usually comparable to that seen in males with mild hemophilia. However, more subtle abnormal bleeding may occur with baseline factor IX clotting activity levels between 30% and 60% [
• If the mother of the proband has an
• If the father of the proband has an
• The maternal aunts and maternal cousins of a male proband may be at risk of having an
• The risk to other family members of a female proband depends on the status of the proband's mother and father: if a parent has the
## Heterozygote Detection
Molecular genetic testing for identification of female heterozygotes is most informative if the
See Management,
Note: Factor IX clotting activity does not reliably identify heterozygous females, as only approximately 30% of females heterozygous for an
## Related Genetic Counseling Issues
See Management,
See the World Federation of Hemophilia
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is recommended that the genetic status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible (see Management,
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is recommended that the genetic status of a female at risk be established prior to pregnancy or as early in a pregnancy as possible (see Management,
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
United Kingdom
Canada
Centers for Disease Control and Prevention
•
• Canada
•
•
•
•
• United Kingdom
•
•
• Canada
•
•
• Centers for Disease Control and Prevention
•
•
•
## Molecular Genetics
Hemophilia B: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hemophilia B (
Factor IX is synthesized in hepatocytes and circulates as a zymogen at 90 nmol/L (5 µg/mL). During coagulation initiation in vivo, it is activated by factor VIIa / tissue factor, and in coagulation amplification and propagation by factor IXa, in a reaction in which the activation peptide is cleaved. Activated factor IX is the intrinsic factor X activator, requiring its cofactor, activated factor VIII, a lipid surface, and calcium. Molecular interactions across multiple regions of the factor IXa molecule are involved in factor Xa activation [
Factor IX includes several distinct domains [
Signal peptide and propeptide domain: cleaved to yield the mature protein, a secreted 415-amino acid peptide
GLA domain
Two domains homologous with epidermal growth factor
Connecting sequence: includes the activation peptide
Catalytic domain: typical of serine proteases
Post-translational modifications include glycosylation, sulfation, phosphorylation, beta-hydroxylation, and gamma-carboxylation. A gamma-carboxylase binds to the propeptide before cleavage and, in a vitamin K-dependent step, converts the first 12 glutamic acid residues (near the amino-terminus) to gamma-carboxyglutamic residues (GLA domain). The GLA domain then binds calcium ions and adopts a conformation capable of binding to a phospholipid surface, where the clot initiation and propagation occurs.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Signal peptide and propeptide domain: cleaved to yield the mature protein, a secreted 415-amino acid peptide
• GLA domain
• Two domains homologous with epidermal growth factor
• Connecting sequence: includes the activation peptide
• Catalytic domain: typical of serine proteases
## Molecular Pathogenesis
Factor IX is synthesized in hepatocytes and circulates as a zymogen at 90 nmol/L (5 µg/mL). During coagulation initiation in vivo, it is activated by factor VIIa / tissue factor, and in coagulation amplification and propagation by factor IXa, in a reaction in which the activation peptide is cleaved. Activated factor IX is the intrinsic factor X activator, requiring its cofactor, activated factor VIII, a lipid surface, and calcium. Molecular interactions across multiple regions of the factor IXa molecule are involved in factor Xa activation [
Factor IX includes several distinct domains [
Signal peptide and propeptide domain: cleaved to yield the mature protein, a secreted 415-amino acid peptide
GLA domain
Two domains homologous with epidermal growth factor
Connecting sequence: includes the activation peptide
Catalytic domain: typical of serine proteases
Post-translational modifications include glycosylation, sulfation, phosphorylation, beta-hydroxylation, and gamma-carboxylation. A gamma-carboxylase binds to the propeptide before cleavage and, in a vitamin K-dependent step, converts the first 12 glutamic acid residues (near the amino-terminus) to gamma-carboxyglutamic residues (GLA domain). The GLA domain then binds calcium ions and adopts a conformation capable of binding to a phospholipid surface, where the clot initiation and propagation occurs.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Signal peptide and propeptide domain: cleaved to yield the mature protein, a secreted 415-amino acid peptide
• GLA domain
• Two domains homologous with epidermal growth factor
• Connecting sequence: includes the activation peptide
• Catalytic domain: typical of serine proteases
## Chapter Notes
Barbara A Konkle (
Cheryl L Brower, RN, MSPH; Puget Sound Blood Center (2008-2011)Frank K Fujimura, PhD, FACMG; GMP Genetics, Inc (2000-2003)Haley Huston, BS; Bloodworks Northwest (2017-2023)Maribel J Johnson, RN, MA; Puget Sound Blood Center (2000-2008)Neil C Josephson, MD; Seattle Genetics (2011-2017)Barbara A Konkle, MD (2011-present)Shelley Nakaya Fletcher, BS (2011-present)Arthur R Thompson, MD, PhD; University of Washington (2000-2014)
7 August 2025 (sw) Comprehensive update posted live
9 February 2023 (sw) Comprehensive update posted live
15 June 2017 (sw) Comprehensive update posted live
5 June 2014 (me) Comprehensive update posted live
22 September 2011 (me) Comprehensive update posted live
8 April 2008 (me) Comprehensive update posted live
17 August 2005 (me) Comprehensive update posted live
8 May 2003 (me) Comprehensive update posted live
2 October 2000 (me) Review posted live
August 2000 (at) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 9 February 2023 (sw) Comprehensive update posted live
• 15 June 2017 (sw) Comprehensive update posted live
• 5 June 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Comprehensive update posted live
• 8 April 2008 (me) Comprehensive update posted live
• 17 August 2005 (me) Comprehensive update posted live
• 8 May 2003 (me) Comprehensive update posted live
• 2 October 2000 (me) Review posted live
• August 2000 (at) Original submission
## Author Notes
Barbara A Konkle (
## Author History
Cheryl L Brower, RN, MSPH; Puget Sound Blood Center (2008-2011)Frank K Fujimura, PhD, FACMG; GMP Genetics, Inc (2000-2003)Haley Huston, BS; Bloodworks Northwest (2017-2023)Maribel J Johnson, RN, MA; Puget Sound Blood Center (2000-2008)Neil C Josephson, MD; Seattle Genetics (2011-2017)Barbara A Konkle, MD (2011-present)Shelley Nakaya Fletcher, BS (2011-present)Arthur R Thompson, MD, PhD; University of Washington (2000-2014)
## Revision History
7 August 2025 (sw) Comprehensive update posted live
9 February 2023 (sw) Comprehensive update posted live
15 June 2017 (sw) Comprehensive update posted live
5 June 2014 (me) Comprehensive update posted live
22 September 2011 (me) Comprehensive update posted live
8 April 2008 (me) Comprehensive update posted live
17 August 2005 (me) Comprehensive update posted live
8 May 2003 (me) Comprehensive update posted live
2 October 2000 (me) Review posted live
August 2000 (at) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 9 February 2023 (sw) Comprehensive update posted live
• 15 June 2017 (sw) Comprehensive update posted live
• 5 June 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Comprehensive update posted live
• 8 April 2008 (me) Comprehensive update posted live
• 17 August 2005 (me) Comprehensive update posted live
• 8 May 2003 (me) Comprehensive update posted live
• 2 October 2000 (me) Review posted live
• August 2000 (at) Original submission
## Key Sections in this
## References
Guidelines regarding genetic testing for this disorder have been published for the UK:
Ludlam CA, Pasi KJ, Bolton-Maggs P, Collins PW, Cumming AM, Dolan G, Fryer A, Harrington C, Hill FG, Peake IR, Perry DJ, Skirton H, Smith M; UK Haemophilia Centre Doctors' Organisation. A framework for genetic service provision for haemophilia and other inherited bleeding disorders. Haemophilia. 2005;11:145-63. [
Mitchell M, Keeney S, Goodeve A. Practice guidelines for the molecular diagnosis of haemophilia B. UK Haemophilia Centre Doctors' Organisation, the Haemophilia Genetics Laboratory Network and the Clinical Molecular Genetics Society. Available
• Ludlam CA, Pasi KJ, Bolton-Maggs P, Collins PW, Cumming AM, Dolan G, Fryer A, Harrington C, Hill FG, Peake IR, Perry DJ, Skirton H, Smith M; UK Haemophilia Centre Doctors' Organisation. A framework for genetic service provision for haemophilia and other inherited bleeding disorders. Haemophilia. 2005;11:145-63. [
• Mitchell M, Keeney S, Goodeve A. Practice guidelines for the molecular diagnosis of haemophilia B. UK Haemophilia Centre Doctors' Organisation, the Haemophilia Genetics Laboratory Network and the Clinical Molecular Genetics Society. Available
## Published Guidelines / Consensus Statements
Guidelines regarding genetic testing for this disorder have been published for the UK:
Ludlam CA, Pasi KJ, Bolton-Maggs P, Collins PW, Cumming AM, Dolan G, Fryer A, Harrington C, Hill FG, Peake IR, Perry DJ, Skirton H, Smith M; UK Haemophilia Centre Doctors' Organisation. A framework for genetic service provision for haemophilia and other inherited bleeding disorders. Haemophilia. 2005;11:145-63. [
Mitchell M, Keeney S, Goodeve A. Practice guidelines for the molecular diagnosis of haemophilia B. UK Haemophilia Centre Doctors' Organisation, the Haemophilia Genetics Laboratory Network and the Clinical Molecular Genetics Society. Available
• Ludlam CA, Pasi KJ, Bolton-Maggs P, Collins PW, Cumming AM, Dolan G, Fryer A, Harrington C, Hill FG, Peake IR, Perry DJ, Skirton H, Smith M; UK Haemophilia Centre Doctors' Organisation. A framework for genetic service provision for haemophilia and other inherited bleeding disorders. Haemophilia. 2005;11:145-63. [
• Mitchell M, Keeney S, Goodeve A. Practice guidelines for the molecular diagnosis of haemophilia B. UK Haemophilia Centre Doctors' Organisation, the Haemophilia Genetics Laboratory Network and the Clinical Molecular Genetics Society. Available
## Literature Cited
|
[] |
2/10/2000
|
7/8/2025
|
6/6/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
hemochromatosis
|
hemochromatosis
|
[
"HFE-Associated Hemochromatosis",
"HFE-Associated Hemochromatosis",
"Hereditary hemochromatosis protein",
"HFE",
"HFE-Related Hemochromatosis"
] |
James C Barton, Charles J Parker
|
Summary The diagnosis of
|
## Diagnosis
In 2022, a new classification of hemochromatosis based on genetic and clinical manifestations was proposed by an expert group, although this classification excludes persons who have loss-of-function
For the purposes of this
Weakness, chronic fatigue
Abdominal pain, weight loss
Arthropathy (especially metacarpophalangeal joints, hips, knees)
Diabetes
Hepatomegaly
Cirrhosis
Primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma)
Hypogonadotropic hypogonadism (decreased libido and impotence in males, amenorrhea in females)
Cardiomyopathy, arrhythmias
Progressive increase in skin pigmentation
The diagnosis of
Note:
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects alleles that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Alleles may include missense, nonsense, and splice site alleles and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Individuals of European ancestry; approximately 60%-90% of individuals of European ancestry with
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Alu-mediated
• Weakness, chronic fatigue
• Abdominal pain, weight loss
• Arthropathy (especially metacarpophalangeal joints, hips, knees)
• Diabetes
• Hepatomegaly
• Cirrhosis
• Primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma)
• Hypogonadotropic hypogonadism (decreased libido and impotence in males, amenorrhea in females)
• Cardiomyopathy, arrhythmias
• Progressive increase in skin pigmentation
• For an introduction to multigene panels click
## Suggestive Findings
Weakness, chronic fatigue
Abdominal pain, weight loss
Arthropathy (especially metacarpophalangeal joints, hips, knees)
Diabetes
Hepatomegaly
Cirrhosis
Primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma)
Hypogonadotropic hypogonadism (decreased libido and impotence in males, amenorrhea in females)
Cardiomyopathy, arrhythmias
Progressive increase in skin pigmentation
• Weakness, chronic fatigue
• Abdominal pain, weight loss
• Arthropathy (especially metacarpophalangeal joints, hips, knees)
• Diabetes
• Hepatomegaly
• Cirrhosis
• Primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma)
• Hypogonadotropic hypogonadism (decreased libido and impotence in males, amenorrhea in females)
• Cardiomyopathy, arrhythmias
• Progressive increase in skin pigmentation
## Establishing the Diagnosis
The diagnosis of
Note:
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects alleles that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Alleles may include missense, nonsense, and splice site alleles and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Individuals of European ancestry; approximately 60%-90% of individuals of European ancestry with
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Alu-mediated
• For an introduction to multigene panels click
## Clinical Characteristics
Individuals with clinical
Individuals with biochemical
Normal serum ferritin concentration at diagnosis of
Some individuals who are heterozygous for either
In 58 screening program participants without
Consumption of more than two alcoholic drinks per day was associated with increased risk of elevated transferrin saturation and elevated serum ferritin in a general population cohort [
Viral hepatitis accelerates liver injury in persons with
Among most populations of European ancestry, the prevalence of individuals homozygous for
## Clinical Description
Individuals with clinical
Individuals with biochemical
Normal serum ferritin concentration at diagnosis of
Some individuals who are heterozygous for either
## Clinical
Individuals with clinical
## Biochemical
Individuals with biochemical
## Non-penetrant
Normal serum ferritin concentration at diagnosis of
Some individuals who are heterozygous for either
## Genotype-Phenotype Correlations
In 58 screening program participants without
## Penetrance
Consumption of more than two alcoholic drinks per day was associated with increased risk of elevated transferrin saturation and elevated serum ferritin in a general population cohort [
Viral hepatitis accelerates liver injury in persons with
## Nomenclature
## Prevalence
Among most populations of European ancestry, the prevalence of individuals homozygous for
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Primary iron overload disorders (summarized in
Primary Iron Overload Disorders in the Differential Diagnosis of
Adults affected
Iron accumulation in parenchymal cells
↑ TS & serum ferritin
Arthralgias in some persons
Adults affected
↑ TS & serum ferritin
Arthralgias in some persons
Iron overload typically milder than in
Iron deposition in hepatocytes & Kupffer cells
Serum hepcidin levels normal or slightly ↑
Heavy iron deposition in brain accounts for neurologic dysfunction in adults.
Iron deposition in retina is distinctive.
Mild iron deficiency anemia by early adulthood; TS is low.
Rare; may be more common among Japanese.
Iron accumulation in parenchymal cells
Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
Earlier onset
More severe clinical manifestations
Hepatocellular cancer not reported (possibly due to short life span)
↑ TS & serum ferritin
Iron deposition in hepatocytes
Iron accumulation in parenchymal cells
Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
Earlier onset
Progression similar to juvenile hemochromatosis
AD = autosomal dominant; AR = autosomal recessive; HC = hemochromatosis;
The phenotype associated with loss-of-function
Liver diseases associated with secondary iron overload include alcoholic liver disease, acute viral hepatitis, chronic viral hepatitis C (uncommon), neoplasms,
Nonalcoholic fatty liver disease in persons with
In persons without
Iron overload can result from ingested iron in foods, cooking ware, and medicines, in addition to parenteral iron from iron injections or transfusions for anemia (e.g.,
Erythroferrone is an inhibitor of hepcidin transcription. Due to bone marrow production of erythroferrone (and consequent hepcidin deficiency), iron absorption is increased in some heritable anemias (e.g., non-transfusion-dependent beta-thalassemia, pyruvate kinase deficiency, hereditary sideroblastic anemia).
Neonatal hemochromatosis develops in utero and is characterized by severe hepatic injury (marked loss of hepatocytes, coarsely granular hepatocyte siderosis) and extrahepatic siderosis (epithelia of thyroid, exocrine pancreas, and salivary glands; myocardium). Gestational alloimmune liver disease is the cause of fetal liver injury in most cases [
• Adults affected
• Iron accumulation in parenchymal cells
• ↑ TS & serum ferritin
• Arthralgias in some persons
• Adults affected
• ↑ TS & serum ferritin
• Arthralgias in some persons
• Iron overload typically milder than in
• Iron deposition in hepatocytes & Kupffer cells
• Serum hepcidin levels normal or slightly ↑
• Heavy iron deposition in brain accounts for neurologic dysfunction in adults.
• Iron deposition in retina is distinctive.
• Mild iron deficiency anemia by early adulthood; TS is low.
• Rare; may be more common among Japanese.
• Iron accumulation in parenchymal cells
• Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
• Earlier onset
• More severe clinical manifestations
• Hepatocellular cancer not reported (possibly due to short life span)
• ↑ TS & serum ferritin
• Iron deposition in hepatocytes
• Iron accumulation in parenchymal cells
• Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
• Earlier onset
• Progression similar to juvenile hemochromatosis
## Primary Iron Overload Disorders
Primary iron overload disorders (summarized in
Primary Iron Overload Disorders in the Differential Diagnosis of
Adults affected
Iron accumulation in parenchymal cells
↑ TS & serum ferritin
Arthralgias in some persons
Adults affected
↑ TS & serum ferritin
Arthralgias in some persons
Iron overload typically milder than in
Iron deposition in hepatocytes & Kupffer cells
Serum hepcidin levels normal or slightly ↑
Heavy iron deposition in brain accounts for neurologic dysfunction in adults.
Iron deposition in retina is distinctive.
Mild iron deficiency anemia by early adulthood; TS is low.
Rare; may be more common among Japanese.
Iron accumulation in parenchymal cells
Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
Earlier onset
More severe clinical manifestations
Hepatocellular cancer not reported (possibly due to short life span)
↑ TS & serum ferritin
Iron deposition in hepatocytes
Iron accumulation in parenchymal cells
Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
Earlier onset
Progression similar to juvenile hemochromatosis
AD = autosomal dominant; AR = autosomal recessive; HC = hemochromatosis;
The phenotype associated with loss-of-function
• Adults affected
• Iron accumulation in parenchymal cells
• ↑ TS & serum ferritin
• Arthralgias in some persons
• Adults affected
• ↑ TS & serum ferritin
• Arthralgias in some persons
• Iron overload typically milder than in
• Iron deposition in hepatocytes & Kupffer cells
• Serum hepcidin levels normal or slightly ↑
• Heavy iron deposition in brain accounts for neurologic dysfunction in adults.
• Iron deposition in retina is distinctive.
• Mild iron deficiency anemia by early adulthood; TS is low.
• Rare; may be more common among Japanese.
• Iron accumulation in parenchymal cells
• Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
• Earlier onset
• More severe clinical manifestations
• Hepatocellular cancer not reported (possibly due to short life span)
• ↑ TS & serum ferritin
• Iron deposition in hepatocytes
• Iron accumulation in parenchymal cells
• Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
• Earlier onset
• Progression similar to juvenile hemochromatosis
## Secondary Iron Overload Disorders
Liver diseases associated with secondary iron overload include alcoholic liver disease, acute viral hepatitis, chronic viral hepatitis C (uncommon), neoplasms,
Nonalcoholic fatty liver disease in persons with
In persons without
Iron overload can result from ingested iron in foods, cooking ware, and medicines, in addition to parenteral iron from iron injections or transfusions for anemia (e.g.,
Erythroferrone is an inhibitor of hepcidin transcription. Due to bone marrow production of erythroferrone (and consequent hepcidin deficiency), iron absorption is increased in some heritable anemias (e.g., non-transfusion-dependent beta-thalassemia, pyruvate kinase deficiency, hereditary sideroblastic anemia).
Neonatal hemochromatosis develops in utero and is characterized by severe hepatic injury (marked loss of hepatocytes, coarsely granular hepatocyte siderosis) and extrahepatic siderosis (epithelia of thyroid, exocrine pancreas, and salivary glands; myocardium). Gestational alloimmune liver disease is the cause of fetal liver injury in most cases [
## Management
In 2022, the European Association for the Study of the Liver updated guidelines for management of hemochromatosis, including the use of hepatic elastography, erythrocytapheresis, dietary recommendations, and management of persons with
To establish the extent of iron overload and optimal management of persons diagnosed with
ALP = alkaline phosphatase; ALT = aminotransferase; AST = aspartate aminotransferase; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; Hb = hemoglobin; HC = hemochromatosis;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse knowledgeable about hemochromatosis
The
Therapeutic phlebotomy (i.e., removal of a unit of blood) is a simple, inexpensive, safe, and effective way to remove excess iron. Each unit of blood (400-500 mL) with a hematocrit of 40% contains 160-200 mg of iron.
The usual therapy is phlebotomy weekly until the serum ferritin is ≤100 µg/L. Twice-weekly phlebotomy may be useful to accelerate iron depletion in individuals with serum ferritin >1,000 µg/L or those with evidence of end-organ damage due to iron overload. Hematocrit or hemoglobin (Hb) concentration should be assessed prior to each phlebotomy. If serum ferritin is very high, serum ferritin measurement should be performed approximately every five to ten phlebotomies. Some persons, especially females, tolerate phlebotomy poorly. In such instances, the interval between phlebotomies should be increased (e.g., every 10-14 days) or phlebotomy volume should be reduced (e.g., 250-300 mL).
Anemia is not a characteristic of
The serum ferritin concentration is the most feasible and inexpensive way to monitor therapeutic phlebotomy. After serum ferritin is ≤100 µg/L, serum ferritin concentration should be quantified after each additional one or two treatments [
Maintenance phlebotomy to prevent reaccumulation of excess iron is indicated for males with serum ferritin ≥300 µg/L and for females with serum ferritin ≥200 µg/L [
Phlebotomy may decrease fatigue, arthralgias, and hepatic enzyme levels in many individuals and induce regression of liver fibrosis and cirrhosis in some individuals. Conclusive data regarding the favorable influence of therapeutic phlebotomy on quality of life, diabetes, liver cancer risk, or cardiomyopathy is lacking [
Whether lowering transferrin saturation should be a target of phlebotomy therapy is debatable. Elevated transferrin saturation in
Note: Hb, mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV) levels are not targets of treatment in persons with
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Optimal implementation of these recommendations involves multidisciplinary care (see
Nonsteroidal anti-inflammatory drugs
Physiotherapy
Joint replacement
Vaccination against hepatitis A & B for persons w/
Treatment of hepatitis B or C w/standard antiviral agents may ↓ liver injury.
Varices: endoscopic surveillance; prophylaxis w/nonselective beta-blockers
Ascites: salt restriction & diuretics, & paracentesis & portosystemic shunts if needed
Spontaneous bacterial peritonitis: antibiotic therapy
Hepatic encephalopathy: nutritional modifications (low-protein diet) & lactulose & rifaximin as needed
Hormone replacement therapy as needed
Gonadotropin treatment for infertility in females as needed
Diuretics, ACE inhibitors, cardiac glycosides, antiarrhythmic agents
Phlebotomy or erythrocytapheresis; consider iron chelation therapy.
Lifelong treatment w/supportive agents may be indicated.
Iron-chelating agents (deferoxamine, deferiprone, & deferasirox) are not approved for treatment of iron overload in
ACE = angiotensin-converting enzyme; HCC = hepatocellular carcinoma;
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, surveillance is based on guidelines proposed for individuals with
In those w/
In those w/
EKG & echocardiography
T
AFP = alpha-fetoprotein; FSH = follicle-stimulating hormone; Hb = hemoglobin;
Avoid the following:
Medicinal iron and nutritional supplements containing iron
Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption.
Daily ingestion of more than 500 mg of supplemental vitamin C, which may enhance iron absorption
Consumption of uncooked seafood, which increases the risk of infection from microorganisms that thrive in conditions of excess iron (
Lifestyle-related behaviors that increase the risk of viral hepatitis infection
Evaluation of adult sibs and offspring of individuals with
Inform probands with
Measurement of transferrin saturation and serum ferritin concentration in sibs with
Phlebotomy therapy for sibs with
Note:
See
Inducing iron depletion during pregnancy or in females who anticipate pregnancy is undesirable. In the absence of severe iron-related liver disease or cardiomyopathy, it is prudent to withhold therapeutic phlebotomy during pregnancy [
The oral iron chelator deferasirox (Exjade
Search
• Nonsteroidal anti-inflammatory drugs
• Physiotherapy
• Joint replacement
• Vaccination against hepatitis A & B for persons w/
• Treatment of hepatitis B or C w/standard antiviral agents may ↓ liver injury.
• Varices: endoscopic surveillance; prophylaxis w/nonselective beta-blockers
• Ascites: salt restriction & diuretics, & paracentesis & portosystemic shunts if needed
• Spontaneous bacterial peritonitis: antibiotic therapy
• Hepatic encephalopathy: nutritional modifications (low-protein diet) & lactulose & rifaximin as needed
• Hormone replacement therapy as needed
• Gonadotropin treatment for infertility in females as needed
• Diuretics, ACE inhibitors, cardiac glycosides, antiarrhythmic agents
• Phlebotomy or erythrocytapheresis; consider iron chelation therapy.
• Lifelong treatment w/supportive agents may be indicated.
• Iron-chelating agents (deferoxamine, deferiprone, & deferasirox) are not approved for treatment of iron overload in
• In those w/
• In those w/
• EKG & echocardiography
• T
• Medicinal iron and nutritional supplements containing iron
• Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption.
• Daily ingestion of more than 500 mg of supplemental vitamin C, which may enhance iron absorption
• Consumption of uncooked seafood, which increases the risk of infection from microorganisms that thrive in conditions of excess iron (
• Lifestyle-related behaviors that increase the risk of viral hepatitis infection
• Inform probands with
• Measurement of transferrin saturation and serum ferritin concentration in sibs with
• Phlebotomy therapy for sibs with
## Evaluations Following Initial Diagnosis
To establish the extent of iron overload and optimal management of persons diagnosed with
ALP = alkaline phosphatase; ALT = aminotransferase; AST = aspartate aminotransferase; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; Hb = hemoglobin; HC = hemochromatosis;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse knowledgeable about hemochromatosis
## Treatment of Manifestations
The
Therapeutic phlebotomy (i.e., removal of a unit of blood) is a simple, inexpensive, safe, and effective way to remove excess iron. Each unit of blood (400-500 mL) with a hematocrit of 40% contains 160-200 mg of iron.
The usual therapy is phlebotomy weekly until the serum ferritin is ≤100 µg/L. Twice-weekly phlebotomy may be useful to accelerate iron depletion in individuals with serum ferritin >1,000 µg/L or those with evidence of end-organ damage due to iron overload. Hematocrit or hemoglobin (Hb) concentration should be assessed prior to each phlebotomy. If serum ferritin is very high, serum ferritin measurement should be performed approximately every five to ten phlebotomies. Some persons, especially females, tolerate phlebotomy poorly. In such instances, the interval between phlebotomies should be increased (e.g., every 10-14 days) or phlebotomy volume should be reduced (e.g., 250-300 mL).
Anemia is not a characteristic of
The serum ferritin concentration is the most feasible and inexpensive way to monitor therapeutic phlebotomy. After serum ferritin is ≤100 µg/L, serum ferritin concentration should be quantified after each additional one or two treatments [
Maintenance phlebotomy to prevent reaccumulation of excess iron is indicated for males with serum ferritin ≥300 µg/L and for females with serum ferritin ≥200 µg/L [
Phlebotomy may decrease fatigue, arthralgias, and hepatic enzyme levels in many individuals and induce regression of liver fibrosis and cirrhosis in some individuals. Conclusive data regarding the favorable influence of therapeutic phlebotomy on quality of life, diabetes, liver cancer risk, or cardiomyopathy is lacking [
Whether lowering transferrin saturation should be a target of phlebotomy therapy is debatable. Elevated transferrin saturation in
Note: Hb, mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV) levels are not targets of treatment in persons with
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Optimal implementation of these recommendations involves multidisciplinary care (see
Nonsteroidal anti-inflammatory drugs
Physiotherapy
Joint replacement
Vaccination against hepatitis A & B for persons w/
Treatment of hepatitis B or C w/standard antiviral agents may ↓ liver injury.
Varices: endoscopic surveillance; prophylaxis w/nonselective beta-blockers
Ascites: salt restriction & diuretics, & paracentesis & portosystemic shunts if needed
Spontaneous bacterial peritonitis: antibiotic therapy
Hepatic encephalopathy: nutritional modifications (low-protein diet) & lactulose & rifaximin as needed
Hormone replacement therapy as needed
Gonadotropin treatment for infertility in females as needed
Diuretics, ACE inhibitors, cardiac glycosides, antiarrhythmic agents
Phlebotomy or erythrocytapheresis; consider iron chelation therapy.
Lifelong treatment w/supportive agents may be indicated.
Iron-chelating agents (deferoxamine, deferiprone, & deferasirox) are not approved for treatment of iron overload in
ACE = angiotensin-converting enzyme; HCC = hepatocellular carcinoma;
• Nonsteroidal anti-inflammatory drugs
• Physiotherapy
• Joint replacement
• Vaccination against hepatitis A & B for persons w/
• Treatment of hepatitis B or C w/standard antiviral agents may ↓ liver injury.
• Varices: endoscopic surveillance; prophylaxis w/nonselective beta-blockers
• Ascites: salt restriction & diuretics, & paracentesis & portosystemic shunts if needed
• Spontaneous bacterial peritonitis: antibiotic therapy
• Hepatic encephalopathy: nutritional modifications (low-protein diet) & lactulose & rifaximin as needed
• Hormone replacement therapy as needed
• Gonadotropin treatment for infertility in females as needed
• Diuretics, ACE inhibitors, cardiac glycosides, antiarrhythmic agents
• Phlebotomy or erythrocytapheresis; consider iron chelation therapy.
• Lifelong treatment w/supportive agents may be indicated.
• Iron-chelating agents (deferoxamine, deferiprone, & deferasirox) are not approved for treatment of iron overload in
## Targeted Therapies
The
Therapeutic phlebotomy (i.e., removal of a unit of blood) is a simple, inexpensive, safe, and effective way to remove excess iron. Each unit of blood (400-500 mL) with a hematocrit of 40% contains 160-200 mg of iron.
The usual therapy is phlebotomy weekly until the serum ferritin is ≤100 µg/L. Twice-weekly phlebotomy may be useful to accelerate iron depletion in individuals with serum ferritin >1,000 µg/L or those with evidence of end-organ damage due to iron overload. Hematocrit or hemoglobin (Hb) concentration should be assessed prior to each phlebotomy. If serum ferritin is very high, serum ferritin measurement should be performed approximately every five to ten phlebotomies. Some persons, especially females, tolerate phlebotomy poorly. In such instances, the interval between phlebotomies should be increased (e.g., every 10-14 days) or phlebotomy volume should be reduced (e.g., 250-300 mL).
Anemia is not a characteristic of
The serum ferritin concentration is the most feasible and inexpensive way to monitor therapeutic phlebotomy. After serum ferritin is ≤100 µg/L, serum ferritin concentration should be quantified after each additional one or two treatments [
Maintenance phlebotomy to prevent reaccumulation of excess iron is indicated for males with serum ferritin ≥300 µg/L and for females with serum ferritin ≥200 µg/L [
Phlebotomy may decrease fatigue, arthralgias, and hepatic enzyme levels in many individuals and induce regression of liver fibrosis and cirrhosis in some individuals. Conclusive data regarding the favorable influence of therapeutic phlebotomy on quality of life, diabetes, liver cancer risk, or cardiomyopathy is lacking [
Whether lowering transferrin saturation should be a target of phlebotomy therapy is debatable. Elevated transferrin saturation in
Note: Hb, mean corpuscular hemoglobin (MCH), and mean corpuscular volume (MCV) levels are not targets of treatment in persons with
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. Optimal implementation of these recommendations involves multidisciplinary care (see
Nonsteroidal anti-inflammatory drugs
Physiotherapy
Joint replacement
Vaccination against hepatitis A & B for persons w/
Treatment of hepatitis B or C w/standard antiviral agents may ↓ liver injury.
Varices: endoscopic surveillance; prophylaxis w/nonselective beta-blockers
Ascites: salt restriction & diuretics, & paracentesis & portosystemic shunts if needed
Spontaneous bacterial peritonitis: antibiotic therapy
Hepatic encephalopathy: nutritional modifications (low-protein diet) & lactulose & rifaximin as needed
Hormone replacement therapy as needed
Gonadotropin treatment for infertility in females as needed
Diuretics, ACE inhibitors, cardiac glycosides, antiarrhythmic agents
Phlebotomy or erythrocytapheresis; consider iron chelation therapy.
Lifelong treatment w/supportive agents may be indicated.
Iron-chelating agents (deferoxamine, deferiprone, & deferasirox) are not approved for treatment of iron overload in
ACE = angiotensin-converting enzyme; HCC = hepatocellular carcinoma;
• Nonsteroidal anti-inflammatory drugs
• Physiotherapy
• Joint replacement
• Vaccination against hepatitis A & B for persons w/
• Treatment of hepatitis B or C w/standard antiviral agents may ↓ liver injury.
• Varices: endoscopic surveillance; prophylaxis w/nonselective beta-blockers
• Ascites: salt restriction & diuretics, & paracentesis & portosystemic shunts if needed
• Spontaneous bacterial peritonitis: antibiotic therapy
• Hepatic encephalopathy: nutritional modifications (low-protein diet) & lactulose & rifaximin as needed
• Hormone replacement therapy as needed
• Gonadotropin treatment for infertility in females as needed
• Diuretics, ACE inhibitors, cardiac glycosides, antiarrhythmic agents
• Phlebotomy or erythrocytapheresis; consider iron chelation therapy.
• Lifelong treatment w/supportive agents may be indicated.
• Iron-chelating agents (deferoxamine, deferiprone, & deferasirox) are not approved for treatment of iron overload in
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, surveillance is based on guidelines proposed for individuals with
In those w/
In those w/
EKG & echocardiography
T
AFP = alpha-fetoprotein; FSH = follicle-stimulating hormone; Hb = hemoglobin;
• In those w/
• In those w/
• EKG & echocardiography
• T
## Agents/Circumstances to Avoid
Avoid the following:
Medicinal iron and nutritional supplements containing iron
Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption.
Daily ingestion of more than 500 mg of supplemental vitamin C, which may enhance iron absorption
Consumption of uncooked seafood, which increases the risk of infection from microorganisms that thrive in conditions of excess iron (
Lifestyle-related behaviors that increase the risk of viral hepatitis infection
• Medicinal iron and nutritional supplements containing iron
• Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption.
• Daily ingestion of more than 500 mg of supplemental vitamin C, which may enhance iron absorption
• Consumption of uncooked seafood, which increases the risk of infection from microorganisms that thrive in conditions of excess iron (
• Lifestyle-related behaviors that increase the risk of viral hepatitis infection
## Evaluation of Relatives at Risk
Evaluation of adult sibs and offspring of individuals with
Inform probands with
Measurement of transferrin saturation and serum ferritin concentration in sibs with
Phlebotomy therapy for sibs with
Note:
See
• Inform probands with
• Measurement of transferrin saturation and serum ferritin concentration in sibs with
• Phlebotomy therapy for sibs with
## Pregnancy Management
Inducing iron depletion during pregnancy or in females who anticipate pregnancy is undesirable. In the absence of severe iron-related liver disease or cardiomyopathy, it is prudent to withhold therapeutic phlebotomy during pregnancy [
## Therapies Under Investigation
The oral iron chelator deferasirox (Exjade
Search
## Genetic Counseling
Pseudodominance (the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) has been observed in
Most parents of individuals with
Infrequently, one parent of a proband with
If both parents of a proband with
If one parent of a proband with
Sibs of probands with
Sibs of probands with
Unless the reproductive partner of a proband with
It is sometimes recommended that reproductive partners of individuals with
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with
Molecular genetic testing for
Population screening has been performed due to the high prevalence of
Molecular genetic testing-based population screening for
Biochemical-based screening (using transferrin saturation and serum ferritin) of males of European descent age >30 years may be considered [
Prenatal testing is not usually performed because
Differences in perspective exist among medical professionals and within families regarding the use of prenatal testing. Although most centers consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most parents of individuals with
• Infrequently, one parent of a proband with
• If both parents of a proband with
• If one parent of a proband with
• Sibs of probands with
• Sibs of probands with
• Unless the reproductive partner of a proband with
• It is sometimes recommended that reproductive partners of individuals with
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with
• Molecular genetic testing-based population screening for
• Biochemical-based screening (using transferrin saturation and serum ferritin) of males of European descent age >30 years may be considered [
## Mode of Inheritance
Pseudodominance (the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) has been observed in
## Risk to Family Members
Most parents of individuals with
Infrequently, one parent of a proband with
If both parents of a proband with
If one parent of a proband with
Sibs of probands with
Sibs of probands with
Unless the reproductive partner of a proband with
It is sometimes recommended that reproductive partners of individuals with
• Most parents of individuals with
• Infrequently, one parent of a proband with
• If both parents of a proband with
• If one parent of a proband with
• Sibs of probands with
• Sibs of probands with
• Unless the reproductive partner of a proband with
• It is sometimes recommended that reproductive partners of individuals with
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with
Molecular genetic testing for
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with
## Population Screening
Population screening has been performed due to the high prevalence of
Molecular genetic testing-based population screening for
Biochemical-based screening (using transferrin saturation and serum ferritin) of males of European descent age >30 years may be considered [
• Molecular genetic testing-based population screening for
• Biochemical-based screening (using transferrin saturation and serum ferritin) of males of European descent age >30 years may be considered [
## Prenatal Testing and Preimplantation Genetic Testing
Prenatal testing is not usually performed because
Differences in perspective exist among medical professionals and within families regarding the use of prenatal testing. Although most centers consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Canada
Australia
United Kingdom
•
• Canada
•
•
•
•
• Australia
•
•
• United Kingdom
•
•
•
•
•
•
•
•
•
## Molecular Genetics
HFE-Related Hemochromatosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for HFE-Related Hemochromatosis (
Alleles listed in the table were provided by the authors.
## Molecular Pathogenesis
Alleles listed in the table were provided by the authors.
## Chapter Notes
James C Barton, MD, is a Clinical Professor of Medicine in the Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, and Medical Director of Southern Iron Disorders Center, Birmingham, AL. As a hematologist, his interests include population screening, diagnosis, and management of hemochromatosis, iron deficiency, and other iron-related disorders. Dr Barton received his MD from the University of Tennessee College of Medicine, Memphis, TN. He received training in internal medicine, hematology, and medical oncology at the University of Tennessee College of Medicine, Memphis, TN, and the University of Alabama at Birmingham, Birmingham, AL. Dr Barton has edited two textbooks on hemochromatosis. Email:
Charles J Parker, MD, is a Professor of Medicine in the Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, at the University of Utah and the Huntsman Cancer Institute, Salt Lake City, UT. As a hematologist, his clinical interests include paroxysmal nocturnal hemoglobinuria (PNH), hemochromatosis, and porphyria. Dr Parker received his MD from The University of North Carolina, Chapel Hill, NC. He received training in medicine and hematology from the North Carolina Memorial Hospital, Chapel Hill, NC, and Duke University, Durham, NC, respectively. In the past, Dr Parker served as President of the International Paroxysmal Nocturnal Hemoglobinuria Interest Group and Editor-in-Chief of
Dr Barton acknowledges Drs Marcel E Conrad, William H Crosby, Ernest Beutler, Corwin Q Edwards, and Ronald T Acton for sharing their experience, collaborations, and enthusiasm about studying hemochromatosis and other iron-related disorders.
James C Barton, MD (2018-present)Robin L Bennett, MS; University of Washington (2000-2015)Corwin Q Edwards, MD; University of Utah School of Medicine (2018-2024)Kris V Kowdley, MD; Virginia Mason Medical Center (2000-2015)Arno G Motulsky, MD; University of Washington (2000-2015)Charles J Parker, MD (2024-present)Lawrie Powell, AC, MD, PhD; Royal Brisbane & Women's Hospital (2015-2018)Rebecca Seckington; University of Queensland (2015-2018)Jonathan F Tait, MD, PhD; University of Washington School of Medicine (2000-2011)
11 April 2024 (sw) Comprehensive update posted live
6 December 2018 (sw) Comprehensive update posted live
17 September 2015 (me) Comprehensive update posted live
19 April 2012 (me) Comprehensive update posted live
4 December 2006 (me) Comprehensive update posted live
7 October 2003 (me) Comprehensive update posted live
3 April 2000 (me) Review posted live
October 1998 (kk) Original submission
• 11 April 2024 (sw) Comprehensive update posted live
• 6 December 2018 (sw) Comprehensive update posted live
• 17 September 2015 (me) Comprehensive update posted live
• 19 April 2012 (me) Comprehensive update posted live
• 4 December 2006 (me) Comprehensive update posted live
• 7 October 2003 (me) Comprehensive update posted live
• 3 April 2000 (me) Review posted live
• October 1998 (kk) Original submission
## Author Notes
James C Barton, MD, is a Clinical Professor of Medicine in the Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, and Medical Director of Southern Iron Disorders Center, Birmingham, AL. As a hematologist, his interests include population screening, diagnosis, and management of hemochromatosis, iron deficiency, and other iron-related disorders. Dr Barton received his MD from the University of Tennessee College of Medicine, Memphis, TN. He received training in internal medicine, hematology, and medical oncology at the University of Tennessee College of Medicine, Memphis, TN, and the University of Alabama at Birmingham, Birmingham, AL. Dr Barton has edited two textbooks on hemochromatosis. Email:
Charles J Parker, MD, is a Professor of Medicine in the Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, at the University of Utah and the Huntsman Cancer Institute, Salt Lake City, UT. As a hematologist, his clinical interests include paroxysmal nocturnal hemoglobinuria (PNH), hemochromatosis, and porphyria. Dr Parker received his MD from The University of North Carolina, Chapel Hill, NC. He received training in medicine and hematology from the North Carolina Memorial Hospital, Chapel Hill, NC, and Duke University, Durham, NC, respectively. In the past, Dr Parker served as President of the International Paroxysmal Nocturnal Hemoglobinuria Interest Group and Editor-in-Chief of
## Acknowledgments
Dr Barton acknowledges Drs Marcel E Conrad, William H Crosby, Ernest Beutler, Corwin Q Edwards, and Ronald T Acton for sharing their experience, collaborations, and enthusiasm about studying hemochromatosis and other iron-related disorders.
## Author History
James C Barton, MD (2018-present)Robin L Bennett, MS; University of Washington (2000-2015)Corwin Q Edwards, MD; University of Utah School of Medicine (2018-2024)Kris V Kowdley, MD; Virginia Mason Medical Center (2000-2015)Arno G Motulsky, MD; University of Washington (2000-2015)Charles J Parker, MD (2024-present)Lawrie Powell, AC, MD, PhD; Royal Brisbane & Women's Hospital (2015-2018)Rebecca Seckington; University of Queensland (2015-2018)Jonathan F Tait, MD, PhD; University of Washington School of Medicine (2000-2011)
## Revision History
11 April 2024 (sw) Comprehensive update posted live
6 December 2018 (sw) Comprehensive update posted live
17 September 2015 (me) Comprehensive update posted live
19 April 2012 (me) Comprehensive update posted live
4 December 2006 (me) Comprehensive update posted live
7 October 2003 (me) Comprehensive update posted live
3 April 2000 (me) Review posted live
October 1998 (kk) Original submission
• 11 April 2024 (sw) Comprehensive update posted live
• 6 December 2018 (sw) Comprehensive update posted live
• 17 September 2015 (me) Comprehensive update posted live
• 19 April 2012 (me) Comprehensive update posted live
• 4 December 2006 (me) Comprehensive update posted live
• 7 October 2003 (me) Comprehensive update posted live
• 3 April 2000 (me) Review posted live
• October 1998 (kk) Original submission
## Key Sections in this
## References
Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:328–43. [
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
European Association for the Study of the Liver. EASL clinical practice guidelines for
European Association for the Study of the Liver. EASL clinical practice guidelines on haemochromatosis. J Hepatol. 2022;77:479-502. [
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:328–43. [
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• European Association for the Study of the Liver. EASL clinical practice guidelines for
• European Association for the Study of the Liver. EASL clinical practice guidelines on haemochromatosis. J Hepatol. 2022;77:479-502. [
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:328–43. [
Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
European Association for the Study of the Liver. EASL clinical practice guidelines for
European Association for the Study of the Liver. EASL clinical practice guidelines on haemochromatosis. J Hepatol. 2022;77:479-502. [
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:328–43. [
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available
• European Association for the Study of the Liver. EASL clinical practice guidelines for
• European Association for the Study of the Liver. EASL clinical practice guidelines on haemochromatosis. J Hepatol. 2022;77:479-502. [
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Literature Cited
Use of serum ferritin concentration to direct management of persons with
ALT =alanine transaminase; AST =aspartate transaminase
|
[] |
3/4/2000
|
11/4/2024
|
13/7/2005
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
hep
|
hep
|
[
"UROD-Related Hepatoerythropoietic Porphyria",
"UROD-Related Hepatoerythropoietic Porphyria",
"Uroporphyrinogen decarboxylase",
"UROD",
"Hepatoerythropoietic Porphyria"
] |
Hepatoerythropoietic Porphyria
|
Sean Rudnick, John Phillips, Herbert Bonkovsky
|
Summary Hepatoerythropoietic porphyria (HEP) is characterized by blistering skin lesions, hypertrichosis, and scarring over the affected skin areas. Disease manifestations occur during infancy or childhood and with similar frequency in females and males. Mild anemia/hemolysis are not uncommon. The diagnosis of HEP is established in a proband with elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin), significantly increased erythrocyte zinc protoporphyrin, and/or biallelic pathogenic (or likely pathogenic) variants in HEP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Hepatoerythropoietic porphyria (HEP)
Blistering skin lesions/vesicles/bullae
Hypertrichosis
Scarring
Passage of red urine
Note: The features of HEP generally resemble those of
Urine and plasma porphyrins show an increase predominantly of uroporphyrin and heptacarboxylporphyrin.
Consider erythrocyte zinc protoporphyrin levels, which are significantly increased in HEP, to differentiate HEP from
Biochemical Characteristics of Hepatoerythropoietic Porphyria
For information on the role of the hepatic enzyme uroporphyrinogen decarboxylase (UROD), see Clinical Characteristics,
Fluorescence emission peak of diluted plasma at neutral pH, following excitation at 400-410 nm
The diagnosis of HEP
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hepatoerythropoietic Porphyria
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Large deletions involving
• Blistering skin lesions/vesicles/bullae
• Hypertrichosis
• Scarring
• Passage of red urine
• Urine and plasma porphyrins show an increase predominantly of uroporphyrin and heptacarboxylporphyrin.
• Consider erythrocyte zinc protoporphyrin levels, which are significantly increased in HEP, to differentiate HEP from
• Urine and plasma porphyrins show an increase predominantly of uroporphyrin and heptacarboxylporphyrin.
• Consider erythrocyte zinc protoporphyrin levels, which are significantly increased in HEP, to differentiate HEP from
• Urine and plasma porphyrins show an increase predominantly of uroporphyrin and heptacarboxylporphyrin.
• Consider erythrocyte zinc protoporphyrin levels, which are significantly increased in HEP, to differentiate HEP from
## Suggestive Findings
Hepatoerythropoietic porphyria (HEP)
Blistering skin lesions/vesicles/bullae
Hypertrichosis
Scarring
Passage of red urine
Note: The features of HEP generally resemble those of
Urine and plasma porphyrins show an increase predominantly of uroporphyrin and heptacarboxylporphyrin.
Consider erythrocyte zinc protoporphyrin levels, which are significantly increased in HEP, to differentiate HEP from
Biochemical Characteristics of Hepatoerythropoietic Porphyria
For information on the role of the hepatic enzyme uroporphyrinogen decarboxylase (UROD), see Clinical Characteristics,
Fluorescence emission peak of diluted plasma at neutral pH, following excitation at 400-410 nm
• Blistering skin lesions/vesicles/bullae
• Hypertrichosis
• Scarring
• Passage of red urine
• Urine and plasma porphyrins show an increase predominantly of uroporphyrin and heptacarboxylporphyrin.
• Consider erythrocyte zinc protoporphyrin levels, which are significantly increased in HEP, to differentiate HEP from
• Urine and plasma porphyrins show an increase predominantly of uroporphyrin and heptacarboxylporphyrin.
• Consider erythrocyte zinc protoporphyrin levels, which are significantly increased in HEP, to differentiate HEP from
• Urine and plasma porphyrins show an increase predominantly of uroporphyrin and heptacarboxylporphyrin.
• Consider erythrocyte zinc protoporphyrin levels, which are significantly increased in HEP, to differentiate HEP from
## Establishing the Diagnosis
The diagnosis of HEP
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hepatoerythropoietic Porphyria
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Large deletions involving
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hepatoerythropoietic Porphyria
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Large deletions involving
## Clinical Characteristics
Hepatoerythropoietic porphyria (HEP) is characterized by extreme photosensitivity, skin lesions with fluid-filled blisters that break and heal slowly, hypertrichosis, and scarring over the affected skin areas. Signs and symptoms of HEP start during infancy or childhood, with similar frequency in females and males, and generally resemble those of
Repeated sun exposure can lead to scleroderma-like changes that result in photomutilation [
With high levels of circulating porphyrins there may be a red-brown discoloration of teeth (erythrodontia) as a result of the deposition of porphyrins in the enamel layer of the developing tooth.
No increased risk for hepatocellular carcinoma has been identified in persons with HEP.
Note: The clinical features of HEP and
Reduced activity of the hepatic enzyme uroporphyrinogen decarboxylase (UROD) to 15%-20% of normal in all tissues leads to the accumulation of substrate, uroporphyrinogen, and the intermediate products of the reaction in all cells. Cells with a high demand for heme production include erythrocytes and hepatocytes; thus, accumulation is more pronounced in these cell types (predominantly in the liver).
The substrates and intermediates accumulate in cells in the form of oxidized porphyrins (mostly uroporphyrin and heptacarboxylporphyrin) that are then transported into the plasma, where they are deposited in the skin and other tissues. In the skin, these porphyrins interact with blue light (the Soret band, ~410 nm) to produce skin damage.
Excess plasma porphyrins (i.e., uroporphyrin and heptacarboxylporphyrin) are excreted via the urine. Intermediates further along in the pathway (i.e., protoporphyrin and zinc protoporphyrin) are eliminated in the bile. For more information about the proposed pathophysiology of HEP, click
No
In HEP, at least one
HEP may also be referred to as "
Porphyria Classification Systems
ALA = aminolevulinic acid
See also
Fewer than 100 individuals with HEP have been reported in the literature. The frequency of HEP can only be inferred based on that of familial porphyria cutanea tarda (F-PCT), which occurs in one in 20,000 individuals. Note: Over a ten-year period from 2007 to 2017, a referral center / porphyria-specific diagnostic laboratory provided molecular diagnostic testing on four unrelated individuals with HEP, identifying one novel variant [
Two founder variants have been identified in Norway [
## Clinical Description
Hepatoerythropoietic porphyria (HEP) is characterized by extreme photosensitivity, skin lesions with fluid-filled blisters that break and heal slowly, hypertrichosis, and scarring over the affected skin areas. Signs and symptoms of HEP start during infancy or childhood, with similar frequency in females and males, and generally resemble those of
Repeated sun exposure can lead to scleroderma-like changes that result in photomutilation [
With high levels of circulating porphyrins there may be a red-brown discoloration of teeth (erythrodontia) as a result of the deposition of porphyrins in the enamel layer of the developing tooth.
No increased risk for hepatocellular carcinoma has been identified in persons with HEP.
Note: The clinical features of HEP and
## Pathophysiology
Reduced activity of the hepatic enzyme uroporphyrinogen decarboxylase (UROD) to 15%-20% of normal in all tissues leads to the accumulation of substrate, uroporphyrinogen, and the intermediate products of the reaction in all cells. Cells with a high demand for heme production include erythrocytes and hepatocytes; thus, accumulation is more pronounced in these cell types (predominantly in the liver).
The substrates and intermediates accumulate in cells in the form of oxidized porphyrins (mostly uroporphyrin and heptacarboxylporphyrin) that are then transported into the plasma, where they are deposited in the skin and other tissues. In the skin, these porphyrins interact with blue light (the Soret band, ~410 nm) to produce skin damage.
Excess plasma porphyrins (i.e., uroporphyrin and heptacarboxylporphyrin) are excreted via the urine. Intermediates further along in the pathway (i.e., protoporphyrin and zinc protoporphyrin) are eliminated in the bile. For more information about the proposed pathophysiology of HEP, click
## Genotype-Phenotype Correlations
No
In HEP, at least one
## Nomenclature
HEP may also be referred to as "
Porphyria Classification Systems
ALA = aminolevulinic acid
See also
## Prevalence
Fewer than 100 individuals with HEP have been reported in the literature. The frequency of HEP can only be inferred based on that of familial porphyria cutanea tarda (F-PCT), which occurs in one in 20,000 individuals. Note: Over a ten-year period from 2007 to 2017, a referral center / porphyria-specific diagnostic laboratory provided molecular diagnostic testing on four unrelated individuals with HEP, identifying one novel variant [
Two founder variants have been identified in Norway [
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Other types of hereditary porphyria in the differential diagnosis of hepatoerythropoietic porphyria (HEP) are summarized in
Other Types of Porphyria in the Differential Diagnosis of Hepatoerythropoietic Porphyria
HCP, an acute hepatic porphyria, is generally accompanied by neurovisceral features, esp bouts of severe abdominal pain, which are not observed in HEP. Development of blistering skin disease is uncommon in HCP, whereas it is present & severe in HEP. Mild manifestations of HEP can be mistaken for HCP.
↑ in zinc protoporphyrin is seen in HEP & not in HCP. In CEP fecal porphyrin levels of coproporphyrin III are significantly ↑.
VP is a cutaneous & acute porphyria & can present w/cutaneous manifestations &/or acute attacks of neurovisceral manifestations similar to AIP.
Plasma porphyrin fluorescence scanning of diluted plasma at neutral pH w/peak wavelength ~626 nm is seen w/VP. This is very useful in differential diagnosis. In PCT & HEP, peak emission wavelength is ~619-622 nm.
AD = autosomal dominant; AIP = acute intermittent porphyria; AR = autosomal recessive; HEP = hepatoerythropoietic porphyria; MOI = mode of inheritance; PCT = porphyria cutanea tarda; UROD = uroporphyrinogen decarboxylase; XL = X-linked
CEP caused by biallelic
• HCP, an acute hepatic porphyria, is generally accompanied by neurovisceral features, esp bouts of severe abdominal pain, which are not observed in HEP. Development of blistering skin disease is uncommon in HCP, whereas it is present & severe in HEP. Mild manifestations of HEP can be mistaken for HCP.
• ↑ in zinc protoporphyrin is seen in HEP & not in HCP. In CEP fecal porphyrin levels of coproporphyrin III are significantly ↑.
• VP is a cutaneous & acute porphyria & can present w/cutaneous manifestations &/or acute attacks of neurovisceral manifestations similar to AIP.
• Plasma porphyrin fluorescence scanning of diluted plasma at neutral pH w/peak wavelength ~626 nm is seen w/VP. This is very useful in differential diagnosis. In PCT & HEP, peak emission wavelength is ~619-622 nm.
## Other Disorders in the Differential Diagnosis of HEP
## Management
No clinical practice guidelines for hepatoerythropoietic porphyria (HEP) have been published.
To establish the extent of disease and needs in an individual diagnosed with HEP, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Evaluation of skin findings including blistering/vesicles over sun-exposed areas of skin with resultant scarring and hypertrichosis
Laboratory evaluation for hemolytic anemia
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of HEP in order to facilitate medical and personal decision making
There are no effective treatment regimens to restore UROD enzyme activity levels in individuals with HEP.
Treatment recommendations at this time are similar to those for
Prompt treatment of any infection superimposed on skin lesions
Low-dose chloroquine and oral charcoal (to bind stool porphyrins), which have been used in specific circumstances with variable success
Strict avoidance of sunlight, including the long-wave ultraviolet light sunlight that passes through window glass, because of the high risk for severe skin damage and possible mutilation
Identification and avoidance of susceptibility factors (where applicable) (See
Avoidance of drugs and agents that induce the hepatic cytochrome P450s
Routine vaccination against hepatitis A and B
There are currently no recommendations or guidelines for surveillance in individuals with HEP.
Monitoring urinary porphyrin levels annually or at some other interval, perhaps determined by clinical findings, may be reasonable.
Persons of all ages should avoid exposure to sunlight.
Older individuals should avoid the known precipitating factors (e.g., alcohol, oral estrogen, smoking, and drugs that induce the cytochrome P450s).
Note: The rarity of HEP makes identification of additional risk factors difficult to assess. However, the existence of instances of late-onset disease suggest that susceptibility factors may play a role in some individuals [
It is reasonable to clarify the genetic status of at-risk relatives in order to identify as early as possible those with a heterozygous (or biallelic)
See
Search
• Evaluation of skin findings including blistering/vesicles over sun-exposed areas of skin with resultant scarring and hypertrichosis
• Laboratory evaluation for hemolytic anemia
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of HEP in order to facilitate medical and personal decision making
• Prompt treatment of any infection superimposed on skin lesions
• Low-dose chloroquine and oral charcoal (to bind stool porphyrins), which have been used in specific circumstances with variable success
• Strict avoidance of sunlight, including the long-wave ultraviolet light sunlight that passes through window glass, because of the high risk for severe skin damage and possible mutilation
• Identification and avoidance of susceptibility factors (where applicable) (See
• Avoidance of drugs and agents that induce the hepatic cytochrome P450s
• Routine vaccination against hepatitis A and B
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with HEP, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Evaluation of skin findings including blistering/vesicles over sun-exposed areas of skin with resultant scarring and hypertrichosis
Laboratory evaluation for hemolytic anemia
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of HEP in order to facilitate medical and personal decision making
• Evaluation of skin findings including blistering/vesicles over sun-exposed areas of skin with resultant scarring and hypertrichosis
• Laboratory evaluation for hemolytic anemia
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of HEP in order to facilitate medical and personal decision making
## Treatment of Manifestations
There are no effective treatment regimens to restore UROD enzyme activity levels in individuals with HEP.
Treatment recommendations at this time are similar to those for
Prompt treatment of any infection superimposed on skin lesions
Low-dose chloroquine and oral charcoal (to bind stool porphyrins), which have been used in specific circumstances with variable success
Strict avoidance of sunlight, including the long-wave ultraviolet light sunlight that passes through window glass, because of the high risk for severe skin damage and possible mutilation
Identification and avoidance of susceptibility factors (where applicable) (See
Avoidance of drugs and agents that induce the hepatic cytochrome P450s
Routine vaccination against hepatitis A and B
• Prompt treatment of any infection superimposed on skin lesions
• Low-dose chloroquine and oral charcoal (to bind stool porphyrins), which have been used in specific circumstances with variable success
• Strict avoidance of sunlight, including the long-wave ultraviolet light sunlight that passes through window glass, because of the high risk for severe skin damage and possible mutilation
• Identification and avoidance of susceptibility factors (where applicable) (See
• Avoidance of drugs and agents that induce the hepatic cytochrome P450s
• Routine vaccination against hepatitis A and B
## Surveillance
There are currently no recommendations or guidelines for surveillance in individuals with HEP.
Monitoring urinary porphyrin levels annually or at some other interval, perhaps determined by clinical findings, may be reasonable.
## Agents/Circumstances to Avoid
Persons of all ages should avoid exposure to sunlight.
Older individuals should avoid the known precipitating factors (e.g., alcohol, oral estrogen, smoking, and drugs that induce the cytochrome P450s).
Note: The rarity of HEP makes identification of additional risk factors difficult to assess. However, the existence of instances of late-onset disease suggest that susceptibility factors may play a role in some individuals [
## Evaluation of Relatives at Risk
It is reasonable to clarify the genetic status of at-risk relatives in order to identify as early as possible those with a heterozygous (or biallelic)
See
## Therapies Under Investigation
Search
## Genetic Counseling
Hepatoerythropoietic porphyria (HEP) is inherited in an autosomal recessive manner.
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a proband with HEP have
If both parents are known to be heterozygous for a
Heterozygous sibs have F-PCT but are generally asymptomatic. If susceptibility factors are present, heterozygous sibs are at increased risk of developing signs and symptoms of F-PCT (see Familial Porphyria Cutanea Tarda,
Targeted genetic testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have HEP.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a proband with HEP have
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygous sibs have F-PCT but are generally asymptomatic. If susceptibility factors are present, heterozygous sibs are at increased risk of developing signs and symptoms of F-PCT (see Familial Porphyria Cutanea Tarda,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have HEP.
## Mode of Inheritance
Hepatoerythropoietic porphyria (HEP) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are presumed to be heterozygous for a
Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a proband with HEP have
If both parents are known to be heterozygous for a
Heterozygous sibs have F-PCT but are generally asymptomatic. If susceptibility factors are present, heterozygous sibs are at increased risk of developing signs and symptoms of F-PCT (see Familial Porphyria Cutanea Tarda,
• The parents of an affected individual are presumed to be heterozygous for a
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a proband with HEP have
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a
• Heterozygous sibs have F-PCT but are generally asymptomatic. If susceptibility factors are present, heterozygous sibs are at increased risk of developing signs and symptoms of F-PCT (see Familial Porphyria Cutanea Tarda,
## Heterozygote Detection
Targeted genetic testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have HEP.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have HEP.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
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Sweden
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## Molecular Genetics
Hepatoerythropoietic Porphyria: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hepatoerythropoietic Porphyria (
In hepatoerythropoietic porphyria (HEP) the developing red blood cell accumulates porphyrin intermediates, including uroporphyrin as well as protoporphyrin and specifically zinc protoporphyrin. These intermediates are at the terminal end of the pathway and are much more hydrophobic and must be eliminated through the liver into the bile (see
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
In hepatoerythropoietic porphyria (HEP) the developing red blood cell accumulates porphyrin intermediates, including uroporphyrin as well as protoporphyrin and specifically zinc protoporphyrin. These intermediates are at the terminal end of the pathway and are much more hydrophobic and must be eliminated through the liver into the bile (see
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
On behalf of the Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network; including Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX; Dr Bruce Wang, University of California, San Francisco, CA; Dr Herbert Bonkovsky, Wake Forest University School of Medicine and NC Baptist Medical Center, Winston-Salem, NC; Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT; Dr Manisha Balwani, Ichan School of Medicine, New York, NY.
Herbert Bonkovsky, MD (2013-present)Lawrence U Liu, MD; Icahn School of Medicine at Mount Sinai (2013-2022)John Phillips, PhD (2013-present)Sean Rudnick, MD (2022-present)
22 December 2022 (bp) Comprehensive update posted live
22 December 2016 (sw) Comprehensive update posted live
31 October 2013 (me) Review posted live
26 April 2012 (hb) Original submission
• 22 December 2022 (bp) Comprehensive update posted live
• 22 December 2016 (sw) Comprehensive update posted live
• 31 October 2013 (me) Review posted live
• 26 April 2012 (hb) Original submission
## Acknowledgments
On behalf of the Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network; including Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX; Dr Bruce Wang, University of California, San Francisco, CA; Dr Herbert Bonkovsky, Wake Forest University School of Medicine and NC Baptist Medical Center, Winston-Salem, NC; Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT; Dr Manisha Balwani, Ichan School of Medicine, New York, NY.
## Author History
Herbert Bonkovsky, MD (2013-present)Lawrence U Liu, MD; Icahn School of Medicine at Mount Sinai (2013-2022)John Phillips, PhD (2013-present)Sean Rudnick, MD (2022-present)
## Revision History
22 December 2022 (bp) Comprehensive update posted live
22 December 2016 (sw) Comprehensive update posted live
31 October 2013 (me) Review posted live
26 April 2012 (hb) Original submission
• 22 December 2022 (bp) Comprehensive update posted live
• 22 December 2016 (sw) Comprehensive update posted live
• 31 October 2013 (me) Review posted live
• 26 April 2012 (hb) Original submission
## References
## Literature Cited
|
[
"AK Aarsand, H Boman, S Sandberg. Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies.. Clin Chem 2009;55:795-803",
"K Beer, D Applebaum, C. Nousari. Pseudoporphyria: discussion of etiologic agents.. J Drugs Dermatol. 2014;13:990-2",
"LG Biesecker, MP Adam, FS Alkuraya, AR Amemiya, MJ Bamshad, AE Beck, JT Bennett, LM Bird, JC Carey, B Chung, RD Clark, TC Cox, C Curry, MBP Dinulos, WB Dobyns, PF Giampietro, KM Girisha, IA Glass, JM Graham, KW Gripp, CR Haldeman-Englert, BD Hall, AM Innes, JM Kalish, KM Keppler-Noreuil, K Kosaki, BA Kozel, GM Mirzaa, JJ Mulvihill, MJM Nowaczyk, RA Pagon, K Retterer, AF Rope, PA Sanchez-Lara, LH Seaver, JT Shieh, AM Slavotinek, AK Sobering, CA Stevens, DA Stevenson, TY Tan, WH Tan, AC Tsai, DD Weaver, MS Williams, E Zackai, YA Zarate. A dyadic approach to the delineation of diagnostic entities in clinical genomics.. Am J Hum Genet. 2021;108:8-15",
"H de Verneuil, F Bourgeois, F de Rooij, PD Siersema, JH Wilson, B Grandchamp, Y Nordmann. Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria.. Hum Genet 1992;89:548-52",
"GH Elder. Hepatic porphyrias in children.. J Inherit Metab Dis. 1997;20:237-46",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"M Méndez, MV Rossetti, S Gómez-Abecia, MJ Morán-Jiménez, V Parera, A Batlle, R Enríquez de Salamanca. Molecular analysis of the UROD gene in 17 Argentinean patients with familial porphyria cutanea tarda: characterization of four novel mutations.. Mol Genet Metab. 2012;105:629-33",
"JD Phillips, HA Bergonia, CA Reilly, MR Franklin, JP Kushner. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda.. Proc Natl Acad Sci U S A 2007;104:5079-84",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD. Hum Genet. 2020;139:1197-207",
"S Triviboonvanich, S Junnu, C Srisawat, N Silpa-archa. Late-onset hepatoerythropoietic porphyria presenting with facial deformities and erythrodontia.. Thai J Dermatol. 2019;35:73-80",
"Y Weiss, B Chen, M Yasuda, I Nazarenko, KE Anderson, RJ Desnick. Porphyria cutanea tarda and hepatoerythropoietic porphyria: identification of 19 novel uroporphyrinogen III decarboxylase mutations.. Molec Genet Metab. 2019;128:363-6"
] |
31/10/2013
|
22/12/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
hepatic-fibrosis
|
hepatic-fibrosis
|
[
"ADP-ribosylation factor-like protein 13B",
"ADP-ribosylation factor-like protein 6",
"Ankyrin repeat and SAM domain-containing protein 6",
"B9 domain-containing protein 1",
"B9 domain-containing protein 2",
"Bardet-Biedl syndrome 1 protein",
"Bardet-Biedl syndrome 10 protein",
"Bardet-Biedl syndrome 12 protein",
"Bardet-Biedl syndrome 2 protein",
"Bardet-Biedl syndrome 4 protein",
"Bardet-Biedl syndrome 5 protein",
"Bardet-Biedl syndrome 7 protein",
"Centrosomal protein of 164 kDa",
"Centrosomal protein of 290 kDa",
"Centrosomal protein of 41 kDa",
"Ciliogenesis and planar polarity effector 1",
"Coiled-coil and C2 domain-containing protein 2A",
"E3 ubiquitin-protein ligase TRIM32",
"Ellis-van Creveld syndrome protein",
"Fibrocystin",
"Intraflagellar transport protein 122 homolog",
"Intraflagellar transport protein 80 homolog",
"Inversin",
"IQ calmodulin-binding motif-containing protein 1",
"Jouberin",
"Kinesin-like protein KIF7",
"Limbin",
"McKusick-Kaufman/Bardet-Biedl syndromes putative chaperonin",
"Meckel syndrome type 1 protein",
"Meckelin",
"Nephrocystin-1",
"Nephrocystin-3",
"Nephrocystin-4",
"Oral-facial-digital syndrome 1 protein",
"Phosphatidylinositol polyphosphate 5-phosphatase type IV",
"Polycystin-1",
"Polycystin-2",
"Protein fantom",
"Protein PTHB1",
"Serine/threonine-protein kinase Nek8",
"Tectonic-1",
"Tectonic-2",
"Tectonic-3",
"Tetratricopeptide repeat protein 21B",
"Tetratricopeptide repeat protein 8",
"Transmembrane protein 138",
"Transmembrane protein 216",
"Transmembrane protein 231",
"Transmembrane protein 237",
"WD repeat-containing protein 19",
"Zinc finger protein 423",
"Zinc finger protein GLIS2",
"AHI1",
"ANKS6",
"ARL13B",
"ARL6",
"B9D1",
"B9D2",
"BBS1",
"BBS10",
"BBS12",
"BBS2",
"BBS4",
"BBS5",
"BBS7",
"BBS9",
"CC2D2A",
"CEP164",
"CEP290",
"CEP41",
"CPLANE1",
"EVC",
"EVC2",
"GLIS2",
"IFT122",
"IFT80",
"INPP5E",
"INVS",
"IQCB1",
"KIF7",
"MKKS",
"MKS1",
"NEK8",
"NPHP1",
"NPHP3",
"NPHP4",
"OFD1",
"PKD1",
"PKD2",
"PKHD1",
"RPGRIP1L",
"TCTN1",
"TCTN2",
"TCTN3",
"TMEM138",
"TMEM216",
"TMEM231",
"TMEM237",
"TMEM67",
"TRIM32",
"TTC21B",
"TTC8",
"WDR19",
"ZNF423",
"Congenital Hepatic Fibrosis",
"Overview"
] |
Congenital Hepatic Fibrosis Overview ─ RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Meral Gunay-Aygun, William A Gahl, Theo Heller
|
Summary Congenital hepatic fibrosis (CHF) is a developmental disorder of the portobiliary system characterized histologically by defective remodeling of the ductal plate (ductal plate malformation; DPM), abnormal branching of the intrahepatic portal veins, and progressive fibrosis of the portal tracts. CHF may or may not be associated with macroscopic cystic dilatation of the intrahepatic bile ducts. Clinical findings include enlarged, abnormally shaped liver, relatively well-preserved hepatocellular function, and portal hypertension (PH) resulting in splenomegaly, hypersplenism, and gastroesophageal varices. Pulmonary hypertension (portopulmonary hypertension) and vascular shunts in the pulmonary parenchyma (hepatopulmonary syndrome), complications of PH, can also be seen rarely. Most frequently CHF is associated with ciliopathies (disorders of the primary cilia) that have associated renal disease, the so-called hepatorenal fibrocystic diseases (FCDs). Although the hepatorenal FCDs are currently classified by phenotype, it is likely that gene-based classification will be quite different in the future because of the tremendous genetic and phenotypic overlap between these disorders. CHF is typically diagnosed by finding increased echogenicity of the liver parenchyma with or without macrocysts on ultrasound examination; MRI including magnetic resonance cholangiopancreatography (MRCP) may also be used. Liver biopsy is rarely required. The multisystem syndromes associated with hepatorenal FCDs are diagnosed by physical examination or other specialized studies, family history, and molecular genetic testing. The syndromes associated with CHF are most commonly inherited in an autosomal recessive manner; however, X-linked and autosomal dominant inheritance are also observed. Genetic counseling depends on accurate determination of the specific genetic diagnosis.
|
## Definition
Congenital hepatic fibrosis (CHF) is a histopathologic diagnosis that refers to a developmental disorder of the portobiliary system characterized by the following [
Defective remodeling of the ductal plate (ductal plate malformation; DPM)
Abnormal branching of the intrahepatic portal veins
Progressive fibrosis of the portal tracts
CHF without macroscopically visible cystic dilatations of the intrahepatic biliary ducts CHF associated with macroscopic liver cysts in continuity with the bile ducts, sometimes referred to as Caroli syndrome (CS)
Note: Caroli disease (CD), which is much rarer than CS, refers to liver cysts contiguous with the biliary tree without CHF [
Large and abnormally shaped liver with the left lobe palpable below the xiphoid and the right lobe typically non-palpable
Increased echogenicity of the liver parenchyma with or without macrocysts on ultrasound examination, often in the presence of relatively well-preserved hepatocellular function
Portal hypertension (PH) resulting in splenomegaly, hypersplenism, and gastroesophageal varices
Note: Although all individuals with CHF have DPM detectable by liver biopsy at birth, abnormal liver echogenicity and splenomegaly may not be detectable during early childhood because portal fibrosis and portal hypertension (PH) are time-dependent pathologies that develop and progress with age.
Other clinical features of CHF can include recurrent cholangitis, especially when CS is part of CHF.
The severity and rate of progression of CHF and its complications vary widely even within the same family.
In general, as hepatic fibrosis increases and PH worsens, the spleen increases in size, platelets and white blood cells decrease in number (hypersplenism), and porto-systemic vascular collaterals develop, including esophageal and gastric varices. As varices enlarge, the risk for bleeding increases [
Other complications of PH including ascites and encephalopathy are less common in CHF than in cirrhosis. Furthermore, individuals with CHF rarely manifest other systemic features associated with chronic liver disease, such as gynecomastia and enlarged parotid gland, with the exception of spider angiomata [
Although the liver disease in individuals with CHF/CS is usually asymptomatic, the risk is increased for cholangitis and, less commonly, biliary stone formation and cholangiocarcinoma, which can develop at a relatively young age [
No prospective studies of the natural history of CHF have been published. A recent thorough review of the literature evaluated a total of 1230 individuals with CHF who had been published in 155 articles [
Most other reports on the natural history of CHF include small numbers of individuals with advanced CHF and an undetermined type of renal disease. Whether the manifestations or rate of progression of CHF differ according to the associated genetic disorder has not been determined (see
Factors that could exacerbate or accelerate fibrosis include excessive alcohol intake, steatohepatitis, hepatotoxic medicines, and viral hepatitis.
Increased echogenicity of the liver;
Cysts in the hepatic parenchyma [
Enlarged spleen;
Accompanying fibrocystic changes in the kidneys.
Standard-resolution ultrasound examination is sufficient to evaluate the liver and spleen; in the authors' experience high-resolution ultrasound using a 5-7 MHz probe is superior to standard-resolution ultrasound to diagnose mild renal cystic disease [
Cystic or fusiform dilatations and irregularities of the intrahepatic bile ducts;
Abnormally large left lobe of the liver extending anteriorly under the xiphoid and to the left over the spleen;
Fusiform dilation of the extrahepatic bile ducts;
Elongation of the gall bladder;
Enlarged spleen, which can be quantified by calculating volume;
Accompanying fibrocystic changes in the kidneys.
Because of the common association of renal disease with CHF and CS, many individuals with CHF have already undergone a renal evaluation.
The ultrasound and MRI findings described are highly suggestive of CHF, especially in the context of the following renal findings, which comprise the hepatorenal fibrocystic diseases (FCDs):
Polycystic kidney disease (PKD). Inherited cystic degeneration of both kidneys associated with progressive decline in renal function and hypertension in most affected individuals.
Glomerulocystic kidney disease and diffuse cystic dysplastic kidneys
The spectrum of tubulointerstitial disorders that includes the following:
Nephronophthisis (NPHP), characterized by normal-size or small kidneys with increased echogenicity on renal ultrasound examination. Renal cysts typically occur after onset of end-stage renal disease (ESRD) and localize primarily at the corticomedullary junction. Before the onset of ESRD individuals with NPHP tend to maintain blood pressure in the normal range.
Chronic tubulointerstitial disease, characterized histologically by renal tubular atrophy and tubulointerstitial fibrosis with relative sparing of glomerular and vascular structures
Urine-concentrating defect, the earliest and mildest manifestation of kidney involvement in FCDs. The urine-concentrating defect results from abnormal regulation of free water absorption in the collecting ducts and manifests as polyuria and polydipsia.
Medullary sponge kidney. A radiologic term referring to microcystic dilatations of the renal collecting ducts observed on contrast imaging such as intravenous pyelography. A subset of individuals with medullary sponge kidney develop medullary nephrocalcinosis (radiologically demonstrable renal parenchymal calcification).
Note: Nephrocalcinosis is different from nephrolithiasis (renal stones), in which calcification is within the lumen of the collecting system or ureter.
Abundant, abnormally formed bile ducts in the portal tracts caused by an excess of embryonic bile duct structures remaining in their primitive ductal plate configuration [
Abnormal branching of the portal vein
Periportal fibrosis without inflammation
Portal-portal bridging fibrosis (i.e., not the portal tract to central vein bridging that is typical of cirrhosis)
Multiple bile duct hamartomas (von Meyenburg complexes) within dense fibrous stroma
Inspissated bile in the lumen of some ducts
Note: The hepatic parenchyma is normal without intrahepatic cholestasis or disruption of the hepatocellular plates.
Histopathologic findings on liver biopsy are the gold standard for diagnosis of CHF. However, liver biopsy is not required in most individuals (especially those with fibrocystic renal disease) because the diagnosis can be established on clinical findings alone [
Diseases of the bile ducts that can lead to cirrhosis include primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) [
In PBC the anti-mitochondrial antibody is positive in most individuals; this is not the case in CHF.
Like CHF, PSC is often associated with cholangitis. Furthermore, the bile duct strictures and dilations often seen in PSC may be mistaken for the dilated extrahepatic bile ducts of CHF and even the intrahepatic cysts of CHF.
Other causes of cirrhosis, such as viral hepatitis, alcohol-related liver disease, autoimmune hepatitis,
The hepatic cysts seen in autosomal dominant polycystic liver disease, a distinct genetic disorder, may also lead to PH, but they are not typically associated with CHF and can be distinguished from cysts associated with CHF by the large number of cysts and the extent of involvement of the hepatic parenchyma [
No prevalence data exist for CHF. However, based on the prevalence of various specific ciliopathies associated with CHF, the prevalence can be estimated at one in 10,000 to 20,000.
• Defective remodeling of the ductal plate (ductal plate malformation; DPM)
• Abnormal branching of the intrahepatic portal veins
• Progressive fibrosis of the portal tracts
• CHF without macroscopically visible cystic dilatations of the intrahepatic biliary ducts CHF associated with macroscopic liver cysts in continuity with the bile ducts, sometimes referred to as Caroli syndrome (CS)
• Note: Caroli disease (CD), which is much rarer than CS, refers to liver cysts contiguous with the biliary tree without CHF [
• Large and abnormally shaped liver with the left lobe palpable below the xiphoid and the right lobe typically non-palpable
• Increased echogenicity of the liver parenchyma with or without macrocysts on ultrasound examination, often in the presence of relatively well-preserved hepatocellular function
• Portal hypertension (PH) resulting in splenomegaly, hypersplenism, and gastroesophageal varices
• Increased echogenicity of the liver;
• Cysts in the hepatic parenchyma [
• Enlarged spleen;
• Accompanying fibrocystic changes in the kidneys.
• Cystic or fusiform dilatations and irregularities of the intrahepatic bile ducts;
• Abnormally large left lobe of the liver extending anteriorly under the xiphoid and to the left over the spleen;
• Fusiform dilation of the extrahepatic bile ducts;
• Elongation of the gall bladder;
• Enlarged spleen, which can be quantified by calculating volume;
• Accompanying fibrocystic changes in the kidneys.
• Polycystic kidney disease (PKD). Inherited cystic degeneration of both kidneys associated with progressive decline in renal function and hypertension in most affected individuals.
• Glomerulocystic kidney disease and diffuse cystic dysplastic kidneys
• The spectrum of tubulointerstitial disorders that includes the following:
• Nephronophthisis (NPHP), characterized by normal-size or small kidneys with increased echogenicity on renal ultrasound examination. Renal cysts typically occur after onset of end-stage renal disease (ESRD) and localize primarily at the corticomedullary junction. Before the onset of ESRD individuals with NPHP tend to maintain blood pressure in the normal range.
• Chronic tubulointerstitial disease, characterized histologically by renal tubular atrophy and tubulointerstitial fibrosis with relative sparing of glomerular and vascular structures
• Urine-concentrating defect, the earliest and mildest manifestation of kidney involvement in FCDs. The urine-concentrating defect results from abnormal regulation of free water absorption in the collecting ducts and manifests as polyuria and polydipsia.
• Nephronophthisis (NPHP), characterized by normal-size or small kidneys with increased echogenicity on renal ultrasound examination. Renal cysts typically occur after onset of end-stage renal disease (ESRD) and localize primarily at the corticomedullary junction. Before the onset of ESRD individuals with NPHP tend to maintain blood pressure in the normal range.
• Chronic tubulointerstitial disease, characterized histologically by renal tubular atrophy and tubulointerstitial fibrosis with relative sparing of glomerular and vascular structures
• Urine-concentrating defect, the earliest and mildest manifestation of kidney involvement in FCDs. The urine-concentrating defect results from abnormal regulation of free water absorption in the collecting ducts and manifests as polyuria and polydipsia.
• Medullary sponge kidney. A radiologic term referring to microcystic dilatations of the renal collecting ducts observed on contrast imaging such as intravenous pyelography. A subset of individuals with medullary sponge kidney develop medullary nephrocalcinosis (radiologically demonstrable renal parenchymal calcification).
• Note: Nephrocalcinosis is different from nephrolithiasis (renal stones), in which calcification is within the lumen of the collecting system or ureter.
• Nephronophthisis (NPHP), characterized by normal-size or small kidneys with increased echogenicity on renal ultrasound examination. Renal cysts typically occur after onset of end-stage renal disease (ESRD) and localize primarily at the corticomedullary junction. Before the onset of ESRD individuals with NPHP tend to maintain blood pressure in the normal range.
• Chronic tubulointerstitial disease, characterized histologically by renal tubular atrophy and tubulointerstitial fibrosis with relative sparing of glomerular and vascular structures
• Urine-concentrating defect, the earliest and mildest manifestation of kidney involvement in FCDs. The urine-concentrating defect results from abnormal regulation of free water absorption in the collecting ducts and manifests as polyuria and polydipsia.
• Abundant, abnormally formed bile ducts in the portal tracts caused by an excess of embryonic bile duct structures remaining in their primitive ductal plate configuration [
• Abnormal branching of the portal vein
• Periportal fibrosis without inflammation
• Portal-portal bridging fibrosis (i.e., not the portal tract to central vein bridging that is typical of cirrhosis)
• Multiple bile duct hamartomas (von Meyenburg complexes) within dense fibrous stroma
• Inspissated bile in the lumen of some ducts
• In PBC the anti-mitochondrial antibody is positive in most individuals; this is not the case in CHF.
• Like CHF, PSC is often associated with cholangitis. Furthermore, the bile duct strictures and dilations often seen in PSC may be mistaken for the dilated extrahepatic bile ducts of CHF and even the intrahepatic cysts of CHF.
## Clinical Manifestations of Congenital Hepatic Fibrosis
Congenital hepatic fibrosis (CHF) is a histopathologic diagnosis that refers to a developmental disorder of the portobiliary system characterized by the following [
Defective remodeling of the ductal plate (ductal plate malformation; DPM)
Abnormal branching of the intrahepatic portal veins
Progressive fibrosis of the portal tracts
CHF without macroscopically visible cystic dilatations of the intrahepatic biliary ducts CHF associated with macroscopic liver cysts in continuity with the bile ducts, sometimes referred to as Caroli syndrome (CS)
Note: Caroli disease (CD), which is much rarer than CS, refers to liver cysts contiguous with the biliary tree without CHF [
Large and abnormally shaped liver with the left lobe palpable below the xiphoid and the right lobe typically non-palpable
Increased echogenicity of the liver parenchyma with or without macrocysts on ultrasound examination, often in the presence of relatively well-preserved hepatocellular function
Portal hypertension (PH) resulting in splenomegaly, hypersplenism, and gastroesophageal varices
Note: Although all individuals with CHF have DPM detectable by liver biopsy at birth, abnormal liver echogenicity and splenomegaly may not be detectable during early childhood because portal fibrosis and portal hypertension (PH) are time-dependent pathologies that develop and progress with age.
Other clinical features of CHF can include recurrent cholangitis, especially when CS is part of CHF.
The severity and rate of progression of CHF and its complications vary widely even within the same family.
In general, as hepatic fibrosis increases and PH worsens, the spleen increases in size, platelets and white blood cells decrease in number (hypersplenism), and porto-systemic vascular collaterals develop, including esophageal and gastric varices. As varices enlarge, the risk for bleeding increases [
Other complications of PH including ascites and encephalopathy are less common in CHF than in cirrhosis. Furthermore, individuals with CHF rarely manifest other systemic features associated with chronic liver disease, such as gynecomastia and enlarged parotid gland, with the exception of spider angiomata [
Although the liver disease in individuals with CHF/CS is usually asymptomatic, the risk is increased for cholangitis and, less commonly, biliary stone formation and cholangiocarcinoma, which can develop at a relatively young age [
No prospective studies of the natural history of CHF have been published. A recent thorough review of the literature evaluated a total of 1230 individuals with CHF who had been published in 155 articles [
Most other reports on the natural history of CHF include small numbers of individuals with advanced CHF and an undetermined type of renal disease. Whether the manifestations or rate of progression of CHF differ according to the associated genetic disorder has not been determined (see
Factors that could exacerbate or accelerate fibrosis include excessive alcohol intake, steatohepatitis, hepatotoxic medicines, and viral hepatitis.
• Defective remodeling of the ductal plate (ductal plate malformation; DPM)
• Abnormal branching of the intrahepatic portal veins
• Progressive fibrosis of the portal tracts
• CHF without macroscopically visible cystic dilatations of the intrahepatic biliary ducts CHF associated with macroscopic liver cysts in continuity with the bile ducts, sometimes referred to as Caroli syndrome (CS)
• Note: Caroli disease (CD), which is much rarer than CS, refers to liver cysts contiguous with the biliary tree without CHF [
• Large and abnormally shaped liver with the left lobe palpable below the xiphoid and the right lobe typically non-palpable
• Increased echogenicity of the liver parenchyma with or without macrocysts on ultrasound examination, often in the presence of relatively well-preserved hepatocellular function
• Portal hypertension (PH) resulting in splenomegaly, hypersplenism, and gastroesophageal varices
## Establishing the Diagnosis of Congenital Hepatic Fibrosis
Increased echogenicity of the liver;
Cysts in the hepatic parenchyma [
Enlarged spleen;
Accompanying fibrocystic changes in the kidneys.
Standard-resolution ultrasound examination is sufficient to evaluate the liver and spleen; in the authors' experience high-resolution ultrasound using a 5-7 MHz probe is superior to standard-resolution ultrasound to diagnose mild renal cystic disease [
Cystic or fusiform dilatations and irregularities of the intrahepatic bile ducts;
Abnormally large left lobe of the liver extending anteriorly under the xiphoid and to the left over the spleen;
Fusiform dilation of the extrahepatic bile ducts;
Elongation of the gall bladder;
Enlarged spleen, which can be quantified by calculating volume;
Accompanying fibrocystic changes in the kidneys.
Because of the common association of renal disease with CHF and CS, many individuals with CHF have already undergone a renal evaluation.
The ultrasound and MRI findings described are highly suggestive of CHF, especially in the context of the following renal findings, which comprise the hepatorenal fibrocystic diseases (FCDs):
Polycystic kidney disease (PKD). Inherited cystic degeneration of both kidneys associated with progressive decline in renal function and hypertension in most affected individuals.
Glomerulocystic kidney disease and diffuse cystic dysplastic kidneys
The spectrum of tubulointerstitial disorders that includes the following:
Nephronophthisis (NPHP), characterized by normal-size or small kidneys with increased echogenicity on renal ultrasound examination. Renal cysts typically occur after onset of end-stage renal disease (ESRD) and localize primarily at the corticomedullary junction. Before the onset of ESRD individuals with NPHP tend to maintain blood pressure in the normal range.
Chronic tubulointerstitial disease, characterized histologically by renal tubular atrophy and tubulointerstitial fibrosis with relative sparing of glomerular and vascular structures
Urine-concentrating defect, the earliest and mildest manifestation of kidney involvement in FCDs. The urine-concentrating defect results from abnormal regulation of free water absorption in the collecting ducts and manifests as polyuria and polydipsia.
Medullary sponge kidney. A radiologic term referring to microcystic dilatations of the renal collecting ducts observed on contrast imaging such as intravenous pyelography. A subset of individuals with medullary sponge kidney develop medullary nephrocalcinosis (radiologically demonstrable renal parenchymal calcification).
Note: Nephrocalcinosis is different from nephrolithiasis (renal stones), in which calcification is within the lumen of the collecting system or ureter.
Abundant, abnormally formed bile ducts in the portal tracts caused by an excess of embryonic bile duct structures remaining in their primitive ductal plate configuration [
Abnormal branching of the portal vein
Periportal fibrosis without inflammation
Portal-portal bridging fibrosis (i.e., not the portal tract to central vein bridging that is typical of cirrhosis)
Multiple bile duct hamartomas (von Meyenburg complexes) within dense fibrous stroma
Inspissated bile in the lumen of some ducts
Note: The hepatic parenchyma is normal without intrahepatic cholestasis or disruption of the hepatocellular plates.
Histopathologic findings on liver biopsy are the gold standard for diagnosis of CHF. However, liver biopsy is not required in most individuals (especially those with fibrocystic renal disease) because the diagnosis can be established on clinical findings alone [
• Increased echogenicity of the liver;
• Cysts in the hepatic parenchyma [
• Enlarged spleen;
• Accompanying fibrocystic changes in the kidneys.
• Cystic or fusiform dilatations and irregularities of the intrahepatic bile ducts;
• Abnormally large left lobe of the liver extending anteriorly under the xiphoid and to the left over the spleen;
• Fusiform dilation of the extrahepatic bile ducts;
• Elongation of the gall bladder;
• Enlarged spleen, which can be quantified by calculating volume;
• Accompanying fibrocystic changes in the kidneys.
• Polycystic kidney disease (PKD). Inherited cystic degeneration of both kidneys associated with progressive decline in renal function and hypertension in most affected individuals.
• Glomerulocystic kidney disease and diffuse cystic dysplastic kidneys
• The spectrum of tubulointerstitial disorders that includes the following:
• Nephronophthisis (NPHP), characterized by normal-size or small kidneys with increased echogenicity on renal ultrasound examination. Renal cysts typically occur after onset of end-stage renal disease (ESRD) and localize primarily at the corticomedullary junction. Before the onset of ESRD individuals with NPHP tend to maintain blood pressure in the normal range.
• Chronic tubulointerstitial disease, characterized histologically by renal tubular atrophy and tubulointerstitial fibrosis with relative sparing of glomerular and vascular structures
• Urine-concentrating defect, the earliest and mildest manifestation of kidney involvement in FCDs. The urine-concentrating defect results from abnormal regulation of free water absorption in the collecting ducts and manifests as polyuria and polydipsia.
• Nephronophthisis (NPHP), characterized by normal-size or small kidneys with increased echogenicity on renal ultrasound examination. Renal cysts typically occur after onset of end-stage renal disease (ESRD) and localize primarily at the corticomedullary junction. Before the onset of ESRD individuals with NPHP tend to maintain blood pressure in the normal range.
• Chronic tubulointerstitial disease, characterized histologically by renal tubular atrophy and tubulointerstitial fibrosis with relative sparing of glomerular and vascular structures
• Urine-concentrating defect, the earliest and mildest manifestation of kidney involvement in FCDs. The urine-concentrating defect results from abnormal regulation of free water absorption in the collecting ducts and manifests as polyuria and polydipsia.
• Medullary sponge kidney. A radiologic term referring to microcystic dilatations of the renal collecting ducts observed on contrast imaging such as intravenous pyelography. A subset of individuals with medullary sponge kidney develop medullary nephrocalcinosis (radiologically demonstrable renal parenchymal calcification).
• Note: Nephrocalcinosis is different from nephrolithiasis (renal stones), in which calcification is within the lumen of the collecting system or ureter.
• Nephronophthisis (NPHP), characterized by normal-size or small kidneys with increased echogenicity on renal ultrasound examination. Renal cysts typically occur after onset of end-stage renal disease (ESRD) and localize primarily at the corticomedullary junction. Before the onset of ESRD individuals with NPHP tend to maintain blood pressure in the normal range.
• Chronic tubulointerstitial disease, characterized histologically by renal tubular atrophy and tubulointerstitial fibrosis with relative sparing of glomerular and vascular structures
• Urine-concentrating defect, the earliest and mildest manifestation of kidney involvement in FCDs. The urine-concentrating defect results from abnormal regulation of free water absorption in the collecting ducts and manifests as polyuria and polydipsia.
• Abundant, abnormally formed bile ducts in the portal tracts caused by an excess of embryonic bile duct structures remaining in their primitive ductal plate configuration [
• Abnormal branching of the portal vein
• Periportal fibrosis without inflammation
• Portal-portal bridging fibrosis (i.e., not the portal tract to central vein bridging that is typical of cirrhosis)
• Multiple bile duct hamartomas (von Meyenburg complexes) within dense fibrous stroma
• Inspissated bile in the lumen of some ducts
## Differential Diagnosis of Congenital Hepatic Fibrosis
Diseases of the bile ducts that can lead to cirrhosis include primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) [
In PBC the anti-mitochondrial antibody is positive in most individuals; this is not the case in CHF.
Like CHF, PSC is often associated with cholangitis. Furthermore, the bile duct strictures and dilations often seen in PSC may be mistaken for the dilated extrahepatic bile ducts of CHF and even the intrahepatic cysts of CHF.
Other causes of cirrhosis, such as viral hepatitis, alcohol-related liver disease, autoimmune hepatitis,
The hepatic cysts seen in autosomal dominant polycystic liver disease, a distinct genetic disorder, may also lead to PH, but they are not typically associated with CHF and can be distinguished from cysts associated with CHF by the large number of cysts and the extent of involvement of the hepatic parenchyma [
• In PBC the anti-mitochondrial antibody is positive in most individuals; this is not the case in CHF.
• Like CHF, PSC is often associated with cholangitis. Furthermore, the bile duct strictures and dilations often seen in PSC may be mistaken for the dilated extrahepatic bile ducts of CHF and even the intrahepatic cysts of CHF.
## Prevalence of the Congenital Hepatic Fibrosis
No prevalence data exist for CHF. However, based on the prevalence of various specific ciliopathies associated with CHF, the prevalence can be estimated at one in 10,000 to 20,000.
## Causes of Congenital Hepatic Fibrosis
Congenital hepatic fibrosis/Caroli syndrome (CHF/CS) can rarely be an isolated finding; the gene(s) in which mutation causes isolated CFF/CS are unknown.
Most frequently CHF/CS is associated with ciliopathies (disorders of the primary cilia) that have associated renal disease: PKD, NPHP, and chronic tubulointerstitial disease, collectively referred to as the hepatorenal FCDs [
The ciliopathies are caused by defects of proteins that reside on the cilia or its basal body structures [
The hepatorenal FCDs are discussed in
Renal ultrasound examination shows normal size or small kidneys with increased echogenicity. In rare cases of infantile NPHP, kidney size may be enlarged. Renal cysts in NPHP are secondary, typically occurring after ESRD develops and localizing primarily at the corticomedullary junction.
Joubert syndrome is characterized by three primary findings: a distinctive cerebellar and brain stem malformation (the molar tooth sign [MTS]), hypotonia, and developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. The designation Joubert syndrome and related disorders (JSRD) is used to describe individuals with JS who have additional findings including retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen. Some individuals with JSRD have clinically symptomatic CHF. Joubert syndrome is genetically heterozygous, with more than 20 genes identified to date.
The term
JSRDs include:
COACH syndrome. COACH is a mnemonic for
Senior-Løken syndrome. Severe retinal degeneration with NPHP. Senior-Løken syndrome is characterized by NPHP and severe retinal degeneration.
Note: Sometimes the severe retinal degeneration of Senior-Løken syndrome is erroneously attributed to
Oral. Lobed tongue, hamartomas or lipomas of the tongue, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities
Facial. Widely spaced eyes or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia
Digital. Brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger; duplicated hallux (great toe); preaxial or postaxial polydactyly of the hands
Brain. Intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation
Kidney. Polycystic kidney disease
Liver/pancreas. Cystic abnormalities of intrahepatic biliary system and pancreatic cysts [
As many as 50% of individuals with OFD1 have some degree of intellectual disability, which is usually mild. Almost all affected individuals are female. However, males with OFD1 have been described, mostly as malformed fetuses delivered by women with OFD1.
The prevalence of liver cysts, the most common extrarenal manifestation of ADPKD, increases with age and may have been underestimated by ultrasound and CT studies. The prevalence of intracranial aneurysms is higher in those with a positive family history of aneurysms or subarachnoid hemorrhage (22%) than in those without such a family history (6%). Mitral valve prolapse, the most common valvular abnormality, occurs in up to 25% of affected individuals. Substantial variability in severity of renal disease and other extrarenal manifestations occurs even within the same family.
In ADPKD hepatic cysts are not usually associated with CHF or PH; however, 19 affected individuals from 14 families with ADPKD have well-documented CHF and PH [
Molecular Genetics of the Hepatorenal Fibrocystic Diseases
AD = autosomal dominant; ADPKD = autosomal dominant polycystic kidney disease; AR = autosomal recessive; ARPKD = autosomal recessive polycystic kidney disease; MOI = mode of inheritance; XL = X-linked
See
Locus names for
Locus names for
Locus names for
See
Locus names for
See
Locus names for
See
The most common phenotypic features of the hepatorenal FCDs are described here. Although each of the hepatorenal FCDs has distinct features, the clinical findings and the associated genes overlap in several (see
CHF is a constant finding in ARPKD and MKS; it occurs with variable frequencies in JSRDs, BBS, OFD1, EVC, JATD, and RHPD.
Developmental abnormalities of the mid/hindbrain that range from Dandy-Walker variant/mega cisterna magna to occipital encephalocele (as in JSRDs and MKS) are the second most common manifestation in the hepatorenal FCDs [
Retinal degeneration, resulting from involvement of the connecting cilia of the photoreceptor cells that are specialized primary cilia of the retina, is a common manifestation of the hepatorenal fibrocystic diseases [
Polydactyly, seen with variable frequencies in many ciliopathies including MKS, BBS, OFD1, and JSRDs, is mostly postaxial and can involve upper and lower extremities.
Right-left sidedness defects (lateralization defects,
Currently, the hepatorenal FCDs are classified by phenotype; however, because of tremendous phenotypic and genetic overlap (see
Furthermore, the large proportion of individuals with a ciliopathy (e.g., NPHP and JSRDs) with only one identified pathogenic variant and the extreme variability of the phenotype associated with pathogenic variants in some genes (e.g.,
• COACH syndrome. COACH is a mnemonic for
• Senior-Løken syndrome. Severe retinal degeneration with NPHP. Senior-Løken syndrome is characterized by NPHP and severe retinal degeneration.
• Note: Sometimes the severe retinal degeneration of Senior-Løken syndrome is erroneously attributed to
• Oral. Lobed tongue, hamartomas or lipomas of the tongue, cleft of the hard or soft palate, accessory gingival frenulae, hypodontia, and other dental abnormalities
• Facial. Widely spaced eyes or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia
• Digital. Brachydactyly, syndactyly of varying degrees, and clinodactyly of the fifth finger; duplicated hallux (great toe); preaxial or postaxial polydactyly of the hands
• Brain. Intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation
• Kidney. Polycystic kidney disease
• Liver/pancreas. Cystic abnormalities of intrahepatic biliary system and pancreatic cysts [
• CHF is a constant finding in ARPKD and MKS; it occurs with variable frequencies in JSRDs, BBS, OFD1, EVC, JATD, and RHPD.
• Developmental abnormalities of the mid/hindbrain that range from Dandy-Walker variant/mega cisterna magna to occipital encephalocele (as in JSRDs and MKS) are the second most common manifestation in the hepatorenal FCDs [
• Retinal degeneration, resulting from involvement of the connecting cilia of the photoreceptor cells that are specialized primary cilia of the retina, is a common manifestation of the hepatorenal fibrocystic diseases [
• Polydactyly, seen with variable frequencies in many ciliopathies including MKS, BBS, OFD1, and JSRDs, is mostly postaxial and can involve upper and lower extremities.
• Right-left sidedness defects (lateralization defects,
## Phenotypic Features Shared by the Hepatorenal Fibrocystic Diseases
The most common phenotypic features of the hepatorenal FCDs are described here. Although each of the hepatorenal FCDs has distinct features, the clinical findings and the associated genes overlap in several (see
CHF is a constant finding in ARPKD and MKS; it occurs with variable frequencies in JSRDs, BBS, OFD1, EVC, JATD, and RHPD.
Developmental abnormalities of the mid/hindbrain that range from Dandy-Walker variant/mega cisterna magna to occipital encephalocele (as in JSRDs and MKS) are the second most common manifestation in the hepatorenal FCDs [
Retinal degeneration, resulting from involvement of the connecting cilia of the photoreceptor cells that are specialized primary cilia of the retina, is a common manifestation of the hepatorenal fibrocystic diseases [
Polydactyly, seen with variable frequencies in many ciliopathies including MKS, BBS, OFD1, and JSRDs, is mostly postaxial and can involve upper and lower extremities.
Right-left sidedness defects (lateralization defects,
Currently, the hepatorenal FCDs are classified by phenotype; however, because of tremendous phenotypic and genetic overlap (see
Furthermore, the large proportion of individuals with a ciliopathy (e.g., NPHP and JSRDs) with only one identified pathogenic variant and the extreme variability of the phenotype associated with pathogenic variants in some genes (e.g.,
• CHF is a constant finding in ARPKD and MKS; it occurs with variable frequencies in JSRDs, BBS, OFD1, EVC, JATD, and RHPD.
• Developmental abnormalities of the mid/hindbrain that range from Dandy-Walker variant/mega cisterna magna to occipital encephalocele (as in JSRDs and MKS) are the second most common manifestation in the hepatorenal FCDs [
• Retinal degeneration, resulting from involvement of the connecting cilia of the photoreceptor cells that are specialized primary cilia of the retina, is a common manifestation of the hepatorenal fibrocystic diseases [
• Polydactyly, seen with variable frequencies in many ciliopathies including MKS, BBS, OFD1, and JSRDs, is mostly postaxial and can involve upper and lower extremities.
• Right-left sidedness defects (lateralization defects,
## Genotype-Phenotype Correlations
## Evaluation Strategy
Once the diagnosis of congenital hepatic fibrosis (CHF) has been established in a proband, the following approach can be used to determine the specific cause of the CHF to aid in discussions of prognosis and genetic counseling.
Attention to a history of consanguinity and medical problems in sibs and evaluation of any unusual findings in sibs may clarify if one of the autosomal recessive disorders discussed in
If an autosomal recessive syndrome is not identified in the proband and/or the findings and/or family history suggest autosomal dominant inheritance, ultrasound examination of parents and sibs to evaluate for the presence of asymptomatic kidney and/or liver disease characteristic of ADPKD is useful even in the absence of a positive family history.
Other evaluations including kidney function tests, echocardiogram, skeletal survey, complete eye examination, and brain MRI may be useful to establish the specific hepatorenal fibrocystic disease associated with CHF based on the abnormalities identified on family history and physical examination.
In typical ARPKD/CHF, the diagnosis is often made on clinical findings; however, molecular genetic testing of
In individuals with MKS who are of European origin, testing for the 29-bp IVS15-7_35 deletion in
For an introduction to multigene panels click
• Attention to a history of consanguinity and medical problems in sibs and evaluation of any unusual findings in sibs may clarify if one of the autosomal recessive disorders discussed in
• If an autosomal recessive syndrome is not identified in the proband and/or the findings and/or family history suggest autosomal dominant inheritance, ultrasound examination of parents and sibs to evaluate for the presence of asymptomatic kidney and/or liver disease characteristic of ADPKD is useful even in the absence of a positive family history.
## Testing
Other evaluations including kidney function tests, echocardiogram, skeletal survey, complete eye examination, and brain MRI may be useful to establish the specific hepatorenal fibrocystic disease associated with CHF based on the abnormalities identified on family history and physical examination.
In typical ARPKD/CHF, the diagnosis is often made on clinical findings; however, molecular genetic testing of
In individuals with MKS who are of European origin, testing for the 29-bp IVS15-7_35 deletion in
For an introduction to multigene panels click
## Genetic Counseling
The syndromes associated with congenital hepatic fibrosis (CHF) can be inherited as a multisystem disorder in an autosomal dominant, autosomal recessive, or X-linked recessive manner. Genetic counseling depends on accurate determination of the specific genetic diagnosis.
CHF is rarely an isolated finding; the gene(s) in which mutation resulting in isolated CHF occurs are unknown.
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
The echogenicity of the fetal liver in individuals with the hepatorenal FCDs discussed in this
In most cases of hepatorenal FCDs, prenatal ultrasound examination is more likely to show findings associated with renal disease than with liver disease (including hyperechoic kidneys that are either enlarged or normal size and oligohydramnios) or to show findings of associated malformations such as polydactyly, posterior encephalocele, cerebellar hypoplasia, or other central nervous system anomalies, oral clefts, or abnormalities of bone growth.
In rare instances of prenatal onset of CS, fetal liver cysts can be visualized on ultrasound examination.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The echogenicity of the fetal liver in individuals with the hepatorenal FCDs discussed in this
• In most cases of hepatorenal FCDs, prenatal ultrasound examination is more likely to show findings associated with renal disease than with liver disease (including hyperechoic kidneys that are either enlarged or normal size and oligohydramnios) or to show findings of associated malformations such as polydactyly, posterior encephalocele, cerebellar hypoplasia, or other central nervous system anomalies, oral clefts, or abnormalities of bone growth.
• In rare instances of prenatal onset of CS, fetal liver cysts can be visualized on ultrasound examination.
## Mode of Inheritance
The syndromes associated with congenital hepatic fibrosis (CHF) can be inherited as a multisystem disorder in an autosomal dominant, autosomal recessive, or X-linked recessive manner. Genetic counseling depends on accurate determination of the specific genetic diagnosis.
CHF is rarely an isolated finding; the gene(s) in which mutation resulting in isolated CHF occurs are unknown.
## Empiric Risks to Family Members – Isolated CHF
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Prenatal Testing and Preimplantation Genetic Testing
The echogenicity of the fetal liver in individuals with the hepatorenal FCDs discussed in this
In most cases of hepatorenal FCDs, prenatal ultrasound examination is more likely to show findings associated with renal disease than with liver disease (including hyperechoic kidneys that are either enlarged or normal size and oligohydramnios) or to show findings of associated malformations such as polydactyly, posterior encephalocele, cerebellar hypoplasia, or other central nervous system anomalies, oral clefts, or abnormalities of bone growth.
In rare instances of prenatal onset of CS, fetal liver cysts can be visualized on ultrasound examination.
• The echogenicity of the fetal liver in individuals with the hepatorenal FCDs discussed in this
• In most cases of hepatorenal FCDs, prenatal ultrasound examination is more likely to show findings associated with renal disease than with liver disease (including hyperechoic kidneys that are either enlarged or normal size and oligohydramnios) or to show findings of associated malformations such as polydactyly, posterior encephalocele, cerebellar hypoplasia, or other central nervous system anomalies, oral clefts, or abnormalities of bone growth.
• In rare instances of prenatal onset of CS, fetal liver cysts can be visualized on ultrasound examination.
## Resources
PO Box 70
Kirkwood PA 17536
75 Maiden Lane
Suite 603
New York NY 10038
36 Great Charles Street
Birmingham B3 3JY
United Kingdom
•
• PO Box 70
• Kirkwood PA 17536
•
•
• 75 Maiden Lane
• Suite 603
• New York NY 10038
•
•
• 36 Great Charles Street
• Birmingham B3 3JY
• United Kingdom
•
## Management
To establish the extent of disease and needs in an individual diagnosed with congenital hepatic fibrosis (CHF), the following evaluations are recommended:
Complete blood count, hepatic panel, and coagulation profile and ultrasound examination to identify mild, moderate, or severe portal hypertension (PH), hypersplenism, and biliary tree abnormalities [
Esophago-gastro-duodenoscopy (EGD) to screen for varices, particularly when the platelet count has decreased significantly over time or prior to interventions such as renal transplantation [
Screening for hepatopulmonary syndrome by measuring upright oxygen saturation and screening for portopulmonary hypertension with echocardiogram to estimate pulmonary artery pressure [
Consultation with a clinical geneticist and/or genetic counselor
There is no known treatment for the underlying defect in CHF: no therapies can repair the primary ductal plate malformation or reverse the fibrosis or biliary tree abnormalities. Therapies based on extrapolations from other forms of liver disease, anecdotal reports, and deductive reasoning are used to manage the complications of the underlying defect [
The most important manifestations of CHF are variceal bleeding, hypersplenism, cholangitis and, to a lesser extent, biliary stones, cholangiocarcinoma, and hepatocellular carcinoma.
Primary prevention (prior to any variceal bleeding) entails screening for varices and treating medium or large varices with nonselective beta blockers with the dose titrated to pulse and blood pressure. If beta blockers are not tolerated, variceal banding should be considered. Management in children is not as well defined as in adults. Affected children should be referred to tertiary centers with experience in the management of varices in children.
Standard procedures for management of variceal bleeding include obtaining adequate initial intravenous access, resuscitation, transfusion without over transfusion, octreotide, antibiotic prophylaxis, proton pump inhibition, and endoscopy when stabilized.
Secondary prevention of variceal bleeding (once bleeding has already occurred) consists of banding of esophageal varices, histacryl injection of gastric varices, and continued use of nonselective beta blockers. Because banding devices do not fit on the smallest endoscopes, small children with variceal bleeding often undergo sclerotherapy instead.
Individuals who have had repeated variceal bleeding (especially if gastric varices are present) should be considered for surgical portosystemic shunting rather than repeated variceal ligation [
Although controversial, consideration of a surgical shunt in an individual with CHF who has never had variceal bleeding may be reasonable if PH is likely to progress and liver transplantation is unlikely given the intact hepatic synthetic function in certain settings. For example, a surgical shunt would be a strong consideration in an individual with large varices that have never bled if appropriate expert care is not available for emergent management of variceal bleeding.
Transjugular intrahepatic portosystemic shunts (TIPS) are widely available. However, it is the authors' opinion that use of TIPS is not indicated outside of an emergency; because of their intrinsic occlusion rate, particularly when considered over long periods of time, TIPS may require repeated procedures to maintain adequate patency. Furthermore, the intravenous contrast often utilized to assess and perform TIPS revisions is potentially nephrotoxic – a serious consideration given the typical association of CHF with ARPKD.
Splenectomy is contraindicated because it does not treat the underlying PH and often exacerbates it.
Cholangitis is best treated with rapid institution of appropriate antibiotics.
Segmental resection of the liver is a controversial option for individuals with segmental bile duct abnormalities who have had repeated episodes of cholangitis [
Recurrent cholangitis with or without more widespread bile duct abnormalities is best treated with liver transplantation. If cysts in the extrahepatic bile duct are complicated by recurrent infection and/or the presence of stones, excision of the common bile duct with a Roux-en-Y hepatojejunal anastomosis has been recommended.
The CDC (Centers for Disease Control) recommends immunization for hepatitis A and B in persons with chronic liver disease.
Although evidence is lacking, antibiotic prophylaxis for recurrent cholangitis is sometimes used in individuals who have had cholangitis [
General health should be closely followed. Decreased growth rate should be investigated as it is less likely to be the result of PH than of other associated problems, such as reduced renal function.
Extrapolating from studies in persons with cirrhosis, individuals with CHF should be screened for esophageal varices particularly when the platelet count decreases significantly over time or prior to interventions such as renal transplantation [
Small varices warrant a repeat esophago-gastro-duodenoscopy (EGD) in a year.
If no varices are identified when EGD is performed because of a decline in platelet count, EGD should be repeated every two to three years.
Screening for hepatopulmonary syndrome is achieved by measuring upright oxygen saturation; screening for portopulmonary hypertension is performed with echocardiogram to estimate pulmonary artery pressure [
Imaging allows for:
Assessment of spleen size to indirectly follow PH;
Visualization of bile duct abnormalities (e.g. cysts in the liver) that could identify individuals at greater risk for cholangitis, bile duct stones, and cholangiocarcinoma.
The appropriate frequency of surveillance imaging is not well defined, and depends on disease severity. For individuals with mild disease, ultrasound examination every two years would be adequate; for those with more severe disease, an annual ultrasound examination could enable adequate monitoring of disease progression.
Note: No data on surveillance for cholangiocarcinoma or hepatocellular carcinoma in this setting are available. However, the incidence in children is thought to be extremely rare (see Definition,
The following agents/illnesses known to accelerate hepatic fibrosis could have the same effect in CHF and should be avoided or aggressively managed:
Alcohol
Obesity
Diabetes mellitus
Malnutrition
Infection with human immunodeficiency virus (HIV)
Immunosuppression (e.g., after renal transplantation)
Hepatotoxic medicines should be avoided.
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in those with varices because of the risk of gastrointestinal bleeding and poor clotting as a result of impaired platelet function.
Behavior that could increase the risk of viral hepatitis should be avoided.
Contact sports, or activities that are likely to result in splenic injury, are to be avoided once the spleen is significantly enlarged.
Although there are theoretic reasons why choleretics such as ursodeoxycholate may impede the development of abnormalities of the bile ducts, or even fibrosis, this has not been proven [
Search
• Complete blood count, hepatic panel, and coagulation profile and ultrasound examination to identify mild, moderate, or severe portal hypertension (PH), hypersplenism, and biliary tree abnormalities [
• Esophago-gastro-duodenoscopy (EGD) to screen for varices, particularly when the platelet count has decreased significantly over time or prior to interventions such as renal transplantation [
• Screening for hepatopulmonary syndrome by measuring upright oxygen saturation and screening for portopulmonary hypertension with echocardiogram to estimate pulmonary artery pressure [
• Consultation with a clinical geneticist and/or genetic counselor
• Small varices warrant a repeat esophago-gastro-duodenoscopy (EGD) in a year.
• If no varices are identified when EGD is performed because of a decline in platelet count, EGD should be repeated every two to three years.
• Assessment of spleen size to indirectly follow PH;
• Visualization of bile duct abnormalities (e.g. cysts in the liver) that could identify individuals at greater risk for cholangitis, bile duct stones, and cholangiocarcinoma.
• Alcohol
• Obesity
• Diabetes mellitus
• Malnutrition
• Infection with human immunodeficiency virus (HIV)
• Immunosuppression (e.g., after renal transplantation)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with congenital hepatic fibrosis (CHF), the following evaluations are recommended:
Complete blood count, hepatic panel, and coagulation profile and ultrasound examination to identify mild, moderate, or severe portal hypertension (PH), hypersplenism, and biliary tree abnormalities [
Esophago-gastro-duodenoscopy (EGD) to screen for varices, particularly when the platelet count has decreased significantly over time or prior to interventions such as renal transplantation [
Screening for hepatopulmonary syndrome by measuring upright oxygen saturation and screening for portopulmonary hypertension with echocardiogram to estimate pulmonary artery pressure [
Consultation with a clinical geneticist and/or genetic counselor
• Complete blood count, hepatic panel, and coagulation profile and ultrasound examination to identify mild, moderate, or severe portal hypertension (PH), hypersplenism, and biliary tree abnormalities [
• Esophago-gastro-duodenoscopy (EGD) to screen for varices, particularly when the platelet count has decreased significantly over time or prior to interventions such as renal transplantation [
• Screening for hepatopulmonary syndrome by measuring upright oxygen saturation and screening for portopulmonary hypertension with echocardiogram to estimate pulmonary artery pressure [
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
There is no known treatment for the underlying defect in CHF: no therapies can repair the primary ductal plate malformation or reverse the fibrosis or biliary tree abnormalities. Therapies based on extrapolations from other forms of liver disease, anecdotal reports, and deductive reasoning are used to manage the complications of the underlying defect [
The most important manifestations of CHF are variceal bleeding, hypersplenism, cholangitis and, to a lesser extent, biliary stones, cholangiocarcinoma, and hepatocellular carcinoma.
Primary prevention (prior to any variceal bleeding) entails screening for varices and treating medium or large varices with nonselective beta blockers with the dose titrated to pulse and blood pressure. If beta blockers are not tolerated, variceal banding should be considered. Management in children is not as well defined as in adults. Affected children should be referred to tertiary centers with experience in the management of varices in children.
Standard procedures for management of variceal bleeding include obtaining adequate initial intravenous access, resuscitation, transfusion without over transfusion, octreotide, antibiotic prophylaxis, proton pump inhibition, and endoscopy when stabilized.
Secondary prevention of variceal bleeding (once bleeding has already occurred) consists of banding of esophageal varices, histacryl injection of gastric varices, and continued use of nonselective beta blockers. Because banding devices do not fit on the smallest endoscopes, small children with variceal bleeding often undergo sclerotherapy instead.
Individuals who have had repeated variceal bleeding (especially if gastric varices are present) should be considered for surgical portosystemic shunting rather than repeated variceal ligation [
Although controversial, consideration of a surgical shunt in an individual with CHF who has never had variceal bleeding may be reasonable if PH is likely to progress and liver transplantation is unlikely given the intact hepatic synthetic function in certain settings. For example, a surgical shunt would be a strong consideration in an individual with large varices that have never bled if appropriate expert care is not available for emergent management of variceal bleeding.
Transjugular intrahepatic portosystemic shunts (TIPS) are widely available. However, it is the authors' opinion that use of TIPS is not indicated outside of an emergency; because of their intrinsic occlusion rate, particularly when considered over long periods of time, TIPS may require repeated procedures to maintain adequate patency. Furthermore, the intravenous contrast often utilized to assess and perform TIPS revisions is potentially nephrotoxic – a serious consideration given the typical association of CHF with ARPKD.
Splenectomy is contraindicated because it does not treat the underlying PH and often exacerbates it.
Cholangitis is best treated with rapid institution of appropriate antibiotics.
Segmental resection of the liver is a controversial option for individuals with segmental bile duct abnormalities who have had repeated episodes of cholangitis [
Recurrent cholangitis with or without more widespread bile duct abnormalities is best treated with liver transplantation. If cysts in the extrahepatic bile duct are complicated by recurrent infection and/or the presence of stones, excision of the common bile duct with a Roux-en-Y hepatojejunal anastomosis has been recommended.
## Prevention of Secondary Complications
The CDC (Centers for Disease Control) recommends immunization for hepatitis A and B in persons with chronic liver disease.
Although evidence is lacking, antibiotic prophylaxis for recurrent cholangitis is sometimes used in individuals who have had cholangitis [
## Surveillance
General health should be closely followed. Decreased growth rate should be investigated as it is less likely to be the result of PH than of other associated problems, such as reduced renal function.
Extrapolating from studies in persons with cirrhosis, individuals with CHF should be screened for esophageal varices particularly when the platelet count decreases significantly over time or prior to interventions such as renal transplantation [
Small varices warrant a repeat esophago-gastro-duodenoscopy (EGD) in a year.
If no varices are identified when EGD is performed because of a decline in platelet count, EGD should be repeated every two to three years.
Screening for hepatopulmonary syndrome is achieved by measuring upright oxygen saturation; screening for portopulmonary hypertension is performed with echocardiogram to estimate pulmonary artery pressure [
Imaging allows for:
Assessment of spleen size to indirectly follow PH;
Visualization of bile duct abnormalities (e.g. cysts in the liver) that could identify individuals at greater risk for cholangitis, bile duct stones, and cholangiocarcinoma.
The appropriate frequency of surveillance imaging is not well defined, and depends on disease severity. For individuals with mild disease, ultrasound examination every two years would be adequate; for those with more severe disease, an annual ultrasound examination could enable adequate monitoring of disease progression.
Note: No data on surveillance for cholangiocarcinoma or hepatocellular carcinoma in this setting are available. However, the incidence in children is thought to be extremely rare (see Definition,
• Small varices warrant a repeat esophago-gastro-duodenoscopy (EGD) in a year.
• If no varices are identified when EGD is performed because of a decline in platelet count, EGD should be repeated every two to three years.
• Assessment of spleen size to indirectly follow PH;
• Visualization of bile duct abnormalities (e.g. cysts in the liver) that could identify individuals at greater risk for cholangitis, bile duct stones, and cholangiocarcinoma.
## Agents/Circumstances to Avoid
The following agents/illnesses known to accelerate hepatic fibrosis could have the same effect in CHF and should be avoided or aggressively managed:
Alcohol
Obesity
Diabetes mellitus
Malnutrition
Infection with human immunodeficiency virus (HIV)
Immunosuppression (e.g., after renal transplantation)
Hepatotoxic medicines should be avoided.
Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in those with varices because of the risk of gastrointestinal bleeding and poor clotting as a result of impaired platelet function.
Behavior that could increase the risk of viral hepatitis should be avoided.
Contact sports, or activities that are likely to result in splenic injury, are to be avoided once the spleen is significantly enlarged.
• Alcohol
• Obesity
• Diabetes mellitus
• Malnutrition
• Infection with human immunodeficiency virus (HIV)
• Immunosuppression (e.g., after renal transplantation)
## Therapies Under Investigation
Although there are theoretic reasons why choleretics such as ursodeoxycholate may impede the development of abnormalities of the bile ducts, or even fibrosis, this has not been proven [
Search
## References
## Literature Cited
## Chapter Notes
The authors thank the ARPKD/CHF Alliance, The Joubert Syndrome & Related Cerebellar Disorders Foundation, and all patients and their families who generously participated in the ongoing NIH research protocol on ARPKD/CHF and other ciliopathies (
14 May 2020 (ma) Retired chapter: histologic diagnosis without strong genetic correlation
24 April 2014 (me) Comprehensive update posted live
9 December 2008 (me) Review posted live
25 July 2008 (mga) Original submission
• 14 May 2020 (ma) Retired chapter: histologic diagnosis without strong genetic correlation
• 24 April 2014 (me) Comprehensive update posted live
• 9 December 2008 (me) Review posted live
• 25 July 2008 (mga) Original submission
## Acknowledgments
The authors thank the ARPKD/CHF Alliance, The Joubert Syndrome & Related Cerebellar Disorders Foundation, and all patients and their families who generously participated in the ongoing NIH research protocol on ARPKD/CHF and other ciliopathies (
## Revision History
14 May 2020 (ma) Retired chapter: histologic diagnosis without strong genetic correlation
24 April 2014 (me) Comprehensive update posted live
9 December 2008 (me) Review posted live
25 July 2008 (mga) Original submission
• 14 May 2020 (ma) Retired chapter: histologic diagnosis without strong genetic correlation
• 24 April 2014 (me) Comprehensive update posted live
• 9 December 2008 (me) Review posted live
• 25 July 2008 (mga) Original submission
|
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"HD Tazelaar, JA Payne, NS Patel. Congenital hepatic fibrosis and asymptomatic familial adult-type polycystic kidney disease in a 19-year-old woman.. Gastroenterology 1984;86:757-60",
"F Ulrich, J Pratschke, A Pascher, UP Neumann, E Lopez-Hanninen, S Jonas, P Neuhaus. Long-term outcome of liver resection and transplantation for Caroli disease and syndrome.. Ann Surg 2008;247:357-64",
"SM White, JA Hurst, H Hamoda, P Chamberlain, CM Bowker. Renal-hepatic-pancreatic dysplasia: a broad entity.. Am J Med Genet 2000;95:399-400",
"JR Whitworth, RJ Sokol. Hepato-portopulmonary disorders--not just in adults!. J Pediatr Gastroenterol Nutr 2005;41:393-5",
"M Zaffanello, F Diomedi-Camassei, ML Melzi, G Torre, F Callea, F Emma. Sensenbrenner syndrome: a new member of the hepatorenal fibrocystic family.. Am J Med Genet A 2006;140:2336-40"
] |
9/12/2008
|
24/4/2014
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
hered-drta
|
hered-drta
|
[
"Classic Renal Tubular Acidosis",
"Type 1 RTA",
"Type 1 RTA",
"Classic Renal Tubular Acidosis",
"Band 3 anion transport protein",
"Forkhead box protein I1",
"V-type proton ATPase 116 kDa subunit a 4",
"V-type proton ATPase subunit B, kidney isoform",
"WD repeat-containing protein 72",
"ATP6V0A4",
"ATP6V1B1",
"FOXI1",
"SLC4A1",
"WDR72",
"Hereditary Distal Renal Tubular Acidosis"
] |
Hereditary Distal Renal Tubular Acidosis
|
R Todd Alexander, Helena Gil-Peña, Larry A Greenbaum, Fernando Santos
|
Summary Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with poor weight gain and growth deficiency, although later presentations can occur, especially in individuals with autosomal dominant The diagnosis of hereditary dRTA is established in a proband with dRTA and biallelic pathogenic variants in Hereditary distal renal tubular acidosis caused by loss-of-function variants in Once the hereditary dRTA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
A clinical diagnosis for hereditary distal renal tubular acidosis (dRTA) can be established in an individual with early-onset dRTA if secondary causes of dRTA (e.g., autoimmune diseases or medications) can be excluded.
Hereditary dRTA
Poor weight gain and growth deficiency in childhood
Sensorineural hearing loss
Symptoms of hypokalemia, including muscle weakness and muscle cramps
Bone manifestations (10%-23%): osteomalacia (in adults), refractory rickets (in children), fractures, bone pain
Exclusion of systemic diseases (e.g., autoimmune disorders) and medications causing dRTA
Hyperchloremic non-anion gap metabolic acidosis in the absence of gastrointestinal losses
Hypokalemia (blood potassium level <3.5 mEq/L)
Hypobicarbonatemia (blood bicarbonate levels <20 mEq/L in infants and <22 mEq/L in older children), but with normal fractional excretion of bicarbonate when blood bicarbonate is normal following alkali administration
Absence of a negative urine anion gap (UAG) in an individual with metabolic acidosis. Calculation of the UAG (U
Elevated urine calcium
Decreased urine citrate
Failure to acidify the urine (urine pH always >5.3):
After an ammonium chloride challenge (100 mg/kg) [
When increased distal delivery of sodium is induced, via the coadministration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) [
In an individual who presents with spontaneous acidosis.
Renal ultrasound. Nephrocalcinosis is almost universal; nephrolithiasis is less common but does occur. Medullary cysts may be detected, typically in later childhood or in adults [
Plain radiographs of the bones may show rachitic changes [
Bone densitometry examination may show decreased bone density in children and adults [
CT examination of the inner ear may demonstrate dilatation of the vestibular aqueduct in individuals with hereditary dRTA associated with hearing loss [
Although molecular testing is recommended, the clinical diagnosis of hereditary dRTA
Laboratory features of dRTA (combination of normal anion gap hyperchloremic metabolic acidosis with an inappropriately elevated urine pH and a positive urine anion gap in the absence of advanced chronic kidney disease and non-renal bicarbonate loss);
Onset in infancy or early childhood; AND
Exclusion of systemic diseases (e.g., autoimmune disorders and medications) causing dRTA.
The molecular diagnosis of hereditary dRTA
Biallelic pathogenic (or likely pathogenic) variants in
A heterozygous or biallelic pathogenic (or likely pathogenic) variant(s) in
Heterozygous pathogenic variants in
Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of hereditary dRTA, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
In the case of adolescent/adult presentation, autosomal dominant inheritance, or dRTA sometimes associated with an inherited hemolytic anemia,
When the diagnosis of hereditary dRTA is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Distal Renal Tubular Acidosis
dRTA = distal renal tubular acidosis
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Large deletions or duplications of this gene have not been reported in individuals with hereditary dRTA.
Intraexon deletions of 27-170 base pairs have been reported [
The majority of affected individuals are of Indian ancestry [
A single case of hereditary dRTA associated with autoimmune thyroiditis, tooth agenesis, enamel hypomaturation, and pulp stones caused by
• Poor weight gain and growth deficiency in childhood
• Sensorineural hearing loss
• Symptoms of hypokalemia, including muscle weakness and muscle cramps
• Bone manifestations (10%-23%): osteomalacia (in adults), refractory rickets (in children), fractures, bone pain
• Exclusion of systemic diseases (e.g., autoimmune disorders) and medications causing dRTA
• Hyperchloremic non-anion gap metabolic acidosis in the absence of gastrointestinal losses
• Hypokalemia (blood potassium level <3.5 mEq/L)
• Hypobicarbonatemia (blood bicarbonate levels <20 mEq/L in infants and <22 mEq/L in older children), but with normal fractional excretion of bicarbonate when blood bicarbonate is normal following alkali administration
• Absence of a negative urine anion gap (UAG) in an individual with metabolic acidosis. Calculation of the UAG (U
• Elevated urine calcium
• Decreased urine citrate
• Failure to acidify the urine (urine pH always >5.3):
• After an ammonium chloride challenge (100 mg/kg) [
• When increased distal delivery of sodium is induced, via the coadministration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) [
• In an individual who presents with spontaneous acidosis.
• After an ammonium chloride challenge (100 mg/kg) [
• When increased distal delivery of sodium is induced, via the coadministration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) [
• In an individual who presents with spontaneous acidosis.
• After an ammonium chloride challenge (100 mg/kg) [
• When increased distal delivery of sodium is induced, via the coadministration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) [
• In an individual who presents with spontaneous acidosis.
• Renal ultrasound. Nephrocalcinosis is almost universal; nephrolithiasis is less common but does occur. Medullary cysts may be detected, typically in later childhood or in adults [
• Plain radiographs of the bones may show rachitic changes [
• Bone densitometry examination may show decreased bone density in children and adults [
• CT examination of the inner ear may demonstrate dilatation of the vestibular aqueduct in individuals with hereditary dRTA associated with hearing loss [
• Laboratory features of dRTA (combination of normal anion gap hyperchloremic metabolic acidosis with an inappropriately elevated urine pH and a positive urine anion gap in the absence of advanced chronic kidney disease and non-renal bicarbonate loss);
• Onset in infancy or early childhood; AND
• Exclusion of systemic diseases (e.g., autoimmune disorders and medications) causing dRTA.
• Biallelic pathogenic (or likely pathogenic) variants in
• A heterozygous or biallelic pathogenic (or likely pathogenic) variant(s) in
• Heterozygous pathogenic variants in
• In the case of adolescent/adult presentation, autosomal dominant inheritance, or dRTA sometimes associated with an inherited hemolytic anemia,
## Suggestive Findings
Hereditary dRTA
Poor weight gain and growth deficiency in childhood
Sensorineural hearing loss
Symptoms of hypokalemia, including muscle weakness and muscle cramps
Bone manifestations (10%-23%): osteomalacia (in adults), refractory rickets (in children), fractures, bone pain
Exclusion of systemic diseases (e.g., autoimmune disorders) and medications causing dRTA
Hyperchloremic non-anion gap metabolic acidosis in the absence of gastrointestinal losses
Hypokalemia (blood potassium level <3.5 mEq/L)
Hypobicarbonatemia (blood bicarbonate levels <20 mEq/L in infants and <22 mEq/L in older children), but with normal fractional excretion of bicarbonate when blood bicarbonate is normal following alkali administration
Absence of a negative urine anion gap (UAG) in an individual with metabolic acidosis. Calculation of the UAG (U
Elevated urine calcium
Decreased urine citrate
Failure to acidify the urine (urine pH always >5.3):
After an ammonium chloride challenge (100 mg/kg) [
When increased distal delivery of sodium is induced, via the coadministration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) [
In an individual who presents with spontaneous acidosis.
Renal ultrasound. Nephrocalcinosis is almost universal; nephrolithiasis is less common but does occur. Medullary cysts may be detected, typically in later childhood or in adults [
Plain radiographs of the bones may show rachitic changes [
Bone densitometry examination may show decreased bone density in children and adults [
CT examination of the inner ear may demonstrate dilatation of the vestibular aqueduct in individuals with hereditary dRTA associated with hearing loss [
• Poor weight gain and growth deficiency in childhood
• Sensorineural hearing loss
• Symptoms of hypokalemia, including muscle weakness and muscle cramps
• Bone manifestations (10%-23%): osteomalacia (in adults), refractory rickets (in children), fractures, bone pain
• Exclusion of systemic diseases (e.g., autoimmune disorders) and medications causing dRTA
• Hyperchloremic non-anion gap metabolic acidosis in the absence of gastrointestinal losses
• Hypokalemia (blood potassium level <3.5 mEq/L)
• Hypobicarbonatemia (blood bicarbonate levels <20 mEq/L in infants and <22 mEq/L in older children), but with normal fractional excretion of bicarbonate when blood bicarbonate is normal following alkali administration
• Absence of a negative urine anion gap (UAG) in an individual with metabolic acidosis. Calculation of the UAG (U
• Elevated urine calcium
• Decreased urine citrate
• Failure to acidify the urine (urine pH always >5.3):
• After an ammonium chloride challenge (100 mg/kg) [
• When increased distal delivery of sodium is induced, via the coadministration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) [
• In an individual who presents with spontaneous acidosis.
• After an ammonium chloride challenge (100 mg/kg) [
• When increased distal delivery of sodium is induced, via the coadministration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) [
• In an individual who presents with spontaneous acidosis.
• After an ammonium chloride challenge (100 mg/kg) [
• When increased distal delivery of sodium is induced, via the coadministration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) [
• In an individual who presents with spontaneous acidosis.
• Renal ultrasound. Nephrocalcinosis is almost universal; nephrolithiasis is less common but does occur. Medullary cysts may be detected, typically in later childhood or in adults [
• Plain radiographs of the bones may show rachitic changes [
• Bone densitometry examination may show decreased bone density in children and adults [
• CT examination of the inner ear may demonstrate dilatation of the vestibular aqueduct in individuals with hereditary dRTA associated with hearing loss [
## Establishing the Diagnosis
Although molecular testing is recommended, the clinical diagnosis of hereditary dRTA
Laboratory features of dRTA (combination of normal anion gap hyperchloremic metabolic acidosis with an inappropriately elevated urine pH and a positive urine anion gap in the absence of advanced chronic kidney disease and non-renal bicarbonate loss);
Onset in infancy or early childhood; AND
Exclusion of systemic diseases (e.g., autoimmune disorders and medications) causing dRTA.
The molecular diagnosis of hereditary dRTA
Biallelic pathogenic (or likely pathogenic) variants in
A heterozygous or biallelic pathogenic (or likely pathogenic) variant(s) in
Heterozygous pathogenic variants in
Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of hereditary dRTA, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
In the case of adolescent/adult presentation, autosomal dominant inheritance, or dRTA sometimes associated with an inherited hemolytic anemia,
When the diagnosis of hereditary dRTA is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Distal Renal Tubular Acidosis
dRTA = distal renal tubular acidosis
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Large deletions or duplications of this gene have not been reported in individuals with hereditary dRTA.
Intraexon deletions of 27-170 base pairs have been reported [
The majority of affected individuals are of Indian ancestry [
A single case of hereditary dRTA associated with autoimmune thyroiditis, tooth agenesis, enamel hypomaturation, and pulp stones caused by
• Laboratory features of dRTA (combination of normal anion gap hyperchloremic metabolic acidosis with an inappropriately elevated urine pH and a positive urine anion gap in the absence of advanced chronic kidney disease and non-renal bicarbonate loss);
• Onset in infancy or early childhood; AND
• Exclusion of systemic diseases (e.g., autoimmune disorders and medications) causing dRTA.
• Biallelic pathogenic (or likely pathogenic) variants in
• A heterozygous or biallelic pathogenic (or likely pathogenic) variant(s) in
• Heterozygous pathogenic variants in
• In the case of adolescent/adult presentation, autosomal dominant inheritance, or dRTA sometimes associated with an inherited hemolytic anemia,
## Clinical Diagnosis
Although molecular testing is recommended, the clinical diagnosis of hereditary dRTA
Laboratory features of dRTA (combination of normal anion gap hyperchloremic metabolic acidosis with an inappropriately elevated urine pH and a positive urine anion gap in the absence of advanced chronic kidney disease and non-renal bicarbonate loss);
Onset in infancy or early childhood; AND
Exclusion of systemic diseases (e.g., autoimmune disorders and medications) causing dRTA.
• Laboratory features of dRTA (combination of normal anion gap hyperchloremic metabolic acidosis with an inappropriately elevated urine pH and a positive urine anion gap in the absence of advanced chronic kidney disease and non-renal bicarbonate loss);
• Onset in infancy or early childhood; AND
• Exclusion of systemic diseases (e.g., autoimmune disorders and medications) causing dRTA.
## Molecular Diagnosis
The molecular diagnosis of hereditary dRTA
Biallelic pathogenic (or likely pathogenic) variants in
A heterozygous or biallelic pathogenic (or likely pathogenic) variant(s) in
Heterozygous pathogenic variants in
Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of hereditary dRTA, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
In the case of adolescent/adult presentation, autosomal dominant inheritance, or dRTA sometimes associated with an inherited hemolytic anemia,
When the diagnosis of hereditary dRTA is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Distal Renal Tubular Acidosis
dRTA = distal renal tubular acidosis
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Large deletions or duplications of this gene have not been reported in individuals with hereditary dRTA.
Intraexon deletions of 27-170 base pairs have been reported [
The majority of affected individuals are of Indian ancestry [
A single case of hereditary dRTA associated with autoimmune thyroiditis, tooth agenesis, enamel hypomaturation, and pulp stones caused by
• Biallelic pathogenic (or likely pathogenic) variants in
• A heterozygous or biallelic pathogenic (or likely pathogenic) variant(s) in
• Heterozygous pathogenic variants in
• In the case of adolescent/adult presentation, autosomal dominant inheritance, or dRTA sometimes associated with an inherited hemolytic anemia,
##
When the phenotypic and laboratory findings suggest the diagnosis of hereditary dRTA, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
In the case of adolescent/adult presentation, autosomal dominant inheritance, or dRTA sometimes associated with an inherited hemolytic anemia,
• In the case of adolescent/adult presentation, autosomal dominant inheritance, or dRTA sometimes associated with an inherited hemolytic anemia,
##
When the diagnosis of hereditary dRTA is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Distal Renal Tubular Acidosis
dRTA = distal renal tubular acidosis
Genes are listed alphabetically.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Large deletions or duplications of this gene have not been reported in individuals with hereditary dRTA.
Intraexon deletions of 27-170 base pairs have been reported [
The majority of affected individuals are of Indian ancestry [
A single case of hereditary dRTA associated with autoimmune thyroiditis, tooth agenesis, enamel hypomaturation, and pulp stones caused by
## Clinical Characteristics
Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with poor weight gain and growth deficiency, although later presentations can occur, especially in individuals with autosomal dominant
Electrolyte manifestations include hypokalemia and hyperchloremic non-anion gap metabolic acidosis with inappropriately elevated urine pH (which may lead to secondary tachypnea if severe [
Nephrocalcinosis, typically bilateral, results from calcium deposition in the renal parenchyma. In a large, mostly European cohort of 340 individuals with dRTA, more than 90% of individuals with molecularly confirmed hereditary dRTA had nephrocalcinosis [
Medullary cysts develop in many individuals during childhood or in adulthood, likely secondary to hypokalemia [
A mild-to-moderate decrease in glomerular filtration rate can occur; this increases in prevalence with age but may be present in childhood [
Bone demineralization can cause rickets in children and osteomalacia in adults. These conditions increase the risk of fractures and may cause bone pain. The frequency and severity of bone findings reported in the literature vary significantly [
Heterozygous
Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
No clinically relevant genotype-phenotype correlations for hereditary dRTA have been identified.
Hereditary dRTA includes both "complete RTA" and "incomplete RTA." Complete RTA refers to a failure to excrete acid leading to metabolic acidosis. Incomplete RTA refers to a failure to excrete acid in the absence of frank metabolic acidosis and is a mild renal acidification defect.
Hereditary dRTA may also be referred to as secretory-defect dRTA.
The prevalence of hereditary dRTA is unclear, although it is certainly rare (~350 individuals have been reported in the literature). A retrospective analysis of records coded in the Clinical Practice Research Datalink (CPRD) of the United Kingdom estimated a prevalence of dRTA in 2017 between 0.46 (diagnosed) and 1.60 (diagnosed and suspected) in 10,000 people; 22% of these individuals had presumed hereditary dRTA [
• Heterozygous
• Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
## Clinical Description
Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with poor weight gain and growth deficiency, although later presentations can occur, especially in individuals with autosomal dominant
Electrolyte manifestations include hypokalemia and hyperchloremic non-anion gap metabolic acidosis with inappropriately elevated urine pH (which may lead to secondary tachypnea if severe [
Nephrocalcinosis, typically bilateral, results from calcium deposition in the renal parenchyma. In a large, mostly European cohort of 340 individuals with dRTA, more than 90% of individuals with molecularly confirmed hereditary dRTA had nephrocalcinosis [
Medullary cysts develop in many individuals during childhood or in adulthood, likely secondary to hypokalemia [
A mild-to-moderate decrease in glomerular filtration rate can occur; this increases in prevalence with age but may be present in childhood [
Bone demineralization can cause rickets in children and osteomalacia in adults. These conditions increase the risk of fractures and may cause bone pain. The frequency and severity of bone findings reported in the literature vary significantly [
Heterozygous
Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
• Heterozygous
• Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations for hereditary dRTA have been identified.
## Nomenclature
Hereditary dRTA includes both "complete RTA" and "incomplete RTA." Complete RTA refers to a failure to excrete acid leading to metabolic acidosis. Incomplete RTA refers to a failure to excrete acid in the absence of frank metabolic acidosis and is a mild renal acidification defect.
Hereditary dRTA may also be referred to as secretory-defect dRTA.
## Prevalence
The prevalence of hereditary dRTA is unclear, although it is certainly rare (~350 individuals have been reported in the literature). A retrospective analysis of records coded in the Clinical Practice Research Datalink (CPRD) of the United Kingdom estimated a prevalence of dRTA in 2017 between 0.46 (diagnosed) and 1.60 (diagnosed and suspected) in 10,000 people; 22% of these individuals had presumed hereditary dRTA [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Digenic inheritance of hearing loss with enlarged vestibular aqueduct has been described involving pathogenic variants in
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
## Differential Diagnosis
Metabolic acidosis with normal anion gap and hypokalemia is also observed in disorders causing loss of bicarbonate either from the proximal tubule or the gastrointestinal tract.
Proximal renal tubular acidosis (pRTA) is characterized by a very high fractional excretion of bicarbonate (>10%-15%) in the presence of normal blood bicarbonate. Large amounts of alkali supplementation are required to correct the acidosis. The ability to acidify the urine is preserved when the blood bicarbonate is below the threshold for proximal bicarbonate wasting.
Isolated hereditary pRTA is extremely rare. Proximal RTA is typically a component of generalized proximal tubular dysfunction (renal Fanconi syndrome). Note: Some medications may cause isolated acquired pRTA (e.g., acetazolamide, topiramate).
Mixed RTA, including pRTA and dRTA, is associated with pathogenic variants in
Chronic gastrointestinal disorders leading to hyperchloremic normal anion gap metabolic acidosis are usually distinguished from dRTA by the clinical context and by intact capacity to decrease urine pH, though volume depletion can also interfere with urinary acidification.
Acquired forms of dRTA are characteristic of adults and are mostly caused by autoimmune tubulopathies with antibodies against the collecting duct, including Sjogren syndrome, primary biliary sclerosis, rheumatoid arthritis, and systemic lupus erythematosus [
Disorder to Consider in the Differential Diagnosis of Hereditary Distal Renal Tubular Acidosis
Metabolic acidosis w/urinary acidification defect
Hypercalciuria & nephrocalcinosis
Copper deposits
Systemic manifestations (hepatic, neurologic, cardiac)
Penicillamine treatment corrects urinary acidification defect.
Proximal RTA
Osteopetrosis
ID
Visual impairment from optic nerve compression
AR = autosomal recessive; dRTA = distal renal tubular acidosis; ID = intellectual disability; MOI = mode of inheritance; RTA = renal tubular acidosis
• Proximal renal tubular acidosis (pRTA) is characterized by a very high fractional excretion of bicarbonate (>10%-15%) in the presence of normal blood bicarbonate. Large amounts of alkali supplementation are required to correct the acidosis. The ability to acidify the urine is preserved when the blood bicarbonate is below the threshold for proximal bicarbonate wasting.
• Isolated hereditary pRTA is extremely rare. Proximal RTA is typically a component of generalized proximal tubular dysfunction (renal Fanconi syndrome). Note: Some medications may cause isolated acquired pRTA (e.g., acetazolamide, topiramate).
• Mixed RTA, including pRTA and dRTA, is associated with pathogenic variants in
• Chronic gastrointestinal disorders leading to hyperchloremic normal anion gap metabolic acidosis are usually distinguished from dRTA by the clinical context and by intact capacity to decrease urine pH, though volume depletion can also interfere with urinary acidification.
• Acquired forms of dRTA are characteristic of adults and are mostly caused by autoimmune tubulopathies with antibodies against the collecting duct, including Sjogren syndrome, primary biliary sclerosis, rheumatoid arthritis, and systemic lupus erythematosus [
• Metabolic acidosis w/urinary acidification defect
• Hypercalciuria & nephrocalcinosis
• Copper deposits
• Systemic manifestations (hepatic, neurologic, cardiac)
• Penicillamine treatment corrects urinary acidification defect.
• Proximal RTA
• Osteopetrosis
• ID
• Visual impairment from optic nerve compression
## Management
The European Rare Kidney Disease Reference Network and the Inherited Kidney Diseases Working Group of the European Society for Paediatric Nephrology published clinical practice guidelines for the management of individuals with distal renal tubular acidosis (dRTA) [
To establish the extent of disease and needs in an individual diagnosed with hereditary dRTA, the evaluations summarized in
Hereditary Distal Renal Tubular Acidosis: Recommended Evaluations Following Initial Diagnosis
Eval of acid-base equilibrium
Sample to be drawn in fasting conditions & immediately before scheduled dose of alkali to assess effectiveness of therapy
Evaluate GFR
Assess hypokalemia & hydration status.
Excretion of sodium & potassium can be estimated by calculation of appropriate indices (mL/dL glomerular filtrate, fractional excretions of sodium & potassium).
Detection of hypercalciuria by calcium-to-creatinine ratio. Hypercalciuria may indicate inadequate correction of acidosis.
Use for calculation of BMI to assess nutritional status.
Use baseline values to assess response to therapy (correction of height deficit expected if short stature is present) & to adjust alkali dosage.
ALP = alkaline phosphatase; BMI = body mass index; CBC = complete blood count; dRTA = distal renal tubular acidosis; ENT = ear, nose, and throat; GFR = glomerular filtration rate; MOI = mode of inheritance; SNHL = sensorineural hearing loss
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Hereditary Distal Renal Tubular Acidosis: Targeted Therapies
Infants: at diagnosis, initial doses ~5 mEq/kg/day or higher may be needed to achieve a sustained correction of acidosis;
Adults: ~1 mEq/kg/day
Goal of treatment is to correct metabolic acidosis & hypokalemia.
Alkali requirement is highest in infants & ↓ in adults.
Dosing is ideally every 6 hrs, although dosing can be adapted to accommodate sleep, work, & school schedules.
Add potassium chloride as needed for hypokalemia despite well-controlled acidosis.
Adults: 2.3 mEq/kg/day (1.3)
Adolescents: 2.6 mEq/kg/day (1.7)
Children: 3.4 mEq/kg/day (1.3)
Toddlers: 4.8 mEq/kg/day (2.0)
Approved in Europe for persons age ≥1 year
Designed to provide 24-hour control of metabolic acidosis & hypokalemia w/2xday dosing
Well-tolerated & safe for control of dRTA in children after 2 yrs of treatment
The less frequent dosing schedule for ADV7103 may be helpful in school-age children, as it obviates need for a dose during school hours.
SD = standard deviation
European study reporting two years of ADV7103 treatment [
Standard of care in dRTA is oral alkaline therapy, usually in the form of a bicarbonate and/or citrate salt [
Note: (1) Compensated metabolic acidosis (normal pH but low bicarbonate) is not sufficient to facilitate growth. (2) Alkali and citrate supplementation prevent the progression of nephrocalcinosis but do not reverse it. (3) Treatment decreases the risk of developing urolithiasis.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Hereditary Distal Renal Tubular Acidosis: Treatment of Manifestations
In those w/
Correction of metabolic acidosis does not correct deafness.
Oral alkaline therapy (See
Transfusion & iron therapy as needed
dRTA = distal renal tubular acidosis
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Hereditary Distal Renal Tubular Acidosis: Recommended Surveillance
In rapidly growing persons (infants & young children): at least every 3-4 mos once blood pH is normalized w/o evidence of respiratory compensation
In older children: every 6 mos
In adults: annually
Sample to be drawn in fasting conditions & immediately before scheduled dose of alkali
In rapidly growing persons (infants & young children): at least every 3-4 mos once adequate control is achieved
In stable older children & adults: every 6-12 mos
Annually
More frequently when adjusting treatment
Measure length/height & weight.
Calculate BMI.
In infants: at least every 3 mos
In older children: at least every 6 mos until achievement of final height
BMI = body mass index; CBC = complete blood count; ENT = ear, nose, and throat
Potassium-sparing diuretics should be used with caution or avoided altogether.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Venous blood gas or total CO
At-risk newborns should undergo assessment of acid-base status and serum electrolytes, specifically blood gas analysis and plasma electrolytes, to identify a normal anion gap metabolic acidosis and hypokalemia pending the results of molecular genetic testing for known familial pathogenic variant(s).
See
Women with hereditary dRTA may develop severe metabolic acidosis and hypokalemia during pregnancy, especially when complicated by hyperemesis gravidarum. Close monitoring of women with hereditary dRTA during pregnancy is necessary [
See
Search
• Eval of acid-base equilibrium
• Sample to be drawn in fasting conditions & immediately before scheduled dose of alkali to assess effectiveness of therapy
• Evaluate GFR
• Assess hypokalemia & hydration status.
• Excretion of sodium & potassium can be estimated by calculation of appropriate indices (mL/dL glomerular filtrate, fractional excretions of sodium & potassium).
• Detection of hypercalciuria by calcium-to-creatinine ratio. Hypercalciuria may indicate inadequate correction of acidosis.
• Use for calculation of BMI to assess nutritional status.
• Use baseline values to assess response to therapy (correction of height deficit expected if short stature is present) & to adjust alkali dosage.
• Infants: at diagnosis, initial doses ~5 mEq/kg/day or higher may be needed to achieve a sustained correction of acidosis;
• Adults: ~1 mEq/kg/day
• Goal of treatment is to correct metabolic acidosis & hypokalemia.
• Alkali requirement is highest in infants & ↓ in adults.
• Dosing is ideally every 6 hrs, although dosing can be adapted to accommodate sleep, work, & school schedules.
• Add potassium chloride as needed for hypokalemia despite well-controlled acidosis.
• Adults: 2.3 mEq/kg/day (1.3)
• Adolescents: 2.6 mEq/kg/day (1.7)
• Children: 3.4 mEq/kg/day (1.3)
• Toddlers: 4.8 mEq/kg/day (2.0)
• Approved in Europe for persons age ≥1 year
• Designed to provide 24-hour control of metabolic acidosis & hypokalemia w/2xday dosing
• Well-tolerated & safe for control of dRTA in children after 2 yrs of treatment
• The less frequent dosing schedule for ADV7103 may be helpful in school-age children, as it obviates need for a dose during school hours.
• In those w/
• Correction of metabolic acidosis does not correct deafness.
• Oral alkaline therapy (See
• Transfusion & iron therapy as needed
• In rapidly growing persons (infants & young children): at least every 3-4 mos once blood pH is normalized w/o evidence of respiratory compensation
• In older children: every 6 mos
• In adults: annually
• Sample to be drawn in fasting conditions & immediately before scheduled dose of alkali
• In rapidly growing persons (infants & young children): at least every 3-4 mos once adequate control is achieved
• In stable older children & adults: every 6-12 mos
• Annually
• More frequently when adjusting treatment
• Measure length/height & weight.
• Calculate BMI.
• In infants: at least every 3 mos
• In older children: at least every 6 mos until achievement of final height
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Venous blood gas or total CO
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hereditary dRTA, the evaluations summarized in
Hereditary Distal Renal Tubular Acidosis: Recommended Evaluations Following Initial Diagnosis
Eval of acid-base equilibrium
Sample to be drawn in fasting conditions & immediately before scheduled dose of alkali to assess effectiveness of therapy
Evaluate GFR
Assess hypokalemia & hydration status.
Excretion of sodium & potassium can be estimated by calculation of appropriate indices (mL/dL glomerular filtrate, fractional excretions of sodium & potassium).
Detection of hypercalciuria by calcium-to-creatinine ratio. Hypercalciuria may indicate inadequate correction of acidosis.
Use for calculation of BMI to assess nutritional status.
Use baseline values to assess response to therapy (correction of height deficit expected if short stature is present) & to adjust alkali dosage.
ALP = alkaline phosphatase; BMI = body mass index; CBC = complete blood count; dRTA = distal renal tubular acidosis; ENT = ear, nose, and throat; GFR = glomerular filtration rate; MOI = mode of inheritance; SNHL = sensorineural hearing loss
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Eval of acid-base equilibrium
• Sample to be drawn in fasting conditions & immediately before scheduled dose of alkali to assess effectiveness of therapy
• Evaluate GFR
• Assess hypokalemia & hydration status.
• Excretion of sodium & potassium can be estimated by calculation of appropriate indices (mL/dL glomerular filtrate, fractional excretions of sodium & potassium).
• Detection of hypercalciuria by calcium-to-creatinine ratio. Hypercalciuria may indicate inadequate correction of acidosis.
• Use for calculation of BMI to assess nutritional status.
• Use baseline values to assess response to therapy (correction of height deficit expected if short stature is present) & to adjust alkali dosage.
## Treatment of Manifestations
Hereditary Distal Renal Tubular Acidosis: Targeted Therapies
Infants: at diagnosis, initial doses ~5 mEq/kg/day or higher may be needed to achieve a sustained correction of acidosis;
Adults: ~1 mEq/kg/day
Goal of treatment is to correct metabolic acidosis & hypokalemia.
Alkali requirement is highest in infants & ↓ in adults.
Dosing is ideally every 6 hrs, although dosing can be adapted to accommodate sleep, work, & school schedules.
Add potassium chloride as needed for hypokalemia despite well-controlled acidosis.
Adults: 2.3 mEq/kg/day (1.3)
Adolescents: 2.6 mEq/kg/day (1.7)
Children: 3.4 mEq/kg/day (1.3)
Toddlers: 4.8 mEq/kg/day (2.0)
Approved in Europe for persons age ≥1 year
Designed to provide 24-hour control of metabolic acidosis & hypokalemia w/2xday dosing
Well-tolerated & safe for control of dRTA in children after 2 yrs of treatment
The less frequent dosing schedule for ADV7103 may be helpful in school-age children, as it obviates need for a dose during school hours.
SD = standard deviation
European study reporting two years of ADV7103 treatment [
Standard of care in dRTA is oral alkaline therapy, usually in the form of a bicarbonate and/or citrate salt [
Note: (1) Compensated metabolic acidosis (normal pH but low bicarbonate) is not sufficient to facilitate growth. (2) Alkali and citrate supplementation prevent the progression of nephrocalcinosis but do not reverse it. (3) Treatment decreases the risk of developing urolithiasis.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Hereditary Distal Renal Tubular Acidosis: Treatment of Manifestations
In those w/
Correction of metabolic acidosis does not correct deafness.
Oral alkaline therapy (See
Transfusion & iron therapy as needed
dRTA = distal renal tubular acidosis
• Infants: at diagnosis, initial doses ~5 mEq/kg/day or higher may be needed to achieve a sustained correction of acidosis;
• Adults: ~1 mEq/kg/day
• Goal of treatment is to correct metabolic acidosis & hypokalemia.
• Alkali requirement is highest in infants & ↓ in adults.
• Dosing is ideally every 6 hrs, although dosing can be adapted to accommodate sleep, work, & school schedules.
• Add potassium chloride as needed for hypokalemia despite well-controlled acidosis.
• Adults: 2.3 mEq/kg/day (1.3)
• Adolescents: 2.6 mEq/kg/day (1.7)
• Children: 3.4 mEq/kg/day (1.3)
• Toddlers: 4.8 mEq/kg/day (2.0)
• Approved in Europe for persons age ≥1 year
• Designed to provide 24-hour control of metabolic acidosis & hypokalemia w/2xday dosing
• Well-tolerated & safe for control of dRTA in children after 2 yrs of treatment
• The less frequent dosing schedule for ADV7103 may be helpful in school-age children, as it obviates need for a dose during school hours.
• In those w/
• Correction of metabolic acidosis does not correct deafness.
• Oral alkaline therapy (See
• Transfusion & iron therapy as needed
## Targeted Therapies
Hereditary Distal Renal Tubular Acidosis: Targeted Therapies
Infants: at diagnosis, initial doses ~5 mEq/kg/day or higher may be needed to achieve a sustained correction of acidosis;
Adults: ~1 mEq/kg/day
Goal of treatment is to correct metabolic acidosis & hypokalemia.
Alkali requirement is highest in infants & ↓ in adults.
Dosing is ideally every 6 hrs, although dosing can be adapted to accommodate sleep, work, & school schedules.
Add potassium chloride as needed for hypokalemia despite well-controlled acidosis.
Adults: 2.3 mEq/kg/day (1.3)
Adolescents: 2.6 mEq/kg/day (1.7)
Children: 3.4 mEq/kg/day (1.3)
Toddlers: 4.8 mEq/kg/day (2.0)
Approved in Europe for persons age ≥1 year
Designed to provide 24-hour control of metabolic acidosis & hypokalemia w/2xday dosing
Well-tolerated & safe for control of dRTA in children after 2 yrs of treatment
The less frequent dosing schedule for ADV7103 may be helpful in school-age children, as it obviates need for a dose during school hours.
SD = standard deviation
European study reporting two years of ADV7103 treatment [
Standard of care in dRTA is oral alkaline therapy, usually in the form of a bicarbonate and/or citrate salt [
Note: (1) Compensated metabolic acidosis (normal pH but low bicarbonate) is not sufficient to facilitate growth. (2) Alkali and citrate supplementation prevent the progression of nephrocalcinosis but do not reverse it. (3) Treatment decreases the risk of developing urolithiasis.
• Infants: at diagnosis, initial doses ~5 mEq/kg/day or higher may be needed to achieve a sustained correction of acidosis;
• Adults: ~1 mEq/kg/day
• Goal of treatment is to correct metabolic acidosis & hypokalemia.
• Alkali requirement is highest in infants & ↓ in adults.
• Dosing is ideally every 6 hrs, although dosing can be adapted to accommodate sleep, work, & school schedules.
• Add potassium chloride as needed for hypokalemia despite well-controlled acidosis.
• Adults: 2.3 mEq/kg/day (1.3)
• Adolescents: 2.6 mEq/kg/day (1.7)
• Children: 3.4 mEq/kg/day (1.3)
• Toddlers: 4.8 mEq/kg/day (2.0)
• Approved in Europe for persons age ≥1 year
• Designed to provide 24-hour control of metabolic acidosis & hypokalemia w/2xday dosing
• Well-tolerated & safe for control of dRTA in children after 2 yrs of treatment
• The less frequent dosing schedule for ADV7103 may be helpful in school-age children, as it obviates need for a dose during school hours.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Hereditary Distal Renal Tubular Acidosis: Treatment of Manifestations
In those w/
Correction of metabolic acidosis does not correct deafness.
Oral alkaline therapy (See
Transfusion & iron therapy as needed
dRTA = distal renal tubular acidosis
• In those w/
• Correction of metabolic acidosis does not correct deafness.
• Oral alkaline therapy (See
• Transfusion & iron therapy as needed
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Hereditary Distal Renal Tubular Acidosis: Recommended Surveillance
In rapidly growing persons (infants & young children): at least every 3-4 mos once blood pH is normalized w/o evidence of respiratory compensation
In older children: every 6 mos
In adults: annually
Sample to be drawn in fasting conditions & immediately before scheduled dose of alkali
In rapidly growing persons (infants & young children): at least every 3-4 mos once adequate control is achieved
In stable older children & adults: every 6-12 mos
Annually
More frequently when adjusting treatment
Measure length/height & weight.
Calculate BMI.
In infants: at least every 3 mos
In older children: at least every 6 mos until achievement of final height
BMI = body mass index; CBC = complete blood count; ENT = ear, nose, and throat
• In rapidly growing persons (infants & young children): at least every 3-4 mos once blood pH is normalized w/o evidence of respiratory compensation
• In older children: every 6 mos
• In adults: annually
• Sample to be drawn in fasting conditions & immediately before scheduled dose of alkali
• In rapidly growing persons (infants & young children): at least every 3-4 mos once adequate control is achieved
• In stable older children & adults: every 6-12 mos
• Annually
• More frequently when adjusting treatment
• Measure length/height & weight.
• Calculate BMI.
• In infants: at least every 3 mos
• In older children: at least every 6 mos until achievement of final height
## Agents/Circumstances to Avoid
Potassium-sparing diuretics should be used with caution or avoided altogether.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Venous blood gas or total CO
At-risk newborns should undergo assessment of acid-base status and serum electrolytes, specifically blood gas analysis and plasma electrolytes, to identify a normal anion gap metabolic acidosis and hypokalemia pending the results of molecular genetic testing for known familial pathogenic variant(s).
See
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Venous blood gas or total CO
## Pregnancy Management
Women with hereditary dRTA may develop severe metabolic acidosis and hypokalemia during pregnancy, especially when complicated by hyperemesis gravidarum. Close monitoring of women with hereditary dRTA during pregnancy is necessary [
See
## Therapies Under Investigation
Search
## Genetic Counseling
Hereditary distal renal tubular acidosis (dRTA) caused by loss-of-function variants in
Hereditary dRTA caused by dominant-negative variants in
Hereditary dRTA caused by heterozygous pathogenic variants in
The parents of an affected child are presumed to be heterozygous for an autosomal recessive dRTA-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an autosomal recessive dRTA-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a child with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
Heterozygous
Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
If both parents are known to be heterozygous for an autosomal recessive dRTA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
The heterozygous sibs of a proband with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
Heterozygous
No manifestations of dRTA have been reported in heterozygous sibs of probands with biallelic
Most individuals diagnosed with autosomal dominant
Very few individuals diagnosed with autosomal dominant
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or death of the parent before the onset of symptoms. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
* A parent with somatic and gonadal mosaicism for an
If a parent of the proband is affected and/or is known to have the autosomal dominant dRTA-related pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known autosomal dominant dRTA-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for autosomal dominant dRTA because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
Once the hereditary dRTA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are presumed to be heterozygous for an autosomal recessive dRTA-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an autosomal recessive dRTA-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a child with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
• Heterozygous
• Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
• Heterozygous
• Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygous
• Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
• If both parents are known to be heterozygous for an autosomal recessive dRTA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• The heterozygous sibs of a proband with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
• Heterozygous
• No manifestations of dRTA have been reported in heterozygous sibs of probands with biallelic
• Heterozygous
• No manifestations of dRTA have been reported in heterozygous sibs of probands with biallelic
• Heterozygous
• No manifestations of dRTA have been reported in heterozygous sibs of probands with biallelic
• Most individuals diagnosed with autosomal dominant
• Very few individuals diagnosed with autosomal dominant
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or death of the parent before the onset of symptoms. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for an
• If a parent of the proband is affected and/or is known to have the autosomal dominant dRTA-related pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known autosomal dominant dRTA-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for autosomal dominant dRTA because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Mode of Inheritance
Hereditary distal renal tubular acidosis (dRTA) caused by loss-of-function variants in
Hereditary dRTA caused by dominant-negative variants in
Hereditary dRTA caused by heterozygous pathogenic variants in
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an autosomal recessive dRTA-related pathogenic variant.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an autosomal recessive dRTA-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a child with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
Heterozygous
Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
If both parents are known to be heterozygous for an autosomal recessive dRTA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
The heterozygous sibs of a proband with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
Heterozygous
No manifestations of dRTA have been reported in heterozygous sibs of probands with biallelic
• The parents of an affected child are presumed to be heterozygous for an autosomal recessive dRTA-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an autosomal recessive dRTA-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a child with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
• Heterozygous
• Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
• Heterozygous
• Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygous
• Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic
• If both parents are known to be heterozygous for an autosomal recessive dRTA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• The heterozygous sibs of a proband with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
• Heterozygous
• No manifestations of dRTA have been reported in heterozygous sibs of probands with biallelic
• Heterozygous
• No manifestations of dRTA have been reported in heterozygous sibs of probands with biallelic
• Heterozygous
• No manifestations of dRTA have been reported in heterozygous sibs of probands with biallelic
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with autosomal dominant
Very few individuals diagnosed with autosomal dominant
If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or death of the parent before the onset of symptoms. Therefore,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
* A parent with somatic and gonadal mosaicism for an
If a parent of the proband is affected and/or is known to have the autosomal dominant dRTA-related pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known autosomal dominant dRTA-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for autosomal dominant dRTA because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.
• Most individuals diagnosed with autosomal dominant
• Very few individuals diagnosed with autosomal dominant
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or death of the parent before the onset of symptoms. Therefore,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• * A parent with somatic and gonadal mosaicism for an
• If a parent of the proband is affected and/or is known to have the autosomal dominant dRTA-related pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known autosomal dominant dRTA-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for autosomal dominant dRTA because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
## Prenatal Testing and Preimplantation Genetic Testing
Once the hereditary dRTA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Spain
Canada
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## Molecular Genetics
Hereditary Distal Renal Tubular Acidosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hereditary Distal Renal Tubular Acidosis (
Distal renal tubular acidosis (dRTA) is the result of a failure of the alpha intercalated cells of the connecting tubule and collecting duct to secrete H
Forkhead box protein I1 (FOXI1), encoded by
In order to secrete acid into the pro-urine, H
The role of WD repeat-containing protein 72 (WDR72), encoded by
Pathogenic variations in
Autosomal dominant disease-causing variants in
Pathogenic Variants Referenced in This
AD = autosomal dominant; dRTA = distal renal tubular acidosis
Variants listed in the table have been provided by the authors.
Genes from
• Pathogenic variations in
• Autosomal dominant disease-causing variants in
## Molecular Pathogenesis
Distal renal tubular acidosis (dRTA) is the result of a failure of the alpha intercalated cells of the connecting tubule and collecting duct to secrete H
Forkhead box protein I1 (FOXI1), encoded by
In order to secrete acid into the pro-urine, H
The role of WD repeat-containing protein 72 (WDR72), encoded by
Pathogenic variations in
Autosomal dominant disease-causing variants in
Pathogenic Variants Referenced in This
AD = autosomal dominant; dRTA = distal renal tubular acidosis
Variants listed in the table have been provided by the authors.
Genes from
• Pathogenic variations in
• Autosomal dominant disease-causing variants in
## Chapter Notes
R Todd Alexander is the Canada Research Chair in Renal Epithelial Transport Physiology.
The Laboratory of R Todd Alexander is funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Canadian Institutes of Health Research (CIHR), the Women and Children's Health Research Institute (WCHRI), and the Kidney Foundation of Canada.
F Santos and H Gil-Peña thank the research support from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III of Spain, and the Fundación Nutrición y Crecimiento.
R Todd Alexander, MD, PhD (2019-present)Helena Gil-Peña, PhD (2019-present)Larry A Greenbaum, MD, PhD (2019-present)Linda Law, MD, MBA; Advicenne (2019-2025)Fernando Santos, MD, PhD (2019-present)
3 April 2025 (sw) Comprehensive updated posted live
10 October 2019 (sw) Review posted live
15 January 2019 (rta) Original submission
• 3 April 2025 (sw) Comprehensive updated posted live
• 10 October 2019 (sw) Review posted live
• 15 January 2019 (rta) Original submission
## Author Notes
R Todd Alexander is the Canada Research Chair in Renal Epithelial Transport Physiology.
## Acknowledgments
The Laboratory of R Todd Alexander is funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Canadian Institutes of Health Research (CIHR), the Women and Children's Health Research Institute (WCHRI), and the Kidney Foundation of Canada.
F Santos and H Gil-Peña thank the research support from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III of Spain, and the Fundación Nutrición y Crecimiento.
## Author History
R Todd Alexander, MD, PhD (2019-present)Helena Gil-Peña, PhD (2019-present)Larry A Greenbaum, MD, PhD (2019-present)Linda Law, MD, MBA; Advicenne (2019-2025)Fernando Santos, MD, PhD (2019-present)
## Revision History
3 April 2025 (sw) Comprehensive updated posted live
10 October 2019 (sw) Review posted live
15 January 2019 (rta) Original submission
• 3 April 2025 (sw) Comprehensive updated posted live
• 10 October 2019 (sw) Review posted live
• 15 January 2019 (rta) Original submission
## Key Sections in This
## References
## Literature Cited
|
[] |
10/10/2019
|
3/4/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
hfg
|
hfg
|
[
"HFGS",
"HFG Syndrome",
"HFGS",
"HFG Syndrome",
"Homeobox protein Hox-A13",
"HOXA13",
"Hand-Foot-Genital Syndrome"
] |
Hand-Foot-Genital Syndrome
|
Jeffrey W Innis
|
Summary Hand-foot-genital syndrome (HFGS) is characterized by limb malformations and urogenital defects. Mild-to-severe bilateral shortening of the thumbs and great toes, caused primarily by shortening of the distal phalanx and/or the first metacarpal or metatarsal, is the most common limb malformation and results in impaired dexterity or apposition of the thumbs. Urogenital malformations include abnormalities of the ureters and urethra and various degrees of incomplete müllerian fusion in females, and hypospadias of variable severity with or without chordee in males. Vesicoureteral reflux, recurrent urinary tract infections, and chronic pyelonephritis may occur; fertility is normal. Diagnosis is based on physical examination including radiographs of the hands and feet and imaging studies of the kidneys, bladder, and female reproductive tract. Identification of a heterozygous Hand-foot-genital syndrome is inherited in an autosomal dominant manner. The proportion of cases caused by a
|
## Diagnosis
Hand-foot-genital syndrome
Limited metacarpophalangeal flexion of the thumb or limited ability to oppose the thumb and fifth finger
Hypoplastic thenar eminences
Hallus valgus of the distal phalanx of the great toe is common; hallux varus can be observed associated with significant metatarsal shortening.
Small great toenail
Sandal gap (i.e., increased gap between 1st and 2nd toes)
Fifth-finger clinodactyly, secondary to a shortened middle phalanx
Short feet
Altered dermatoglyphics of the hands; when present, primarily involving distal placement of the axial triradius, lack of thenar or hypothenar patterning, low arches on the thumbs, thin ulnar loops (deficiency of radial loops and whorls), and a greatly reduced ridge count on the fingers
Hypoplasia of the distal phalanx and first metacarpal of the thumbs and great toes; rare hypoplasia of the distal phalanges of other digits
Pointed distal phalanges of the thumb
Lack of normal tufting of the distal phalanges of the great toes
Fusions of the cuneiform to other tarsal bones or trapezium-scaphoid fusion of the carpals
Short calcaneus
Occasional bony fusions of the middle and distal phalanges of the second, third, fourth, or fifth toes
Delayed carpal or tarsal maturation
Metacarpophalangeal profile reflecting shortening of the first metacarpal, the first and second phalanges, and the second phalanx of the second and fifth digits
Vesicoureteral reflux secondary to ureteric incompetence
Ectopic ureteral orifices
Trigonal hypoplasia
Hypospadiac urethra
Subsymphyseal epispadias
Patulous urethra
Urinary incontinence
Small hymenal opening
Various degrees of incomplete müllerian fusion with or without two cervices or a longitudinal vaginal septum
Vesicoureteral reflux
Hypospadias of variable severity with or without chordee
The diagnosis of hand-foot-genital syndrome
The diagnosis of hand-foot-genital syndrome
A heterozygous polyalanine expansion involving
A heterozygous sequence variant involving
The significance of a shortened allele of eight polyalanine residues observed in one family is not clear given the occurrence of another disorder in the same family that complicates interpretation of the skeletal phenotype [
It is unknown whether a shortened allele of 12 polyalanine residues observed in expressed sequence tag databases [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of hand-foot-genital syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of hand-foot-genital syndrome, molecular genetic testing approaches can include
Sequence analysis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by limb anomalies,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hand-Foot-Genital Syndrome
See
See
PCR-based methods to identify
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Other than in-frame contractions of polyalanine repeats, intragenic deletions causing HFGS that involve only part or all of
A few individuals with the clinical features of HFGS do not have
• Limited metacarpophalangeal flexion of the thumb or limited ability to oppose the thumb and fifth finger
• Hypoplastic thenar eminences
• Hallus valgus of the distal phalanx of the great toe is common; hallux varus can be observed associated with significant metatarsal shortening.
• Small great toenail
• Sandal gap (i.e., increased gap between 1st and 2nd toes)
• Fifth-finger clinodactyly, secondary to a shortened middle phalanx
• Short feet
• Altered dermatoglyphics of the hands; when present, primarily involving distal placement of the axial triradius, lack of thenar or hypothenar patterning, low arches on the thumbs, thin ulnar loops (deficiency of radial loops and whorls), and a greatly reduced ridge count on the fingers
• Hypoplasia of the distal phalanx and first metacarpal of the thumbs and great toes; rare hypoplasia of the distal phalanges of other digits
• Pointed distal phalanges of the thumb
• Lack of normal tufting of the distal phalanges of the great toes
• Fusions of the cuneiform to other tarsal bones or trapezium-scaphoid fusion of the carpals
• Short calcaneus
• Occasional bony fusions of the middle and distal phalanges of the second, third, fourth, or fifth toes
• Delayed carpal or tarsal maturation
• Metacarpophalangeal profile reflecting shortening of the first metacarpal, the first and second phalanges, and the second phalanx of the second and fifth digits
• Vesicoureteral reflux secondary to ureteric incompetence
• Ectopic ureteral orifices
• Trigonal hypoplasia
• Hypospadiac urethra
• Subsymphyseal epispadias
• Patulous urethra
• Urinary incontinence
• Small hymenal opening
• Various degrees of incomplete müllerian fusion with or without two cervices or a longitudinal vaginal septum
• Vesicoureteral reflux
• Hypospadias of variable severity with or without chordee
• A heterozygous polyalanine expansion involving
• A heterozygous sequence variant involving
•
•
•
• The significance of a shortened allele of eight polyalanine residues observed in one family is not clear given the occurrence of another disorder in the same family that complicates interpretation of the skeletal phenotype [
• It is unknown whether a shortened allele of 12 polyalanine residues observed in expressed sequence tag databases [
• The significance of a shortened allele of eight polyalanine residues observed in one family is not clear given the occurrence of another disorder in the same family that complicates interpretation of the skeletal phenotype [
• It is unknown whether a shortened allele of 12 polyalanine residues observed in expressed sequence tag databases [
• The significance of a shortened allele of eight polyalanine residues observed in one family is not clear given the occurrence of another disorder in the same family that complicates interpretation of the skeletal phenotype [
• It is unknown whether a shortened allele of 12 polyalanine residues observed in expressed sequence tag databases [
• Sequence analysis of
• For an introduction to multigene panels click
## Suggestive Findings
Hand-foot-genital syndrome
Limited metacarpophalangeal flexion of the thumb or limited ability to oppose the thumb and fifth finger
Hypoplastic thenar eminences
Hallus valgus of the distal phalanx of the great toe is common; hallux varus can be observed associated with significant metatarsal shortening.
Small great toenail
Sandal gap (i.e., increased gap between 1st and 2nd toes)
Fifth-finger clinodactyly, secondary to a shortened middle phalanx
Short feet
Altered dermatoglyphics of the hands; when present, primarily involving distal placement of the axial triradius, lack of thenar or hypothenar patterning, low arches on the thumbs, thin ulnar loops (deficiency of radial loops and whorls), and a greatly reduced ridge count on the fingers
Hypoplasia of the distal phalanx and first metacarpal of the thumbs and great toes; rare hypoplasia of the distal phalanges of other digits
Pointed distal phalanges of the thumb
Lack of normal tufting of the distal phalanges of the great toes
Fusions of the cuneiform to other tarsal bones or trapezium-scaphoid fusion of the carpals
Short calcaneus
Occasional bony fusions of the middle and distal phalanges of the second, third, fourth, or fifth toes
Delayed carpal or tarsal maturation
Metacarpophalangeal profile reflecting shortening of the first metacarpal, the first and second phalanges, and the second phalanx of the second and fifth digits
Vesicoureteral reflux secondary to ureteric incompetence
Ectopic ureteral orifices
Trigonal hypoplasia
Hypospadiac urethra
Subsymphyseal epispadias
Patulous urethra
Urinary incontinence
Small hymenal opening
Various degrees of incomplete müllerian fusion with or without two cervices or a longitudinal vaginal septum
Vesicoureteral reflux
Hypospadias of variable severity with or without chordee
• Limited metacarpophalangeal flexion of the thumb or limited ability to oppose the thumb and fifth finger
• Hypoplastic thenar eminences
• Hallus valgus of the distal phalanx of the great toe is common; hallux varus can be observed associated with significant metatarsal shortening.
• Small great toenail
• Sandal gap (i.e., increased gap between 1st and 2nd toes)
• Fifth-finger clinodactyly, secondary to a shortened middle phalanx
• Short feet
• Altered dermatoglyphics of the hands; when present, primarily involving distal placement of the axial triradius, lack of thenar or hypothenar patterning, low arches on the thumbs, thin ulnar loops (deficiency of radial loops and whorls), and a greatly reduced ridge count on the fingers
• Hypoplasia of the distal phalanx and first metacarpal of the thumbs and great toes; rare hypoplasia of the distal phalanges of other digits
• Pointed distal phalanges of the thumb
• Lack of normal tufting of the distal phalanges of the great toes
• Fusions of the cuneiform to other tarsal bones or trapezium-scaphoid fusion of the carpals
• Short calcaneus
• Occasional bony fusions of the middle and distal phalanges of the second, third, fourth, or fifth toes
• Delayed carpal or tarsal maturation
• Metacarpophalangeal profile reflecting shortening of the first metacarpal, the first and second phalanges, and the second phalanx of the second and fifth digits
• Vesicoureteral reflux secondary to ureteric incompetence
• Ectopic ureteral orifices
• Trigonal hypoplasia
• Hypospadiac urethra
• Subsymphyseal epispadias
• Patulous urethra
• Urinary incontinence
• Small hymenal opening
• Various degrees of incomplete müllerian fusion with or without two cervices or a longitudinal vaginal septum
• Vesicoureteral reflux
• Hypospadias of variable severity with or without chordee
## Limb Malformations
Limited metacarpophalangeal flexion of the thumb or limited ability to oppose the thumb and fifth finger
Hypoplastic thenar eminences
Hallus valgus of the distal phalanx of the great toe is common; hallux varus can be observed associated with significant metatarsal shortening.
Small great toenail
Sandal gap (i.e., increased gap between 1st and 2nd toes)
Fifth-finger clinodactyly, secondary to a shortened middle phalanx
Short feet
Altered dermatoglyphics of the hands; when present, primarily involving distal placement of the axial triradius, lack of thenar or hypothenar patterning, low arches on the thumbs, thin ulnar loops (deficiency of radial loops and whorls), and a greatly reduced ridge count on the fingers
Hypoplasia of the distal phalanx and first metacarpal of the thumbs and great toes; rare hypoplasia of the distal phalanges of other digits
Pointed distal phalanges of the thumb
Lack of normal tufting of the distal phalanges of the great toes
Fusions of the cuneiform to other tarsal bones or trapezium-scaphoid fusion of the carpals
Short calcaneus
Occasional bony fusions of the middle and distal phalanges of the second, third, fourth, or fifth toes
Delayed carpal or tarsal maturation
Metacarpophalangeal profile reflecting shortening of the first metacarpal, the first and second phalanges, and the second phalanx of the second and fifth digits
• Limited metacarpophalangeal flexion of the thumb or limited ability to oppose the thumb and fifth finger
• Hypoplastic thenar eminences
• Hallus valgus of the distal phalanx of the great toe is common; hallux varus can be observed associated with significant metatarsal shortening.
• Small great toenail
• Sandal gap (i.e., increased gap between 1st and 2nd toes)
• Fifth-finger clinodactyly, secondary to a shortened middle phalanx
• Short feet
• Altered dermatoglyphics of the hands; when present, primarily involving distal placement of the axial triradius, lack of thenar or hypothenar patterning, low arches on the thumbs, thin ulnar loops (deficiency of radial loops and whorls), and a greatly reduced ridge count on the fingers
• Hypoplasia of the distal phalanx and first metacarpal of the thumbs and great toes; rare hypoplasia of the distal phalanges of other digits
• Pointed distal phalanges of the thumb
• Lack of normal tufting of the distal phalanges of the great toes
• Fusions of the cuneiform to other tarsal bones or trapezium-scaphoid fusion of the carpals
• Short calcaneus
• Occasional bony fusions of the middle and distal phalanges of the second, third, fourth, or fifth toes
• Delayed carpal or tarsal maturation
• Metacarpophalangeal profile reflecting shortening of the first metacarpal, the first and second phalanges, and the second phalanx of the second and fifth digits
## Urogenital Defects
Vesicoureteral reflux secondary to ureteric incompetence
Ectopic ureteral orifices
Trigonal hypoplasia
Hypospadiac urethra
Subsymphyseal epispadias
Patulous urethra
Urinary incontinence
Small hymenal opening
Various degrees of incomplete müllerian fusion with or without two cervices or a longitudinal vaginal septum
Vesicoureteral reflux
Hypospadias of variable severity with or without chordee
• Vesicoureteral reflux secondary to ureteric incompetence
• Ectopic ureteral orifices
• Trigonal hypoplasia
• Hypospadiac urethra
• Subsymphyseal epispadias
• Patulous urethra
• Urinary incontinence
• Small hymenal opening
• Various degrees of incomplete müllerian fusion with or without two cervices or a longitudinal vaginal septum
• Vesicoureteral reflux
• Hypospadias of variable severity with or without chordee
## Establishing the Diagnosis
The diagnosis of hand-foot-genital syndrome
The diagnosis of hand-foot-genital syndrome
A heterozygous polyalanine expansion involving
A heterozygous sequence variant involving
The significance of a shortened allele of eight polyalanine residues observed in one family is not clear given the occurrence of another disorder in the same family that complicates interpretation of the skeletal phenotype [
It is unknown whether a shortened allele of 12 polyalanine residues observed in expressed sequence tag databases [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of hand-foot-genital syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of hand-foot-genital syndrome, molecular genetic testing approaches can include
Sequence analysis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by limb anomalies,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hand-Foot-Genital Syndrome
See
See
PCR-based methods to identify
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Other than in-frame contractions of polyalanine repeats, intragenic deletions causing HFGS that involve only part or all of
A few individuals with the clinical features of HFGS do not have
• A heterozygous polyalanine expansion involving
• A heterozygous sequence variant involving
•
•
•
• The significance of a shortened allele of eight polyalanine residues observed in one family is not clear given the occurrence of another disorder in the same family that complicates interpretation of the skeletal phenotype [
• It is unknown whether a shortened allele of 12 polyalanine residues observed in expressed sequence tag databases [
• The significance of a shortened allele of eight polyalanine residues observed in one family is not clear given the occurrence of another disorder in the same family that complicates interpretation of the skeletal phenotype [
• It is unknown whether a shortened allele of 12 polyalanine residues observed in expressed sequence tag databases [
• The significance of a shortened allele of eight polyalanine residues observed in one family is not clear given the occurrence of another disorder in the same family that complicates interpretation of the skeletal phenotype [
• It is unknown whether a shortened allele of 12 polyalanine residues observed in expressed sequence tag databases [
• Sequence analysis of
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of hand-foot-genital syndrome, molecular genetic testing approaches can include
Sequence analysis of
For an introduction to multigene panels click
• Sequence analysis of
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by limb anomalies,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hand-Foot-Genital Syndrome
See
See
PCR-based methods to identify
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Other than in-frame contractions of polyalanine repeats, intragenic deletions causing HFGS that involve only part or all of
A few individuals with the clinical features of HFGS do not have
## Clinical Characteristics
Hand-foot-genital syndrome (HFGS) has been reported in several families and individuals [
HFGS may first be suspected in infants or children during evaluation for urogenital problems including hypospadias, ureteral reflux, urethral misplacement, recurrent urinary tract infections, or chronic pyelonephritis, or for small thumbs with impaired dexterity or apposition. Renal insufficiency leading to renal transplantation has been reported in one female.
Of all affected males, only one has had a documented history of urinary tract infection (UTI); two brothers had hypospadias (Grades II and III); one had bilateral vesicoureteral reflux with UTI, and the other had ureteropelvic junction (UPJ) obstruction. This family was first reported by
Affected males are not at increased risk for cryptorchidism and are fertile. No anomalies of the prostate or seminal vesicles have been described; however, directed examinations in males with HFGS to evaluate for such abnormalities have not been reported.
Menarche is usually normal. Females with varying degrees of incomplete müllerian fusion are at increased risk for premature labor, premature birth, second-trimester fetal loss, or stillbirth.
Other, possibly unrelated abnormalities are found rarely in individuals or families with HFGS:
Strabismus
Ventriculoseptal defect (propositus of
Inguinal hernia, epididymal cyst, short stature, cervical ribs, supernumerary nipple, lower limit of functioning, onychodysplasia
Sacral dimple
Psychomotor retardation, microcephaly, and hypertelorism (in 1 of 4 affected members of a single family in which HFGS occurs)
Difficulty with balance when standing (in 1 adult)
The following are normal:
Developmental milestones
External ears and hearing
Although the number of affected individuals in whom pathogenic variants in
The limb malformations in individuals with the heterozygous pathogenic nonsense variants in either exon 1 or 2 or a polyalanine expansion in exon 1 are similar to those described in individuals with a cytogenetic deletion of the
Generally speaking,
The variables that determine whether an individual heterozygous for a
Skeletal defects are 100% penetrant.
Penetrance for urogenital malformations is greater than 50% overall and may be greater for affected females.
Anticipation is not observed. Polyalanine expansions are stable for many generations.
HFGS is extremely rare.
• Strabismus
• Ventriculoseptal defect (propositus of
• Inguinal hernia, epididymal cyst, short stature, cervical ribs, supernumerary nipple, lower limit of functioning, onychodysplasia
• Sacral dimple
• Psychomotor retardation, microcephaly, and hypertelorism (in 1 of 4 affected members of a single family in which HFGS occurs)
• Difficulty with balance when standing (in 1 adult)
• Developmental milestones
• External ears and hearing
## Clinical Description
Hand-foot-genital syndrome (HFGS) has been reported in several families and individuals [
HFGS may first be suspected in infants or children during evaluation for urogenital problems including hypospadias, ureteral reflux, urethral misplacement, recurrent urinary tract infections, or chronic pyelonephritis, or for small thumbs with impaired dexterity or apposition. Renal insufficiency leading to renal transplantation has been reported in one female.
Of all affected males, only one has had a documented history of urinary tract infection (UTI); two brothers had hypospadias (Grades II and III); one had bilateral vesicoureteral reflux with UTI, and the other had ureteropelvic junction (UPJ) obstruction. This family was first reported by
Affected males are not at increased risk for cryptorchidism and are fertile. No anomalies of the prostate or seminal vesicles have been described; however, directed examinations in males with HFGS to evaluate for such abnormalities have not been reported.
Menarche is usually normal. Females with varying degrees of incomplete müllerian fusion are at increased risk for premature labor, premature birth, second-trimester fetal loss, or stillbirth.
Other, possibly unrelated abnormalities are found rarely in individuals or families with HFGS:
Strabismus
Ventriculoseptal defect (propositus of
Inguinal hernia, epididymal cyst, short stature, cervical ribs, supernumerary nipple, lower limit of functioning, onychodysplasia
Sacral dimple
Psychomotor retardation, microcephaly, and hypertelorism (in 1 of 4 affected members of a single family in which HFGS occurs)
Difficulty with balance when standing (in 1 adult)
The following are normal:
Developmental milestones
External ears and hearing
• Strabismus
• Ventriculoseptal defect (propositus of
• Inguinal hernia, epididymal cyst, short stature, cervical ribs, supernumerary nipple, lower limit of functioning, onychodysplasia
• Sacral dimple
• Psychomotor retardation, microcephaly, and hypertelorism (in 1 of 4 affected members of a single family in which HFGS occurs)
• Difficulty with balance when standing (in 1 adult)
• Developmental milestones
• External ears and hearing
## Genotype-Phenotype Correlations
Although the number of affected individuals in whom pathogenic variants in
The limb malformations in individuals with the heterozygous pathogenic nonsense variants in either exon 1 or 2 or a polyalanine expansion in exon 1 are similar to those described in individuals with a cytogenetic deletion of the
Generally speaking,
The variables that determine whether an individual heterozygous for a
## Penetrance
Skeletal defects are 100% penetrant.
Penetrance for urogenital malformations is greater than 50% overall and may be greater for affected females.
## Anticipation
Anticipation is not observed. Polyalanine expansions are stable for many generations.
## Prevalence
HFGS is extremely rare.
## Genetically Related (Allelic) Disorders
Guttmacher syndrome (OMIM
An individual with a
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of Hand-Foot-Genital Syndrome (HFGS)
Bone marrow failure
↑ risk of malignancy
Rash, poikiloderma
Cataracts
↑ risk of malignancy
Characteristic facial features
Dental anomalies
Radial ray malformation
Duane anomaly
Obesity
Rod-cone dystrophy
Ocular involvement
Ear anomalies
Renal cystic dysplasia
Biliary abnormalities & liver fibrosis
Encephalocele
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Beckwith-Wiedemann syndrome is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5. Most individuals with BWS are reported to have normal chromosome studies or karyotypes. Approximately 85% of individuals with BWS have no family history of BWS; approximately 15% have a family history consistent with parent-of-origin autosomal dominant transmission.
Note:
• Bone marrow failure
• ↑ risk of malignancy
• Rash, poikiloderma
• Cataracts
• ↑ risk of malignancy
• Characteristic facial features
• Dental anomalies
• Radial ray malformation
• Duane anomaly
• Obesity
• Rod-cone dystrophy
• Ocular involvement
• Ear anomalies
• Renal cystic dysplasia
• Biliary abnormalities & liver fibrosis
• Encephalocele
## Management
To establish the extent of disease and needs in an individual diagnosed with hand-foot-genital syndrome (HFGS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hand-Foot-Genital Syndrome
Gynecologic exam prior to menstruation or pregnancy.
Eval may incl ultrasound, hysterosalpingogram, hysteroscopy, sonohysterogram, MRI, or other imaging studies.
For evidence of incomplete müllerian fusion, longitudinal vaginal septum, or extremely small hymenal opening
Such studies could be accomplished at the same time as urologic imaging.
UPJ = ureteropelvic junction; VCUG = voiding cystourethrogram
Treatment of Manifestations in Individuals with Hand-Foot-Genital Syndrome
Surgical removal of longitudinal vaginal septum is rarely indicated, even in anticipation of labor.
Surgery for removal of a uterine septum or reunification of a bicornuate uterus is likewise exceptional in the absence of recurrent mid-trimester pregnancy losses.
Hymenectomy may be necessary for tight constriction ring.
The following are appropriate:
Prophylactic antibiotics or surgery as needed to prevent urinary tract infections or other complications of ureteral reflux or UPJ obstruction
Gynecologic examination prior to menstruation for small hymenal opening
Pre-pregnancy evaluation of the vaginal and uterine anatomy because of the increased risk for premature labor and fetal loss associated with structural abnormalities of the uterus
Follow up with a urologist in the presence of vesicoureteral reflux and/or documented urinary tract infection is warranted.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those at risk for genitourinary and reproductive tract complications.
Evaluations can include:
Molecular genetic testing if the
Physical examination, radiographic examination of hands and feet, and consideration of referral for urologic and/or gynecologic examination if the pathogenic variant in the family is not known.
See
In women with HFGS, pregnancy loss is possible secondary to uterine malformation. Consultation with an obstetrician before pregnancy is recommended and should include evaluation for and discussion of potential pregnancy complications. Affected fetuses are generally healthy, but could be at risk for premature birth secondary to maternal uterine malformation if the mother is also affected.
Search
• Gynecologic exam prior to menstruation or pregnancy.
• Eval may incl ultrasound, hysterosalpingogram, hysteroscopy, sonohysterogram, MRI, or other imaging studies.
• For evidence of incomplete müllerian fusion, longitudinal vaginal septum, or extremely small hymenal opening
• Such studies could be accomplished at the same time as urologic imaging.
• Surgical removal of longitudinal vaginal septum is rarely indicated, even in anticipation of labor.
• Surgery for removal of a uterine septum or reunification of a bicornuate uterus is likewise exceptional in the absence of recurrent mid-trimester pregnancy losses.
• Hymenectomy may be necessary for tight constriction ring.
• Prophylactic antibiotics or surgery as needed to prevent urinary tract infections or other complications of ureteral reflux or UPJ obstruction
• Gynecologic examination prior to menstruation for small hymenal opening
• Pre-pregnancy evaluation of the vaginal and uterine anatomy because of the increased risk for premature labor and fetal loss associated with structural abnormalities of the uterus
• Molecular genetic testing if the
• Physical examination, radiographic examination of hands and feet, and consideration of referral for urologic and/or gynecologic examination if the pathogenic variant in the family is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hand-foot-genital syndrome (HFGS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hand-Foot-Genital Syndrome
Gynecologic exam prior to menstruation or pregnancy.
Eval may incl ultrasound, hysterosalpingogram, hysteroscopy, sonohysterogram, MRI, or other imaging studies.
For evidence of incomplete müllerian fusion, longitudinal vaginal septum, or extremely small hymenal opening
Such studies could be accomplished at the same time as urologic imaging.
UPJ = ureteropelvic junction; VCUG = voiding cystourethrogram
• Gynecologic exam prior to menstruation or pregnancy.
• Eval may incl ultrasound, hysterosalpingogram, hysteroscopy, sonohysterogram, MRI, or other imaging studies.
• For evidence of incomplete müllerian fusion, longitudinal vaginal septum, or extremely small hymenal opening
• Such studies could be accomplished at the same time as urologic imaging.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Hand-Foot-Genital Syndrome
Surgical removal of longitudinal vaginal septum is rarely indicated, even in anticipation of labor.
Surgery for removal of a uterine septum or reunification of a bicornuate uterus is likewise exceptional in the absence of recurrent mid-trimester pregnancy losses.
Hymenectomy may be necessary for tight constriction ring.
• Surgical removal of longitudinal vaginal septum is rarely indicated, even in anticipation of labor.
• Surgery for removal of a uterine septum or reunification of a bicornuate uterus is likewise exceptional in the absence of recurrent mid-trimester pregnancy losses.
• Hymenectomy may be necessary for tight constriction ring.
## Prevention of Secondary Complications
The following are appropriate:
Prophylactic antibiotics or surgery as needed to prevent urinary tract infections or other complications of ureteral reflux or UPJ obstruction
Gynecologic examination prior to menstruation for small hymenal opening
Pre-pregnancy evaluation of the vaginal and uterine anatomy because of the increased risk for premature labor and fetal loss associated with structural abnormalities of the uterus
• Prophylactic antibiotics or surgery as needed to prevent urinary tract infections or other complications of ureteral reflux or UPJ obstruction
• Gynecologic examination prior to menstruation for small hymenal opening
• Pre-pregnancy evaluation of the vaginal and uterine anatomy because of the increased risk for premature labor and fetal loss associated with structural abnormalities of the uterus
## Surveillance
Follow up with a urologist in the presence of vesicoureteral reflux and/or documented urinary tract infection is warranted.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those at risk for genitourinary and reproductive tract complications.
Evaluations can include:
Molecular genetic testing if the
Physical examination, radiographic examination of hands and feet, and consideration of referral for urologic and/or gynecologic examination if the pathogenic variant in the family is not known.
See
• Molecular genetic testing if the
• Physical examination, radiographic examination of hands and feet, and consideration of referral for urologic and/or gynecologic examination if the pathogenic variant in the family is not known.
## Pregnancy Management
In women with HFGS, pregnancy loss is possible secondary to uterine malformation. Consultation with an obstetrician before pregnancy is recommended and should include evaluation for and discussion of potential pregnancy complications. Affected fetuses are generally healthy, but could be at risk for premature birth secondary to maternal uterine malformation if the mother is also affected.
## Therapies Under Investigation
Search
## Genetic Counseling
Hand-foot-genital syndrome (HFGS) is inherited in an autosomal dominant manner.
Some individuals diagnosed with HFGS have an affected parent.
A proband with HFGS may have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the proband has a pathogenic variant that cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with HFGS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation or death of the parent before appropriate evaluation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected or unaffected [
If a parent of the proband is affected and/or is known to have the
If the proband has a known
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Some individuals diagnosed with HFGS have an affected parent.
• A proband with HFGS may have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the proband has a pathogenic variant that cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with HFGS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation or death of the parent before appropriate evaluation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected or unaffected [
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Hand-foot-genital syndrome (HFGS) is inherited in an autosomal dominant manner.
## Risk to Family Members
Some individuals diagnosed with HFGS have an affected parent.
A proband with HFGS may have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the proband has a pathogenic variant that cannot be detected in the leukocyte DNA of either parent, possible explanations include a
The family history of some individuals diagnosed with HFGS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation or death of the parent before appropriate evaluation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected or unaffected [
If a parent of the proband is affected and/or is known to have the
If the proband has a known
• Some individuals diagnosed with HFGS have an affected parent.
• A proband with HFGS may have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the proband has a pathogenic variant that cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• The family history of some individuals diagnosed with HFGS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation or death of the parent before appropriate evaluation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected or unaffected [
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Hand-Foot-Genital Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hand-Foot-Genital Syndrome (
There are four
## Molecular Pathogenesis
There are four
## References
## Literature Cited
## Chapter Notes
8 August 2019 (sw) Comprehensive update posted live
3 May 2012 (me) Comprehensive update posted live
2 February 2010 (me) Comprehensive update posted live
11 July 2006 (me) Review posted live
16 February (jwi) Original submission
• 8 August 2019 (sw) Comprehensive update posted live
• 3 May 2012 (me) Comprehensive update posted live
• 2 February 2010 (me) Comprehensive update posted live
• 11 July 2006 (me) Review posted live
• 16 February (jwi) Original submission
## Author Notes
## Revision History
8 August 2019 (sw) Comprehensive update posted live
3 May 2012 (me) Comprehensive update posted live
2 February 2010 (me) Comprehensive update posted live
11 July 2006 (me) Review posted live
16 February (jwi) Original submission
• 8 August 2019 (sw) Comprehensive update posted live
• 3 May 2012 (me) Comprehensive update posted live
• 2 February 2010 (me) Comprehensive update posted live
• 11 July 2006 (me) Review posted live
• 16 February (jwi) Original submission
|
[] |
11/7/2006
|
8/8/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
hfi
|
hfi
|
[
"Fructose-bisphosphate aldolase B",
"ALDOB",
"Hereditary Fructose Intolerance"
] |
Hereditary Fructose Intolerance
|
Sommer Gaughan, Lachlan Ayres, Peter R Baker
|
Summary Following dietary exposure to fructose, sucrose, or sorbitol, untreated hereditary fructose intolerance (HFI) is characterized by metabolic disturbances (hypoglycemia, lactic acidemia, hypophosphatemia, hyperuricemia, hypermagnesemia, hyperalaninemia) and clinical findings (nausea, vomiting, and abdominal distress; chronic growth restriction / failure to thrive). While untreated HFI typically first manifested when fructose- and sucrose-containing foods were introduced in the course of weaning young infants from breast milk, it is now presenting earlier, due to the addition of fructose-containing nutrients in infant formulas. If the infant ingests large quantities of fructose, the infant may acutely develop lethargy, seizures, and/or progressive coma. Untreated HFI may result in renal and hepatic failure. If identified and treated before permanent organ injury occurs, individuals with HFI can experience a normal quality of life and life expectancy. The diagnosis of HFI is established in a proband with suggestive metabolic disturbances and clinical findings following dietary exposure to fructose, sucrose, or sorbitol and either biallelic pathogenic variants in Potential sources of fructose should be removed immediately if HFI is suspected. Although vaccinations are generally safe in children with HFI, the two potentially harmful vaccines are the sucrose-containing rotavirus vaccines, Rotarix HFI is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
No consensus clinical diagnostic criteria for hereditary fructose intolerance (HFI) have been published.
HFI
Note that the clinical presentation of HFI can be multifaceted and nonspecific, making it difficult to suspect based on clinical findings alone. If HFI is suspected, potential sources of fructose need to be removed immediately (see
Nausea, vomiting, and abdominal distress (including pain, distention, ascites, and hepatomegaly)
Chronic growth restriction / failure to thrive
Any individual with a severe adverse reaction (e.g., vomiting, hypoglycemia, lethargy, liver or renal insufficiency) immediately following administration of either of the two sucrose-containing vaccines, Rotarix
Characteristic Metabolic Disturbances in Hereditary Fructose Intolerance
The diagnosis of HFI
Biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Deficient hepatic fructose 1-phosphate aldolase (aldolase B) activity on liver biopsy
Note: Because of the relatively high sensitivity of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Fructose Intolerance
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No large deletions were identified by Southern blotting in 56 individuals from Spain [
A large (6.5-kb) intragenic deletion with an allele frequency of 11% was identified in a small Italian cohort [
Note: While molecular genetic testing is the first-line diagnostic test for HFI, assay of aldolase B activity on liver biopsy, which is more invasive but more sensitive than molecular genetic testing, can be used if necessary.
• Nausea, vomiting, and abdominal distress (including pain, distention, ascites, and hepatomegaly)
• Chronic growth restriction / failure to thrive
• Any individual with a severe adverse reaction (e.g., vomiting, hypoglycemia, lethargy, liver or renal insufficiency) immediately following administration of either of the two sucrose-containing vaccines, Rotarix
• Biallelic pathogenic (or likely pathogenic) variants in
• Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
• Deficient hepatic fructose 1-phosphate aldolase (aldolase B) activity on liver biopsy
## Suggestive Findings
HFI
Note that the clinical presentation of HFI can be multifaceted and nonspecific, making it difficult to suspect based on clinical findings alone. If HFI is suspected, potential sources of fructose need to be removed immediately (see
Nausea, vomiting, and abdominal distress (including pain, distention, ascites, and hepatomegaly)
Chronic growth restriction / failure to thrive
Any individual with a severe adverse reaction (e.g., vomiting, hypoglycemia, lethargy, liver or renal insufficiency) immediately following administration of either of the two sucrose-containing vaccines, Rotarix
Characteristic Metabolic Disturbances in Hereditary Fructose Intolerance
• Nausea, vomiting, and abdominal distress (including pain, distention, ascites, and hepatomegaly)
• Chronic growth restriction / failure to thrive
• Any individual with a severe adverse reaction (e.g., vomiting, hypoglycemia, lethargy, liver or renal insufficiency) immediately following administration of either of the two sucrose-containing vaccines, Rotarix
## Establishing the Diagnosis
The diagnosis of HFI
Biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
Deficient hepatic fructose 1-phosphate aldolase (aldolase B) activity on liver biopsy
Note: Because of the relatively high sensitivity of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Fructose Intolerance
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No large deletions were identified by Southern blotting in 56 individuals from Spain [
A large (6.5-kb) intragenic deletion with an allele frequency of 11% was identified in a small Italian cohort [
Note: While molecular genetic testing is the first-line diagnostic test for HFI, assay of aldolase B activity on liver biopsy, which is more invasive but more sensitive than molecular genetic testing, can be used if necessary.
• Biallelic pathogenic (or likely pathogenic) variants in
• Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [
• Deficient hepatic fructose 1-phosphate aldolase (aldolase B) activity on liver biopsy
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Fructose Intolerance
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
No large deletions were identified by Southern blotting in 56 individuals from Spain [
A large (6.5-kb) intragenic deletion with an allele frequency of 11% was identified in a small Italian cohort [
Note: While molecular genetic testing is the first-line diagnostic test for HFI, assay of aldolase B activity on liver biopsy, which is more invasive but more sensitive than molecular genetic testing, can be used if necessary.
## Clinical Characteristics
Hereditary fructose intolerance (HFI) typically manifests when fructose- and sucrose-containing foods are introduced in the course of weaning young infants from breast milk [
Impaired gluconeogenesis following fructose ingestion results in acute hypoglycemia that is refractory to glucagon [
Presently, the clinical presentation of HFI can be multifaceted and nonspecific. The classic presentation of the infant transitioning to solids and developing hypoglycemia is still true; however, with fructose-containing components added to infant formulas, clinical presentation can be earlier than five to six months of age [
Other variable common findings in HFI include the following.
Hepatomegaly with steatosis and lipid vacuolization may remain a persistent complication despite fructose restriction and resolution of initial fibrosis, including in individuals ascertained by family history and treated from birth [
A potential long-term risk of developing hepatic adenoma and fibrosis [
There have been multiple examples of persistent hepatomegaly, non-alcoholic fatty liver disease, and abnormal carbohydrate-deficient transferrin testing [
Lenticular cataracts with hepatic fibrosis in untreated adolescents and adults [
Chronic renal insufficiency, specifically proximal tubular dysfunction, may also persist despite fructose restriction. Typically, resolution of renal disease occurs shortly after starting fructose restriction [
More recently longitudinal study of adults with HFI revealed higher glomerular filtration and higher systolic blood pressure versus controls, potentially predisposing individuals with HFI to greater cardiovascular risk [
Chronic renal disease may be a result of early, chronic exposure, as some reported individuals tended to manage themselves with inadequate self-restriction of fructose- and sucrose-containing foods. It may also be in part due to ongoing primary defects in aldolase function and ATPase interaction within the proximal tubule, leading to dysfunctional acid-base regulation, renal tubular insufficiency (manifesting as glucosuria, aminoaciduria, and phosphaturia), and nephrocalcinosis despite strict dietary restrictions [
Coagulopathy [
Isolated poor growth (i.e., in the absence of other symptoms or affected organ systems) [
Intermittent vomiting in the setting of fructose aversion and pristine dentition [
Conversely, when individuals with HFI do not adhere to recommended dietary restrictions, chronic liver and/or renal disease are expected (as detailed above).
No genotype-phenotype correlations have been identified for HFI; clinical severity and extent of organ damage appear to depend on an individual's nutritional environment.
"Fructosaemia," a term originally proposed by
HFI is rare, making precise prevalence estimates challenging.
Population-based estimates for the prevalence (based on results of carrier testing for common
It is important to note that the US study that targeted five specific
HFI Prevalence by Population Based on Carrier Testing for Specific
AA = African American; ME = Middle Eastern
Extrapolated prevalence based on detection rate of variants tested
Based on the UK population prevalence of the
In a large carrier screening study of multiple disorders in an ethnically diverse population in the United States, overall carrier frequency for an
• Hepatomegaly with steatosis and lipid vacuolization may remain a persistent complication despite fructose restriction and resolution of initial fibrosis, including in individuals ascertained by family history and treated from birth [
• A potential long-term risk of developing hepatic adenoma and fibrosis [
• There have been multiple examples of persistent hepatomegaly, non-alcoholic fatty liver disease, and abnormal carbohydrate-deficient transferrin testing [
• Lenticular cataracts with hepatic fibrosis in untreated adolescents and adults [
• Chronic renal insufficiency, specifically proximal tubular dysfunction, may also persist despite fructose restriction. Typically, resolution of renal disease occurs shortly after starting fructose restriction [
• More recently longitudinal study of adults with HFI revealed higher glomerular filtration and higher systolic blood pressure versus controls, potentially predisposing individuals with HFI to greater cardiovascular risk [
• Chronic renal disease may be a result of early, chronic exposure, as some reported individuals tended to manage themselves with inadequate self-restriction of fructose- and sucrose-containing foods. It may also be in part due to ongoing primary defects in aldolase function and ATPase interaction within the proximal tubule, leading to dysfunctional acid-base regulation, renal tubular insufficiency (manifesting as glucosuria, aminoaciduria, and phosphaturia), and nephrocalcinosis despite strict dietary restrictions [
• Coagulopathy [
• Isolated poor growth (i.e., in the absence of other symptoms or affected organ systems) [
• Intermittent vomiting in the setting of fructose aversion and pristine dentition [
## Clinical Description
Hereditary fructose intolerance (HFI) typically manifests when fructose- and sucrose-containing foods are introduced in the course of weaning young infants from breast milk [
Impaired gluconeogenesis following fructose ingestion results in acute hypoglycemia that is refractory to glucagon [
Presently, the clinical presentation of HFI can be multifaceted and nonspecific. The classic presentation of the infant transitioning to solids and developing hypoglycemia is still true; however, with fructose-containing components added to infant formulas, clinical presentation can be earlier than five to six months of age [
Other variable common findings in HFI include the following.
Hepatomegaly with steatosis and lipid vacuolization may remain a persistent complication despite fructose restriction and resolution of initial fibrosis, including in individuals ascertained by family history and treated from birth [
A potential long-term risk of developing hepatic adenoma and fibrosis [
There have been multiple examples of persistent hepatomegaly, non-alcoholic fatty liver disease, and abnormal carbohydrate-deficient transferrin testing [
Lenticular cataracts with hepatic fibrosis in untreated adolescents and adults [
Chronic renal insufficiency, specifically proximal tubular dysfunction, may also persist despite fructose restriction. Typically, resolution of renal disease occurs shortly after starting fructose restriction [
More recently longitudinal study of adults with HFI revealed higher glomerular filtration and higher systolic blood pressure versus controls, potentially predisposing individuals with HFI to greater cardiovascular risk [
Chronic renal disease may be a result of early, chronic exposure, as some reported individuals tended to manage themselves with inadequate self-restriction of fructose- and sucrose-containing foods. It may also be in part due to ongoing primary defects in aldolase function and ATPase interaction within the proximal tubule, leading to dysfunctional acid-base regulation, renal tubular insufficiency (manifesting as glucosuria, aminoaciduria, and phosphaturia), and nephrocalcinosis despite strict dietary restrictions [
Coagulopathy [
Isolated poor growth (i.e., in the absence of other symptoms or affected organ systems) [
Intermittent vomiting in the setting of fructose aversion and pristine dentition [
Conversely, when individuals with HFI do not adhere to recommended dietary restrictions, chronic liver and/or renal disease are expected (as detailed above).
• Hepatomegaly with steatosis and lipid vacuolization may remain a persistent complication despite fructose restriction and resolution of initial fibrosis, including in individuals ascertained by family history and treated from birth [
• A potential long-term risk of developing hepatic adenoma and fibrosis [
• There have been multiple examples of persistent hepatomegaly, non-alcoholic fatty liver disease, and abnormal carbohydrate-deficient transferrin testing [
• Lenticular cataracts with hepatic fibrosis in untreated adolescents and adults [
• Chronic renal insufficiency, specifically proximal tubular dysfunction, may also persist despite fructose restriction. Typically, resolution of renal disease occurs shortly after starting fructose restriction [
• More recently longitudinal study of adults with HFI revealed higher glomerular filtration and higher systolic blood pressure versus controls, potentially predisposing individuals with HFI to greater cardiovascular risk [
• Chronic renal disease may be a result of early, chronic exposure, as some reported individuals tended to manage themselves with inadequate self-restriction of fructose- and sucrose-containing foods. It may also be in part due to ongoing primary defects in aldolase function and ATPase interaction within the proximal tubule, leading to dysfunctional acid-base regulation, renal tubular insufficiency (manifesting as glucosuria, aminoaciduria, and phosphaturia), and nephrocalcinosis despite strict dietary restrictions [
• Coagulopathy [
• Isolated poor growth (i.e., in the absence of other symptoms or affected organ systems) [
• Intermittent vomiting in the setting of fructose aversion and pristine dentition [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified for HFI; clinical severity and extent of organ damage appear to depend on an individual's nutritional environment.
## Nomenclature
"Fructosaemia," a term originally proposed by
## Prevalence
HFI is rare, making precise prevalence estimates challenging.
Population-based estimates for the prevalence (based on results of carrier testing for common
It is important to note that the US study that targeted five specific
HFI Prevalence by Population Based on Carrier Testing for Specific
AA = African American; ME = Middle Eastern
Extrapolated prevalence based on detection rate of variants tested
Based on the UK population prevalence of the
In a large carrier screening study of multiple disorders in an ethnically diverse population in the United States, overall carrier frequency for an
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
In addition to hereditary fructose intolerance (HFI), the following acquired and
Infectious hepatitis, sepsis, or disseminated intravascular coagulation
Autoimmune liver disease
Neonatal hemochromatosis, which is considered a congenital alloimmune hepatitis
Toxic ingestion
Hemophagocytic lymphohistiocytosis (See
Hereditary Disorders to Consider in the Evaluation of Hepatic Insufficiency, Unexplained Jaundice, and Hypoglycemia, or in the Setting of Reye-Like Illness in Infancy or Early Childhood
AR = autosomal recessive; GSD = glycogen storage disease; LCHAD = long-chain 3-hydroxyacyl-coa dehydrogenase; MCAD = medium-chain acyl-coenzyme A dehydrogenase; MOI = mode of inheritance; mtDNA = mitochondrial DNA; VLCAD = very long-chain acyl-CoA dehydrogenase; XL = X-linked
Forty-two different enzymes in the N-linked oligosaccharide synthetic pathway or interactive pathways are currently recognized to be deficient in each of the types of CDG-N-linked or among the multiple-pathway disorders.
In addition to HFI, severe infection/sepsis and hereditary disorders including
Hereditary Disorders to Consider in the Evaluation of Infants with Hyperlacticemia in Combination with Hypoglycemia
AR = autosomal recessive; LCHAD = long-chain 3-hydroxyacyl-coa dehydrogenase; MCAD = medium-chain acyl-coenzyme A dehydrogenase; MOI = mode of inheritance; VLCAD = very long-chain acyl-CoA dehydrogenase; XL = X-linked
In addition to HFI, renal tubular acidosis and hereditary disorders including
Hereditary Disorders to Consider in the Evaluation of Infants with Renal Fanconi/Aminoaciduria and Failure to Thrive
AR = autosomal recessive; MOI = mode of inheritance
Forty-two different enzymes in the N-linked oligosaccharide synthetic pathway or interactive pathways are currently recognized to be deficient in each of the types of CDG-N-linked or among the multiple-pathway disorders.
Note:
In HFI, clinical analysis of transferrin glycosylation may be positive, and should correct once fructose is adequately restricted and liver disease subsides. The pattern of abnormal glycosylation is not characteristic of a particular glycosylation defect; thus, when there is clinical suspicion for HFI,
In addition to HFI, infection, toxic ingestion, and neoplasm should be considered in the evaluation of adult- or childhood-onset of chronic liver disease.
In addition to HFI, gastroesophageal reflux, pyloric stenosis,
In children or adults with early-onset and unexplained cataracts,
The co-occurrence of HFI and other conditions (e.g.,
• Infectious hepatitis, sepsis, or disseminated intravascular coagulation
• Autoimmune liver disease
• Neonatal hemochromatosis, which is considered a congenital alloimmune hepatitis
• Toxic ingestion
• Hemophagocytic lymphohistiocytosis (See
• In addition to HFI, infection, toxic ingestion, and neoplasm should be considered in the evaluation of adult- or childhood-onset of chronic liver disease.
• In addition to HFI, gastroesophageal reflux, pyloric stenosis,
• In children or adults with early-onset and unexplained cataracts,
• The co-occurrence of HFI and other conditions (e.g.,
## Management
No clinical practice guidelines for hereditary fructose intolerance have been published.
Note: If HFI is suspected, potential sources of fructose need to be removed immediately (see
To establish the extent of disease and needs in an individual diagnosed with hereditary fructose intolerance (HFI), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Fructose Intolerance
Remove potential sources of fructose immediately.
Assess current diet & nutritional status.
Advise affected person, family members, & caregivers about
Community or
Social work involvement for parental support.
BUN = blood urea nitrogen; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Management by multidisciplinary specialists, including gastroenterology, nephrology, ophthalmology, and clinical/metabolic nutrition, is recommended.
Treatment of Manifestations in Individuals with Hereditary Fructose Intolerance
Intravenous glucose (dextrose)
Supportive treatment of hepatic insufficiency (incl fresh frozen plasma or exchange transfusion)
Treatment of metabolic acidosis, if present
See
Dietary assessment should be ongoing as the child grows, develops different tastes, & tries different foods.
Remove sources of fructose.
Treat manifestations of hepatic insufficiency (e.g., hypoalbuminemia, coagulopathy).
Monitor renal function until normalized.
If necessary, implement renal replacement therapy.
Also to avoid are medicines and formulas in which fructose/sucrose may not be listed as a primary component, examples of which include syrups, enema solutions, some immunoglobulin solutions, and many infant and pediatric nutritional drinks. When ingredients are listed, the terms "sugar," "table sugar," "natural flavorings," and even in some cases "sugar-free" or "no added sugar" (with no further clarification on the type of carbohydrate used) should raise suspicion for the presence of fructose, sucrose, or sorbitol.
An extensive list of tolerated and non-tolerated sugars in HFI can be found
Dietary restriction should be strictly followed and maintained, especially in infancy. Currently, there are no specific guidelines regarding dietary fructose limits in any age group.
Ensuring adequate vitamin supplementation in the setting of reduced fruit and vegetable intake is imperative. Daily supplementation with a "sugar-free" multivitamin is recommended to prevent micronutrient deficiencies, specifically the water-soluble vitamins.
Tolerance of dietary fructose probably depends on an individual's residual enzyme activity. Furthermore, because actual fructose content in foods may be unreliably reported or difficult to ascertain, adherence to complete dietary restriction of fructose, sucrose, sorbitol, and sucralose may be difficult to attain and unrealistic for some individuals with HFI.
Dietary Guidelines for Hereditary Fructose Intolerance (HFI)
Adapted from
The following are recommendations:
During any hospitalization, all members of the care team should be aware of the diagnosis of HFI, and the patient is advised to always wear a medically approved alert bracelet/necklace that provides information about the diagnosis of HFI.
"Red flags" should be placed in the patient's chart or medical record to alert practitioners to the HFI diagnosis and to the medical risks associated with exposures to foods and/or medications (oral or parenteral) containing fructose, sucrose, sorbitol, or sucralose.
For parenteral medications, hospital pharmacists should clear use of medications on a case-by-case basis.
The 24% sucrose solution (routinely administered to hospitalized neonates for minor procedures)
Oral fructose challenge is no longer considered a favorable approach to diagnosis of HFI.
Note: Although there is no single list of medications for these or related sugars, an advanced search on
There are no formal guidelines for surveillance for individuals with HFI (e.g., frequency of subspecialty visits with physicians and/or dieticians with expertise in management of inherited metabolic diseases).
Once the diagnosis of HFI has been made, periodic evaluation of liver function, renal function, and growth is reasonable, particularly if there are concerns regarding compliance with the fructose/sucrose/sorbitol/sucralose-restricted diet.
Note: Isoelectric focusing of transferrin (or N-glycan evaluation by MS/MS) and/or monitoring of plasma lysosomal enzymes (aspartylglucosaminidase aspartylglucosaminidase and alpha-manosidase) may be elevated in untreated HFI, and thus, have been suggested as markers of disease control in HFI. None of these clinically available tests have definitively proven utility in diagnosis or surveillance [
Recommended Surveillance for Individuals with Hereditary Fructose Intolerance
Dietary assessment by nutritionist as child grows, develops different tastes, & tries different foods
Monitor for vitamin & mineral deficiencies.
N-glycan eval
Plasma lysosomal enzyme analysis
Dietary intake assessment
BUN = blood urea nitrogen; NAFLD = non-alcoholic fatty liver disease
Great care should be taken to avoid enteral or parenteral exposure to fructose, sorbitol, sucrose, sucralose, and polysorbate, as administration of these substances to individuals with HFI can be fatal.
The following resources can be valuable in determining medical and dietary safety:
Dietary guidance (including prohibited foods) outlined in
An extensive list of tolerated and non-tolerated
Note: Fructose tolerance testing ("fructose challenge") to diagnose HFI can be hazardous and should not be used.
The vaccines M-M-RVAXPRO and Proquad
Rotarix
Vaccines
Once the
See
There are few reports of management of pregnant women with HFI or pregnancy-related complications in HFI. In general, in familial reports in which pregnancies are not expressly discussed, it appears that HFI in a pregnant mother does not cause harm to the mother or the child provided that strict fructose avoidance is followed during the pregnancy.
In one family a woman with enzymatically documented HFI had three children (presumably from the same father), all of whom also had HFI [
Search
• Remove potential sources of fructose immediately.
• Assess current diet & nutritional status.
• Advise affected person, family members, & caregivers about
• Community or
• Social work involvement for parental support.
• Intravenous glucose (dextrose)
• Supportive treatment of hepatic insufficiency (incl fresh frozen plasma or exchange transfusion)
• Treatment of metabolic acidosis, if present
• See
• Dietary assessment should be ongoing as the child grows, develops different tastes, & tries different foods.
• Remove sources of fructose.
• Treat manifestations of hepatic insufficiency (e.g., hypoalbuminemia, coagulopathy).
• Monitor renal function until normalized.
• If necessary, implement renal replacement therapy.
• During any hospitalization, all members of the care team should be aware of the diagnosis of HFI, and the patient is advised to always wear a medically approved alert bracelet/necklace that provides information about the diagnosis of HFI.
• "Red flags" should be placed in the patient's chart or medical record to alert practitioners to the HFI diagnosis and to the medical risks associated with exposures to foods and/or medications (oral or parenteral) containing fructose, sucrose, sorbitol, or sucralose.
• For parenteral medications, hospital pharmacists should clear use of medications on a case-by-case basis.
• The 24% sucrose solution (routinely administered to hospitalized neonates for minor procedures)
• Oral fructose challenge is no longer considered a favorable approach to diagnosis of HFI.
• Dietary assessment by nutritionist as child grows, develops different tastes, & tries different foods
• Monitor for vitamin & mineral deficiencies.
• N-glycan eval
• Plasma lysosomal enzyme analysis
• Dietary intake assessment
• Dietary guidance (including prohibited foods) outlined in
• An extensive list of tolerated and non-tolerated
• The vaccines M-M-RVAXPRO and Proquad
• Rotarix
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hereditary fructose intolerance (HFI), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Fructose Intolerance
Remove potential sources of fructose immediately.
Assess current diet & nutritional status.
Advise affected person, family members, & caregivers about
Community or
Social work involvement for parental support.
BUN = blood urea nitrogen; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Remove potential sources of fructose immediately.
• Assess current diet & nutritional status.
• Advise affected person, family members, & caregivers about
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Management by multidisciplinary specialists, including gastroenterology, nephrology, ophthalmology, and clinical/metabolic nutrition, is recommended.
Treatment of Manifestations in Individuals with Hereditary Fructose Intolerance
Intravenous glucose (dextrose)
Supportive treatment of hepatic insufficiency (incl fresh frozen plasma or exchange transfusion)
Treatment of metabolic acidosis, if present
See
Dietary assessment should be ongoing as the child grows, develops different tastes, & tries different foods.
Remove sources of fructose.
Treat manifestations of hepatic insufficiency (e.g., hypoalbuminemia, coagulopathy).
Monitor renal function until normalized.
If necessary, implement renal replacement therapy.
• Intravenous glucose (dextrose)
• Supportive treatment of hepatic insufficiency (incl fresh frozen plasma or exchange transfusion)
• Treatment of metabolic acidosis, if present
• See
• Dietary assessment should be ongoing as the child grows, develops different tastes, & tries different foods.
• Remove sources of fructose.
• Treat manifestations of hepatic insufficiency (e.g., hypoalbuminemia, coagulopathy).
• Monitor renal function until normalized.
• If necessary, implement renal replacement therapy.
## Prevention of Primary Manifestations
Also to avoid are medicines and formulas in which fructose/sucrose may not be listed as a primary component, examples of which include syrups, enema solutions, some immunoglobulin solutions, and many infant and pediatric nutritional drinks. When ingredients are listed, the terms "sugar," "table sugar," "natural flavorings," and even in some cases "sugar-free" or "no added sugar" (with no further clarification on the type of carbohydrate used) should raise suspicion for the presence of fructose, sucrose, or sorbitol.
An extensive list of tolerated and non-tolerated sugars in HFI can be found
Dietary restriction should be strictly followed and maintained, especially in infancy. Currently, there are no specific guidelines regarding dietary fructose limits in any age group.
Ensuring adequate vitamin supplementation in the setting of reduced fruit and vegetable intake is imperative. Daily supplementation with a "sugar-free" multivitamin is recommended to prevent micronutrient deficiencies, specifically the water-soluble vitamins.
Tolerance of dietary fructose probably depends on an individual's residual enzyme activity. Furthermore, because actual fructose content in foods may be unreliably reported or difficult to ascertain, adherence to complete dietary restriction of fructose, sucrose, sorbitol, and sucralose may be difficult to attain and unrealistic for some individuals with HFI.
Dietary Guidelines for Hereditary Fructose Intolerance (HFI)
Adapted from
The following are recommendations:
During any hospitalization, all members of the care team should be aware of the diagnosis of HFI, and the patient is advised to always wear a medically approved alert bracelet/necklace that provides information about the diagnosis of HFI.
"Red flags" should be placed in the patient's chart or medical record to alert practitioners to the HFI diagnosis and to the medical risks associated with exposures to foods and/or medications (oral or parenteral) containing fructose, sucrose, sorbitol, or sucralose.
For parenteral medications, hospital pharmacists should clear use of medications on a case-by-case basis.
The 24% sucrose solution (routinely administered to hospitalized neonates for minor procedures)
Oral fructose challenge is no longer considered a favorable approach to diagnosis of HFI.
Note: Although there is no single list of medications for these or related sugars, an advanced search on
• During any hospitalization, all members of the care team should be aware of the diagnosis of HFI, and the patient is advised to always wear a medically approved alert bracelet/necklace that provides information about the diagnosis of HFI.
• "Red flags" should be placed in the patient's chart or medical record to alert practitioners to the HFI diagnosis and to the medical risks associated with exposures to foods and/or medications (oral or parenteral) containing fructose, sucrose, sorbitol, or sucralose.
• For parenteral medications, hospital pharmacists should clear use of medications on a case-by-case basis.
• The 24% sucrose solution (routinely administered to hospitalized neonates for minor procedures)
• Oral fructose challenge is no longer considered a favorable approach to diagnosis of HFI.
## Surveillance
There are no formal guidelines for surveillance for individuals with HFI (e.g., frequency of subspecialty visits with physicians and/or dieticians with expertise in management of inherited metabolic diseases).
Once the diagnosis of HFI has been made, periodic evaluation of liver function, renal function, and growth is reasonable, particularly if there are concerns regarding compliance with the fructose/sucrose/sorbitol/sucralose-restricted diet.
Note: Isoelectric focusing of transferrin (or N-glycan evaluation by MS/MS) and/or monitoring of plasma lysosomal enzymes (aspartylglucosaminidase aspartylglucosaminidase and alpha-manosidase) may be elevated in untreated HFI, and thus, have been suggested as markers of disease control in HFI. None of these clinically available tests have definitively proven utility in diagnosis or surveillance [
Recommended Surveillance for Individuals with Hereditary Fructose Intolerance
Dietary assessment by nutritionist as child grows, develops different tastes, & tries different foods
Monitor for vitamin & mineral deficiencies.
N-glycan eval
Plasma lysosomal enzyme analysis
Dietary intake assessment
BUN = blood urea nitrogen; NAFLD = non-alcoholic fatty liver disease
• Dietary assessment by nutritionist as child grows, develops different tastes, & tries different foods
• Monitor for vitamin & mineral deficiencies.
• N-glycan eval
• Plasma lysosomal enzyme analysis
• Dietary intake assessment
## Agents/Circumstances to Avoid
Great care should be taken to avoid enteral or parenteral exposure to fructose, sorbitol, sucrose, sucralose, and polysorbate, as administration of these substances to individuals with HFI can be fatal.
The following resources can be valuable in determining medical and dietary safety:
Dietary guidance (including prohibited foods) outlined in
An extensive list of tolerated and non-tolerated
Note: Fructose tolerance testing ("fructose challenge") to diagnose HFI can be hazardous and should not be used.
The vaccines M-M-RVAXPRO and Proquad
Rotarix
Vaccines
• Dietary guidance (including prohibited foods) outlined in
• An extensive list of tolerated and non-tolerated
• The vaccines M-M-RVAXPRO and Proquad
• Rotarix
## Evaluation of Relatives at Risk
Once the
See
## Pregnancy Management
There are few reports of management of pregnant women with HFI or pregnancy-related complications in HFI. In general, in familial reports in which pregnancies are not expressly discussed, it appears that HFI in a pregnant mother does not cause harm to the mother or the child provided that strict fructose avoidance is followed during the pregnancy.
In one family a woman with enzymatically documented HFI had three children (presumably from the same father), all of whom also had HFI [
## Therapies Under Investigation
Search
## Genetic Counseling
Hereditary fructose intolerance (HFI) is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are generally asymptomatic and are not at risk of developing HFI (see
If both parents are known to be heterozygous for an
Intrafamilial clinical variability has been observed in sibs who inherited biallelic
Heterozygotes (carriers) are generally asymptomatic and are not at risk of developing HFI (see
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are generally asymptomatic and are not at risk of developing HFI (see
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Intrafamilial clinical variability has been observed in sibs who inherited biallelic
• Heterozygotes (carriers) are generally asymptomatic and are not at risk of developing HFI (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Hereditary fructose intolerance (HFI) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
One of the pathogenic variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes (carriers) are generally asymptomatic and are not at risk of developing HFI (see
If both parents are known to be heterozygous for an
Intrafamilial clinical variability has been observed in sibs who inherited biallelic
Heterozygotes (carriers) are generally asymptomatic and are not at risk of developing HFI (see
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are generally asymptomatic and are not at risk of developing HFI (see
• One of the pathogenic variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an
• Intrafamilial clinical variability has been observed in sibs who inherited biallelic
• Heterozygotes (carriers) are generally asymptomatic and are not at risk of developing HFI (see
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
Hereditary Fructose Intolerance: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hereditary Fructose Intolerance (
Together with fructokinase and triokinase, the enzyme aldolase B participates in fructose metabolism, mostly in the liver, renal cortex, and intestinal mucosa. Aldolase B splits fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde. Hepatic formation of glycogen from fructose is principally catalyzed by aldolase B.
HFI results from loss of aldolase B function. Normally aldolase B rapidly converts intravenous fructose to glucose, resulting in hyperglycemia; fructose may also be converted to lactate, provoking metabolic acidosis. Accumulation of fructose-1-phosphate in the setting of diminished aldolase B function inhibits gluconeogenesis and glycogenolysis, causes overutilization and diminished regeneration of ATP, and impairs protein glycosylation.
Notable
Variant designation that does not conform to current naming conventions
Most common in all studies
## Molecular Pathogenesis
Together with fructokinase and triokinase, the enzyme aldolase B participates in fructose metabolism, mostly in the liver, renal cortex, and intestinal mucosa. Aldolase B splits fructose-1-phosphate into dihydroxyacetone phosphate and glyceraldehyde. Hepatic formation of glycogen from fructose is principally catalyzed by aldolase B.
HFI results from loss of aldolase B function. Normally aldolase B rapidly converts intravenous fructose to glucose, resulting in hyperglycemia; fructose may also be converted to lactate, provoking metabolic acidosis. Accumulation of fructose-1-phosphate in the setting of diminished aldolase B function inhibits gluconeogenesis and glycogenolysis, causes overutilization and diminished regeneration of ATP, and impairs protein glycosylation.
Notable
Variant designation that does not conform to current naming conventions
Most common in all studies
## Chapter Notes
Lachlan Ayres, MB, ChB, MRCP (2015-present)Peter R Baker II, MD, FAAP, FACMG (2015-present)Sommer Gaughan, RD, CSP (2015-present)James Weisfeld-Adams, MB, ChB, FAAP, FACMG; Children's Hospital Colorado (2015-2021)
18 February 2021 (bp) Comprehensive update posted live
17 December 2015 (me) Review posted live
15 July 2015 (jwa) Original submission
• 18 February 2021 (bp) Comprehensive update posted live
• 17 December 2015 (me) Review posted live
• 15 July 2015 (jwa) Original submission
## Author History
Lachlan Ayres, MB, ChB, MRCP (2015-present)Peter R Baker II, MD, FAAP, FACMG (2015-present)Sommer Gaughan, RD, CSP (2015-present)James Weisfeld-Adams, MB, ChB, FAAP, FACMG; Children's Hospital Colorado (2015-2021)
## Revision History
18 February 2021 (bp) Comprehensive update posted live
17 December 2015 (me) Review posted live
15 July 2015 (jwa) Original submission
• 18 February 2021 (bp) Comprehensive update posted live
• 17 December 2015 (me) Review posted live
• 15 July 2015 (jwa) Original submission
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|
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"J Jaeken, M Pirard, M Adamowicz, E Pronicka, E van Schaftingen. Inhibition of phosphomannose isomerase by fructose 1-phosphate: an explanation for defective N-glycosylation in hereditary fructose intolerance.. Pediatr Res. 1996;40:764-6",
"CL James, P Rellos, M Ali, AF Heeley, TM Cox. Neonatal screening for hereditary fructose intolerance: frequency of the most common mutant aldolase B allele (A149P) in the British population.. J Med Genet. 1996;33:837-41",
"H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22",
"GA Lazarin, IS Haque, S Nazareth, K Iori, AS Patterson, JL Jacobson, JR Marshall, WK Seltzer, P Patrizio, EA Evans, BS Srinivasan. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.. Genet Med. 2013;15:178-86",
"B Levin, VG Oberholzer, GJ Snodgrass, L Stimmler, MJ Wilmers. Fructosaemia: an inborn error of fructose metabolism.. Arch Dis Child. 1963;38:220-30",
"H Li, HM Byers, A Diaz-Kuan, MB Vos, PL Hall, S Tortorelli, R Singh, MB Wallenstein, M Allain, DP Dimmock, RM Farrell, S McCandless, MJ Gambello. Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas.. Mol Genet Metab. 2018;123:428-32",
"S. Locher. Acute liver and kidney failure following sorbitol infusion in a 28-year-old patient with undiagnosed fructose intolerance.. Anasth Intensivther Notfallmed. 1987;22:194-7",
"M Lu, LS Holliday, L Zhang, WA Dunn, SL Gluck. Interaction between aldolase and vacuolar H+-ATPase: evidence for direct coupling of glycolysis to the ATP-hydrolyzing proton pump.. J Biol Chem. 2001;276:30407-13",
"APPS Magalhães, MG Burin, CFM Souza, FH de Bitencourt, FM Sebastião, TO Silva, FPE Vairo, IVD Schwartz. Transferrin isoelectric focusing for the investigation of congenital disorders of glycosylation: analysis of a ten-year experience in a Brazilian center.. J Pediatr (Rio J) 2020;96:710-6",
"A Maiorana, A Sabia, T Corsetti, C Dionisi-Vici. Safety of vaccines administration in hereditary fructose intolerance.. Orphanet J Rare Dis 2020;15:274",
"F Marks, S Ordorica, I Hoskins, BK Young. Congenital hereditary fructose intolerance and pregnancy.. Am J Obstet Gynecol. 1989;160:362-3",
"RE Mass, WR Smith, JR Walsh. The association of hereditary fructose intolerance and renal tubular acidosis.. Am J Med Sci. 1966;251:516-23",
"H Michelakakis, M Moraitou, I Mavridou, E Dimitriou. Plasma lysosomal enzyme activities in congenital disorders of glycosylation, galactosemia and fructosemia.. Clin Chim Acta. 2009;401:81-3",
"DM Mock, JA Perman, M Thaler, RC Morris. Chronic fructose intoxication after infancy in children with hereditary fructose intolerance. A cause of growth retardation.. N Engl J Med. 1983;309:764-70",
"RC Morris. An experimental renal acidification defect in patients with hereditary fructose intolerance.. J Clin Invest. 1968;47:1648-63",
"P Müller, C Meier, HJ Böhme, T Richter. Fructose breath hydrogen test--is it really a harmless diagnostic procedure?. Dig Dis. 2003;21:276-8",
"E Newbrun, C Hoover, G Mettraux, H Graf. Comparison of dietary habits and dental health of subjects with hereditary fructose intolerance and control subjects.. J Am Dent Assoc. 1980;101:619-26",
"RD Oberhaensli, B Rajagopalan, DJ Taylor, GK Radda, JE Collins, JV Leonard, H Schwarz, N Herschkowitz. Study of hereditary fructose intolerance by use of 31P magnetic resonance spectroscopy.. Lancet. 1987;2:931-4",
"M Odièvre, C Gentil, M Gautier, D Alagille. Hereditary fructose intolerance in childhood. Diagnosis, management, and course in 55 patients.. Am J Dis Child. 1978;132:605-8",
"G Paolella, P Pisano, R Albano, L Cannaviello, C Mauro, G Esposito, P Vajro. Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance.. Ital J Pediatr. 2012;38:64",
"E Pronicka, M Adamowicz, A Kowalik, R Płoski, B Radomyska, M Rogaszewska, D Rokicki, J. Sykut-Cegielska. Elevated carbohydrate-deficient transferrin (CDT) and its normalization on dietary treatment as a useful biochemical test for hereditary fructose intolerance and galactosemia.. Pediatr Res. 2007;62:101-5",
"E Quintana, L Sturiale, R Montero, F Andrade, C Fernandez, ML Couce, R Barone, L Aldamiz-Echevarria, A Ribes, R Artuch, P Briones. Secondary disorders of glycosylation in inborn errors of fructose metabolism.. J Inherit Metab Dis. 2009;32:S273-8",
"S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24",
"M Sachs, F Asskali, H Förster, A Encke. Repeated perioperative administration of fructose and sorbitol in a female patient with hereditary fructose intolerance.. Z Ernahrungswiss. 1993;32:56-66",
"JC Sánchez-Gutiérrez, T Benlloch, MA Leal, B Samper, I García-Ripoll, JE Felíu. Molecular analysis of the aldolase B gene in patients with hereditary fructose intolerance from Spain.. J Med Genet. 2002;39",
"R Santer, J Rischewski, M von Weihe, M Niederhaus, S Schneppenheim, K Baerlocher, A Kohlschütter, A Muntau, HG Posselt, B Steinmann, R Schneppenheim. The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe.. Hum Mutat 2005;25:594",
"SJ Schrodi, A DeBarber, M He, Z Ye, P Peissig, JJ Van Wormer, R Haws, MH Brilliant, RD Steiner. Prevalence estimation for monogenic autosomal recessive diseases using population-based genetic data.. Hum Genet. 2015;134:659-69",
"JE Seegmiller, RM Dixon, GJ Kemp, PW Angus, TE McAlindon, P Dieppe, B Rajagopalan, GK Radda. Fructose-induced aberration of metabolism in familial gout identified by 31P magnetic resonance spectroscopy.. Proc Natl Acad Sci U S A. 1990;87:8326-30",
"N Simons, FG Debray, NC Schaper, EJM Feskens, CEM Hollak, JAP Bons, J Bierau, AJHM Houben, CG Schalkwijk, CDA Stehouwer, D Cassiman, MCGJ Brouwers. Kidney and vascular function in adult patients with hereditary fructose intolerance.. Mol Genet Metab Rep. 2020;23",
"G Van Den Berghe, L Hue, HG Hers. Effect of administration of the fructose on the glycogenolytic action of glucagon. An investigation of the pathogeny of hereditary fructose intolerance.. Biochem J. 1973;134:637-45"
] |
17/12/2015
|
18/2/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
hfpoik-tmp
|
hfpoik-tmp
|
[
"POIKTMP",
"POIKTMP",
"Serine protease FAM111B",
"FAM111B",
"Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis"
] |
Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
|
Sandra Mercier, Sébastien Küry, Sébastien Barbarot
|
Summary Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is characterized by the skin findings of poikiloderma (typically beginning in the first six months and mainly localized to the face), hypohidrosis with heat intolerance, mild lymphedema of the extremities, chronic erythematous and scaly skin lesions on the extremities, sclerosis of the digits, and mild palmoplantar keratoderma. Scalp hair, eyelashes, and/or eyebrows are typically sparse. Muscle contractures are usually seen in childhood and can be present as early as age two years. The majority of affected individuals develop progressive weakness of the proximal and distal muscles of all four limbs. Some adults develop progressive interstitial pulmonary fibrosis, which can be life threatening within three to four years after respiratory symptoms appear. Other features are exocrine pancreatic insufficiency, liver impairment, hematologic abnormalities, relative short stature, and cataract. The diagnosis of POIKTMP is established in a proband with early-onset poikiloderma with other findings, especially muscle contractures and/or muscle weakness and a heterozygous missense pathogenic variant in POIKTMP is inherited in an autosomal dominant manner. In approximately 50% of affected individuals, the
|
## Diagnosis
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP)
Skin (
Early-onset poikiloderma (characterized by erythema of the cheeks and face, skin atrophy, telangiectasias, and mottled pigmentation)
Hypotrichosis with sparse scalp hair, sparse or absent eyelashes and/or eyebrows
Hypohidrosis with heat intolerance
Mild lymphedema of the extremities
Multiple contractures, in particular triceps surae contractures in childhood
Myopathy with diffuse progressive muscular weakness, scoliosis
Restrictive pulmonary syndrome and/or pulmonary fibrosis
Exocrine pancreatic insufficiency
Liver impairment
Hematologic abnormalities (e.g., eosinophilia, thrombocytopenia, and/or bone marrow hypocellularity)
Other
Relative short stature
Cataract
Nail dystrophy
See
The vastus lateralis muscles (with relative sparing of the tibialis posterior); and
The anterior compartment of thighs (with relative sparing of posterior compartment).
These findings can confirm muscle involvement in asymptomatic individuals.
The diagnosis of POIKTMP
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Gene-targeted deletion/duplication analysis may be performed; however, since POIKTMP likely occurs as the result of a dominant-negative genetic mechanism and since large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The spectrum of variants detected in affected individuals and functional studies [Author, unpublished observations] suggest a dominant-negative mechanism of disease; therefore, deletion/duplication testing is unlikely to detect a disease-causing variant.
• Skin (
• Early-onset poikiloderma (characterized by erythema of the cheeks and face, skin atrophy, telangiectasias, and mottled pigmentation)
• Hypotrichosis with sparse scalp hair, sparse or absent eyelashes and/or eyebrows
• Hypohidrosis with heat intolerance
• Mild lymphedema of the extremities
• Early-onset poikiloderma (characterized by erythema of the cheeks and face, skin atrophy, telangiectasias, and mottled pigmentation)
• Hypotrichosis with sparse scalp hair, sparse or absent eyelashes and/or eyebrows
• Hypohidrosis with heat intolerance
• Mild lymphedema of the extremities
• Multiple contractures, in particular triceps surae contractures in childhood
• Myopathy with diffuse progressive muscular weakness, scoliosis
• Restrictive pulmonary syndrome and/or pulmonary fibrosis
• Exocrine pancreatic insufficiency
• Liver impairment
• Hematologic abnormalities (e.g., eosinophilia, thrombocytopenia, and/or bone marrow hypocellularity)
• Other
• Relative short stature
• Cataract
• Nail dystrophy
• Relative short stature
• Cataract
• Nail dystrophy
• Early-onset poikiloderma (characterized by erythema of the cheeks and face, skin atrophy, telangiectasias, and mottled pigmentation)
• Hypotrichosis with sparse scalp hair, sparse or absent eyelashes and/or eyebrows
• Hypohidrosis with heat intolerance
• Mild lymphedema of the extremities
• Relative short stature
• Cataract
• Nail dystrophy
• See
• The vastus lateralis muscles (with relative sparing of the tibialis posterior); and
• The anterior compartment of thighs (with relative sparing of posterior compartment).
• The vastus lateralis muscles (with relative sparing of the tibialis posterior); and
• The anterior compartment of thighs (with relative sparing of posterior compartment).
• These findings can confirm muscle involvement in asymptomatic individuals.
• The vastus lateralis muscles (with relative sparing of the tibialis posterior); and
• The anterior compartment of thighs (with relative sparing of posterior compartment).
## Suggestive Findings
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP)
Skin (
Early-onset poikiloderma (characterized by erythema of the cheeks and face, skin atrophy, telangiectasias, and mottled pigmentation)
Hypotrichosis with sparse scalp hair, sparse or absent eyelashes and/or eyebrows
Hypohidrosis with heat intolerance
Mild lymphedema of the extremities
Multiple contractures, in particular triceps surae contractures in childhood
Myopathy with diffuse progressive muscular weakness, scoliosis
Restrictive pulmonary syndrome and/or pulmonary fibrosis
Exocrine pancreatic insufficiency
Liver impairment
Hematologic abnormalities (e.g., eosinophilia, thrombocytopenia, and/or bone marrow hypocellularity)
Other
Relative short stature
Cataract
Nail dystrophy
See
The vastus lateralis muscles (with relative sparing of the tibialis posterior); and
The anterior compartment of thighs (with relative sparing of posterior compartment).
These findings can confirm muscle involvement in asymptomatic individuals.
• Skin (
• Early-onset poikiloderma (characterized by erythema of the cheeks and face, skin atrophy, telangiectasias, and mottled pigmentation)
• Hypotrichosis with sparse scalp hair, sparse or absent eyelashes and/or eyebrows
• Hypohidrosis with heat intolerance
• Mild lymphedema of the extremities
• Early-onset poikiloderma (characterized by erythema of the cheeks and face, skin atrophy, telangiectasias, and mottled pigmentation)
• Hypotrichosis with sparse scalp hair, sparse or absent eyelashes and/or eyebrows
• Hypohidrosis with heat intolerance
• Mild lymphedema of the extremities
• Multiple contractures, in particular triceps surae contractures in childhood
• Myopathy with diffuse progressive muscular weakness, scoliosis
• Restrictive pulmonary syndrome and/or pulmonary fibrosis
• Exocrine pancreatic insufficiency
• Liver impairment
• Hematologic abnormalities (e.g., eosinophilia, thrombocytopenia, and/or bone marrow hypocellularity)
• Other
• Relative short stature
• Cataract
• Nail dystrophy
• Relative short stature
• Cataract
• Nail dystrophy
• Early-onset poikiloderma (characterized by erythema of the cheeks and face, skin atrophy, telangiectasias, and mottled pigmentation)
• Hypotrichosis with sparse scalp hair, sparse or absent eyelashes and/or eyebrows
• Hypohidrosis with heat intolerance
• Mild lymphedema of the extremities
• Relative short stature
• Cataract
• Nail dystrophy
• See
• The vastus lateralis muscles (with relative sparing of the tibialis posterior); and
• The anterior compartment of thighs (with relative sparing of posterior compartment).
• The vastus lateralis muscles (with relative sparing of the tibialis posterior); and
• The anterior compartment of thighs (with relative sparing of posterior compartment).
• These findings can confirm muscle involvement in asymptomatic individuals.
• The vastus lateralis muscles (with relative sparing of the tibialis posterior); and
• The anterior compartment of thighs (with relative sparing of posterior compartment).
## Establishing the Diagnosis
The diagnosis of POIKTMP
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Gene-targeted deletion/duplication analysis may be performed; however, since POIKTMP likely occurs as the result of a dominant-negative genetic mechanism and since large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The spectrum of variants detected in affected individuals and functional studies [Author, unpublished observations] suggest a dominant-negative mechanism of disease; therefore, deletion/duplication testing is unlikely to detect a disease-causing variant.
## Option 1
Gene-targeted deletion/duplication analysis may be performed; however, since POIKTMP likely occurs as the result of a dominant-negative genetic mechanism and since large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant (see
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
The spectrum of variants detected in affected individuals and functional studies [Author, unpublished observations] suggest a dominant-negative mechanism of disease; therefore, deletion/duplication testing is unlikely to detect a disease-causing variant.
## Clinical Characteristics
To date, 31 individuals have been identified with a pathogenic variant in
Individuals with hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) can exhibit few or many of the associated clinical features. The severity of the features (e.g., skin or muscle abnormalities) can vary. Intrafamilial clinical variability has been observed [
Skin abnormalities are the earliest findings. Of note, skin lesions – particularly facial poikiloderma – improve with time.
Muscle weakness is generally associated with muscle atrophy and sometimes thoracolumbar scoliosis.
Serum creatine kinase is either normal or slightly increased. When performed, electromyography may show a normal or myopathic pattern.
Recurrent bronchitis can be observed. Abnormal lung function with restrictive pulmonary disease is common.
Some adults develop progressive interstitial pulmonary fibrosis, manifest as progressive breathlessness and dry cough; it can be life threatening within three to four years after the first respiratory symptoms appear.
POIKTMP is most frequently caused by heterozygosity for missense
Upstream variants located outside the loop (codons 421, 430) appear to be associated with a less severe phenotype, especially regarding muscle features [
The phenotype of pathogenic variants in codon 621 appears to be less severe than the phenotype observed with pathogenic variants in codons 625, 627, and 628 [
Further studies are needed to confirm these preliminary genotype-phenotype correlations.
To the authors' knowledge the penetrance of POIKTMP is 100%, with occurrence of skin features in early childhood.
The prevalence of POIKTMP is unknown. The condition is thought to be ubiquitous and is likely underdiagnosed.
• Upstream variants located outside the loop (codons 421, 430) appear to be associated with a less severe phenotype, especially regarding muscle features [
• The phenotype of pathogenic variants in codon 621 appears to be less severe than the phenotype observed with pathogenic variants in codons 625, 627, and 628 [
## Clinical Description
To date, 31 individuals have been identified with a pathogenic variant in
Individuals with hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) can exhibit few or many of the associated clinical features. The severity of the features (e.g., skin or muscle abnormalities) can vary. Intrafamilial clinical variability has been observed [
Skin abnormalities are the earliest findings. Of note, skin lesions – particularly facial poikiloderma – improve with time.
Muscle weakness is generally associated with muscle atrophy and sometimes thoracolumbar scoliosis.
Serum creatine kinase is either normal or slightly increased. When performed, electromyography may show a normal or myopathic pattern.
Recurrent bronchitis can be observed. Abnormal lung function with restrictive pulmonary disease is common.
Some adults develop progressive interstitial pulmonary fibrosis, manifest as progressive breathlessness and dry cough; it can be life threatening within three to four years after the first respiratory symptoms appear.
## Skin
Skin abnormalities are the earliest findings. Of note, skin lesions – particularly facial poikiloderma – improve with time.
## Muscle
Muscle weakness is generally associated with muscle atrophy and sometimes thoracolumbar scoliosis.
Serum creatine kinase is either normal or slightly increased. When performed, electromyography may show a normal or myopathic pattern.
## Lung
Recurrent bronchitis can be observed. Abnormal lung function with restrictive pulmonary disease is common.
Some adults develop progressive interstitial pulmonary fibrosis, manifest as progressive breathlessness and dry cough; it can be life threatening within three to four years after the first respiratory symptoms appear.
## Gastrointestinal
## Other Features
## Histopathology
## Genotype-Phenotype Correlations
POIKTMP is most frequently caused by heterozygosity for missense
Upstream variants located outside the loop (codons 421, 430) appear to be associated with a less severe phenotype, especially regarding muscle features [
The phenotype of pathogenic variants in codon 621 appears to be less severe than the phenotype observed with pathogenic variants in codons 625, 627, and 628 [
Further studies are needed to confirm these preliminary genotype-phenotype correlations.
• Upstream variants located outside the loop (codons 421, 430) appear to be associated with a less severe phenotype, especially regarding muscle features [
• The phenotype of pathogenic variants in codon 621 appears to be less severe than the phenotype observed with pathogenic variants in codons 625, 627, and 628 [
## Penetrance
To the authors' knowledge the penetrance of POIKTMP is 100%, with occurrence of skin features in early childhood.
## Prevalence
The prevalence of POIKTMP is unknown. The condition is thought to be ubiquitous and is likely underdiagnosed.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders with phenotypic similarity to hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) are summarized in
Genes and Disorders to Consider in the Differential Diagnosis of Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
AR = autosomal recessive; MOI = mode of inheritance
## Management
To establish the extent of disease and needs in an individual diagnosed with hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
MOI = mode of inheritance; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
Avoidance of excessive sun exposure
Use of sunscreens w/both UVA & UVB protection
Avoidance of excessive heat exposure
Control of fever
Manual lymphatic drainage
Compression
PT & exercise to promote mobility & prevent contractures
Calcium & vitamin D supplements may also be warranted in those w/muscle weakness to prevent osteopenia.
Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device if needed
Noninvasive ventilation if needed
PT = physical therapy
Recommended Surveillance for Individuals with Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
PT assessment for muscle weakness or contractures
Orthopedic eval for contractures (w/attn to Achilles tendon contractures) & scoliosis
Blood ionogram (Na
TSH
DLCO = diffusing capacity of the lungs for carbon monoxide; FVC = forced vital capacity; PT = physical therapy
Avoid the following:
Excessive sun exposure, which may exacerbate the rash
Exposure to heat because of heat intolerance secondary to hypohidrosis
See
Search
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• Avoidance of excessive sun exposure
• Use of sunscreens w/both UVA & UVB protection
• Avoidance of excessive heat exposure
• Control of fever
• Manual lymphatic drainage
• Compression
• PT & exercise to promote mobility & prevent contractures
• Calcium & vitamin D supplements may also be warranted in those w/muscle weakness to prevent osteopenia.
• Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device if needed
• Noninvasive ventilation if needed
• PT assessment for muscle weakness or contractures
• Orthopedic eval for contractures (w/attn to Achilles tendon contractures) & scoliosis
• Blood ionogram (Na
• TSH
• Excessive sun exposure, which may exacerbate the rash
• Exposure to heat because of heat intolerance secondary to hypohidrosis
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
MOI = mode of inheritance; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
Avoidance of excessive sun exposure
Use of sunscreens w/both UVA & UVB protection
Avoidance of excessive heat exposure
Control of fever
Manual lymphatic drainage
Compression
PT & exercise to promote mobility & prevent contractures
Calcium & vitamin D supplements may also be warranted in those w/muscle weakness to prevent osteopenia.
Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device if needed
Noninvasive ventilation if needed
PT = physical therapy
• Avoidance of excessive sun exposure
• Use of sunscreens w/both UVA & UVB protection
• Avoidance of excessive heat exposure
• Control of fever
• Manual lymphatic drainage
• Compression
• PT & exercise to promote mobility & prevent contractures
• Calcium & vitamin D supplements may also be warranted in those w/muscle weakness to prevent osteopenia.
• Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device if needed
• Noninvasive ventilation if needed
## Surveillance
Recommended Surveillance for Individuals with Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis
PT assessment for muscle weakness or contractures
Orthopedic eval for contractures (w/attn to Achilles tendon contractures) & scoliosis
Blood ionogram (Na
TSH
DLCO = diffusing capacity of the lungs for carbon monoxide; FVC = forced vital capacity; PT = physical therapy
• PT assessment for muscle weakness or contractures
• Orthopedic eval for contractures (w/attn to Achilles tendon contractures) & scoliosis
• Blood ionogram (Na
• TSH
## Agents/Circumstances to Avoid
Avoid the following:
Excessive sun exposure, which may exacerbate the rash
Exposure to heat because of heat intolerance secondary to hypohidrosis
• Excessive sun exposure, which may exacerbate the rash
• Exposure to heat because of heat intolerance secondary to hypohidrosis
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is inherited in an autosomal dominant manner.
Approximately 50% of individuals diagnosed with POIKTMP have an affected parent.
Approximately 50% of individuals diagnosed with POIKTMP have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Although all sibs who inherit a
If the
If the parents have not been tested for the
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Approximately 50% of individuals diagnosed with POIKTMP have an affected parent.
• Approximately 50% of individuals diagnosed with POIKTMP have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Although all sibs who inherit a
• If the
• If the parents have not been tested for the
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is inherited in an autosomal dominant manner.
## Risk to Family Members
Approximately 50% of individuals diagnosed with POIKTMP have an affected parent.
Approximately 50% of individuals diagnosed with POIKTMP have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Although all sibs who inherit a
If the
If the parents have not been tested for the
• Approximately 50% of individuals diagnosed with POIKTMP have an affected parent.
• Approximately 50% of individuals diagnosed with POIKTMP have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Although all sibs who inherit a
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hereditary Fibrosing Poikiloderma with Tendon Contractures, Myopathy, and Pulmonary Fibrosis (
The FAM111B protein is predicted to contain a trypsin-like cysteine/serine peptidase domain. A role in DNA replication is suggested [
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is most frequently caused by heterozygosity for missense
Notable
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
## Molecular Pathogenesis
The FAM111B protein is predicted to contain a trypsin-like cysteine/serine peptidase domain. A role in DNA replication is suggested [
Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is most frequently caused by heterozygosity for missense
Notable
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
## Chapter Notes
Areas of interest/inquiry:
Prof Sandra Mercier, MD, PhD, clinician geneticist; Dr Sébastien Barbarot, MD, PhD, dermatologist: diagnosis and clinical follow up of patients with POIKTMP
Sébastien Küry, DVM, PhD:
Prof Sandra Mercier and Dr Sébastien Küry are part of the Inserm UMR 1087 / CNRS UMR 6291 research team where functional studies are underway to understand the pathophysiology of the disease and find therapeutic approaches.
Contact: [email protected]
We thank the families and patients for their cooperation and support.
9 September 2021 (sm) Revision: nucleotide variant correction: c.1881A>T
5 August 2021 (sw) Comprehensive update posted live
13 October 2016 (bp) Review posted live
1 February 2016 (sm) Original submission
• Prof Sandra Mercier, MD, PhD, clinician geneticist; Dr Sébastien Barbarot, MD, PhD, dermatologist: diagnosis and clinical follow up of patients with POIKTMP
• Sébastien Küry, DVM, PhD:
• 9 September 2021 (sm) Revision: nucleotide variant correction: c.1881A>T
• 5 August 2021 (sw) Comprehensive update posted live
• 13 October 2016 (bp) Review posted live
• 1 February 2016 (sm) Original submission
## Author Notes
Areas of interest/inquiry:
Prof Sandra Mercier, MD, PhD, clinician geneticist; Dr Sébastien Barbarot, MD, PhD, dermatologist: diagnosis and clinical follow up of patients with POIKTMP
Sébastien Küry, DVM, PhD:
Prof Sandra Mercier and Dr Sébastien Küry are part of the Inserm UMR 1087 / CNRS UMR 6291 research team where functional studies are underway to understand the pathophysiology of the disease and find therapeutic approaches.
Contact: [email protected]
• Prof Sandra Mercier, MD, PhD, clinician geneticist; Dr Sébastien Barbarot, MD, PhD, dermatologist: diagnosis and clinical follow up of patients with POIKTMP
• Sébastien Küry, DVM, PhD:
## Acknowledgments
We thank the families and patients for their cooperation and support.
## Revision History
9 September 2021 (sm) Revision: nucleotide variant correction: c.1881A>T
5 August 2021 (sw) Comprehensive update posted live
13 October 2016 (bp) Review posted live
1 February 2016 (sm) Original submission
• 9 September 2021 (sm) Revision: nucleotide variant correction: c.1881A>T
• 5 August 2021 (sw) Comprehensive update posted live
• 13 October 2016 (bp) Review posted live
• 1 February 2016 (sm) Original submission
## References
## Literature Cited
Facial and scalp skin lesions
A-E. Poikiloderma and alopecia of the scalp, eyebrows, and eyelashes in childhood
F. Improvement of the facial lesions in adulthood
From
Skin lesions of the upper and lower limbs
A. Eczema-like and psoriasis-like dermatosis of the upper limbs
B. Hyperpigmented regions
C-F. Chronic lymphedema of lower limbs (D, E ) and hands (C, F)
E, G. Diffuse skin lesions of the lower limbs and cellulitis
From
Muscle MRI (coronal images of the thighs and calves; T
A. Diffuse bright appearance of the anterior compartment of the thighs (upper images), particularly in the vastus lateralis muscles, and the posterior compartment of the calves (lower images) in an individual age seven years
B. Relative sparing of the posterior compartment of the thighs (upper images) in an individual age 30 years with severe disease
C. Specific involvement of the vastus lateralis muscles (white asterisks) with sparing of other thigh muscles in an individual age 38 years
From
A-D. Muscle histology:
A, B. Fatty tissue, fragmented muscle fascicles next to normal fascicles
C, D. Nonspecific myopathic changes with variation in fiber size
(hematoxylin and eosin staining [H&E]; A: x20 magnification and B-D: x100)
E-F. Skin histology:
E. Epidermal atrophy, scleroderma-like features with diffuse mild collagen sclerosis (H&E; x20 magnification)
F. Elastic dystrophy with formation of elastic globules (arrowheads) in the papillary dermis (Weigert staining; x150)
From
|
[
"R Aviner, A Shenoy, O Elroy-Stein, T Geiger. Uncovering hidden layers of cell cycle regulation through integrative multi-omic analysis.. PLoS Genet. 2015;11",
"E Chasseuil, JA McGrath, A Seo, X Balguerie, N Bodak, H Chasseuil, M Denis-Musquer, A Goldenberg, R Goussot, AD Irvine, NP Khumalo, MC King, S Küry, D Lipsker, S Mallet, BM Mayosi, A Nanda, E Puzenat, E Salort-Campana, R Sidbury, A Shimamura, S Bézieau, S Mercier, S Barbarot. Dermatological manifestations of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP): a case series of 28 patients.. Br J Dermatol. 2019;181:862-4",
"F Chen, L Zheng, Y Li, H Li, Z Yao, M. Li. Mutation in FAM111B causes hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis.. Acta Derm Venereol. 2019;99:695-6",
"Y Dokic, Y Albahrani, T Phung, K Patel, M de Guzman, P Hertel, R Hunt. Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis: Hepatic disease in a child with a novel pathogenic variant of FAM111B.. JAAD Case Rep. 2020;6:1217-20",
"R Goussot, M Prasad, C Stoetzel, C Lenormand, H Dollfus, D Lipsker. Expanding phenotype of hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis caused by FAM111B mutations: Report of an additional family raising the question of cancer predisposition and a short review of early-onset poikiloderma.. JAAD Case Rep. 2017;3:143-50",
"V Kazlouskaya, EJ Feldman, J Jakus, E Heilman, S Glick. A case of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP) with the emphasis on cutaneous histopathological findings.. J Eur Acad Dermatol Venereol. 2018;32:e443-e445",
"NP Khumalo, K Pillay, P Beighton, H Wainwright, B Walker, N Saxe, BM Mayosi, ED Bateman. Poikiloderma, tendon contracture and pulmonary fibrosis: a new autosomal dominant syndrome?. Br J Dermatol. 2006;155:1057-61",
"S Mercier, S Küry, E Salort-Campana, A Magot, U Agbim, T Besnard, N Bodak, C Bou-Hanna, F Breheret, P Brunelle, F Caillon, B Chabrol, V Cormier-Daire, A David, B Eymard, L Faivre, D Figarella-Branger, E Fleurence, M Ganapathi, R Gherardi, A Goldenberg, A Hamel, J Igual, AD Irvine, D Israel-Biet, C Kannengiesser, C Laboisse, C Le Caignec, JY Mahe, S Mallet, S MacGowan, MA McAleer, I McLean, C Meni, A Munnich, JM Mussini, PL Nagy, J Odel, GM O'Regan, Y Pereon, J Perrier, J Piard, E Puzenat, JB Sampson, F Smith, N Soufir, K Tanji, C Thauvin, C Ulane, RM Watson, NP Khumalo, BM Mayosi, S Barbarot, S Bezieau. Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations.. Orphanet J Rare Dis. 2015;10:135",
"S Mercier, S Küry, G Shaboodien, DT Houniet, NP Khumalo, C Bou-Hanna, N Bodak, V Cormier-Daire, A David, L Faivre, D Figarella-Branger, RK Gherardi, E Glen, A Hamel, C Laboisse, C Le Caignec, P Lindenbaum, A Magot, A Munnich, JM Mussini, K Pillay, T Rahman, R Redon, E Salort-Campana, M Santibanez-Koref, C Thauvin, S Barbarot, B Keavney, S Bézieau, BM Mayosi. Mutations in FAM111B cause hereditary fibrosing poikiloderma with tendon contracture, myopathy, and pulmonary fibrosis.. Am J Hum Genet. 2013;93:1100-7",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"A Seo, T Walsh, MK Lee, PA Ho, EK Hsu, R Sidbury, MC King, A Shimamura. FAM111B mutation is associated with inherited exocrine pancreatic dysfunction.. Pancreas. 2016;45:858-62",
"T Takeichi, A Nanda, HS Yang, CK Hsu, JY Lee, H Al-Ajmi, M Akiyama, MA Simpson, JA McGrath. Syndromic inherited poikiloderma due to a de novo mutation in FAM111B.. Br J Dermatol. 2017;176:534-6",
"Z Zhang, J Zhang, F Chen, L Zheng, H Li, M Liu, M Li, Z Yao. Family of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis caused by a novel FAM111B mutation.. J Dermatol. 2019;46:1014-8"
] |
13/10/2016
|
5/8/2021
|
9/9/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
hgc
|
hgc
|
[
"DGLBCS",
"Hereditary Diffuse Gastric Cancer (HDGC)",
"Hereditary Diffuse Gastric Cancer (HDGC)",
"DGLBCS",
"Cadherin-1",
"Catenin alpha-1",
"CDH1",
"CTNNA1",
"Diffuse Gastric and Lobular Breast Cancer Syndrome"
] |
Diffuse Gastric and Lobular Breast Cancer Syndrome
|
Rita Barbosa-Matos, Lilian Córdova, Kasmintan Schrader, Carla Oliveira
|
Summary Diffuse gastric and lobular breast cancer syndrome (DGLBCS) is associated with an increased risk, in males and females, of diffuse gastric cancer (DGC), a poorly differentiated adenocarcinoma (also referred to as signet ring cell carcinoma or isolated cell-type carcinoma) that infiltrates into the stomach wall, causing thickening of the wall ( The diagnosis of DGLBCS can be established in an individual with suggestive findings and a germline heterozygous pathogenic variant in For females with In individuals with In individuals with suspected DGLBCS of unknown cause (also referred to as HDGC-like), referral to a high-risk gastric screening program with a thorough ≥30-minute upper endoscopy with multiple targeted and random biopsies annually beginning at age 40 years or ten years prior to the earliest gastric cancer diagnosis in the family; endoscopy interval can be increased after two consecutive normal biopsies at the discretion of the endoscopist. Referral to a high-risk breast cancer screening program; in those with a personal or family history of breast cancer of any type, monthly self-exams beginning at age 20 years, annual clinical breast exam and education of clinical features of breast cancer beginning at age 30 years; additional breast screening as recommended by high-risk breast cancer specialists. DGLBCS is inherited in an autosomal dominant manner. The majority of individuals diagnosed with
|
## Diagnosis
Consensus genetic testing criteria for diffuse gastric and lobular breast cancer syndrome (DGLBCS), also known as hereditary diffuse gastric cancer (HDGC), have been published [
DGLBCS
Diffuse gastric cancer (DGC) diagnosed at age <50 years
DGC in an individual of Māori ethnicity diagnosed at any age
DGC diagnosed at any age in an individual with a personal history or first-degree relative with cleft lip or cleft palate
DGC and lobular breast cancer (LBC), both diagnosed in an individual at age <70 years
Bilateral LBC, diagnosed at age <70 years
Pathologically confirmed gastric signet ring cell carcinoma in situ or pagetoid spread of signet ring cells identified at age <50 years
≥2 first- or second-degree relatives with gastric cancer diagnosed at any age, and at least one of these family members diagnosed with DGC
≥1 first- or second-degree relative with DGC at any age and ≥1 first- or second-degree relative with LBC diagnosed at age <70 years
≥2 first- or second-degree relatives with LBC diagnosed at age <50 years
Note: Although it is advisable for all cancer diagnoses to be confirmed with histopathology findings, in criteria with two or more cancer diagnoses, at least one should be accompanied by confirmed histologic evidence.
A diagnosis of DGLBCS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
A proband with one of the clinical features described in
≥2 family members (first- or second-degree relatives of each other) with gastric cancer regardless of age of diagnosis, with at least one of these individuals with confirmed DGC;
≥1 family member with DGC at any age and ≥1 different family member with LBC diagnosed at age <70 years (first- or second-degree relatives of each other).
Note: For these criteria, the proband is included in the family member(s).
For an introduction to multigene panels click
Molecular Genetic Testing Used in Diffuse Gastric and Lobular Breast Cancer Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Individuals who meet consensus genetic testing criteria but do not have a pathogenic variant identified in either
• Diffuse gastric cancer (DGC) diagnosed at age <50 years
• DGC in an individual of Māori ethnicity diagnosed at any age
• DGC diagnosed at any age in an individual with a personal history or first-degree relative with cleft lip or cleft palate
• DGC and lobular breast cancer (LBC), both diagnosed in an individual at age <70 years
• Bilateral LBC, diagnosed at age <70 years
• Pathologically confirmed gastric signet ring cell carcinoma in situ or pagetoid spread of signet ring cells identified at age <50 years
• ≥2 first- or second-degree relatives with gastric cancer diagnosed at any age, and at least one of these family members diagnosed with DGC
• ≥1 first- or second-degree relative with DGC at any age and ≥1 first- or second-degree relative with LBC diagnosed at age <70 years
• ≥2 first- or second-degree relatives with LBC diagnosed at age <50 years
• ≥2 family members (first- or second-degree relatives of each other) with gastric cancer regardless of age of diagnosis, with at least one of these individuals with confirmed DGC;
• ≥1 family member with DGC at any age and ≥1 different family member with LBC diagnosed at age <70 years (first- or second-degree relatives of each other).
## Suggestive Findings
DGLBCS
Diffuse gastric cancer (DGC) diagnosed at age <50 years
DGC in an individual of Māori ethnicity diagnosed at any age
DGC diagnosed at any age in an individual with a personal history or first-degree relative with cleft lip or cleft palate
DGC and lobular breast cancer (LBC), both diagnosed in an individual at age <70 years
Bilateral LBC, diagnosed at age <70 years
Pathologically confirmed gastric signet ring cell carcinoma in situ or pagetoid spread of signet ring cells identified at age <50 years
≥2 first- or second-degree relatives with gastric cancer diagnosed at any age, and at least one of these family members diagnosed with DGC
≥1 first- or second-degree relative with DGC at any age and ≥1 first- or second-degree relative with LBC diagnosed at age <70 years
≥2 first- or second-degree relatives with LBC diagnosed at age <50 years
Note: Although it is advisable for all cancer diagnoses to be confirmed with histopathology findings, in criteria with two or more cancer diagnoses, at least one should be accompanied by confirmed histologic evidence.
• Diffuse gastric cancer (DGC) diagnosed at age <50 years
• DGC in an individual of Māori ethnicity diagnosed at any age
• DGC diagnosed at any age in an individual with a personal history or first-degree relative with cleft lip or cleft palate
• DGC and lobular breast cancer (LBC), both diagnosed in an individual at age <70 years
• Bilateral LBC, diagnosed at age <70 years
• Pathologically confirmed gastric signet ring cell carcinoma in situ or pagetoid spread of signet ring cells identified at age <50 years
• ≥2 first- or second-degree relatives with gastric cancer diagnosed at any age, and at least one of these family members diagnosed with DGC
• ≥1 first- or second-degree relative with DGC at any age and ≥1 first- or second-degree relative with LBC diagnosed at age <70 years
• ≥2 first- or second-degree relatives with LBC diagnosed at age <50 years
## Establishing the Diagnosis
A diagnosis of DGLBCS
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
A proband with one of the clinical features described in
≥2 family members (first- or second-degree relatives of each other) with gastric cancer regardless of age of diagnosis, with at least one of these individuals with confirmed DGC;
≥1 family member with DGC at any age and ≥1 different family member with LBC diagnosed at age <70 years (first- or second-degree relatives of each other).
Note: For these criteria, the proband is included in the family member(s).
For an introduction to multigene panels click
Molecular Genetic Testing Used in Diffuse Gastric and Lobular Breast Cancer Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Individuals who meet consensus genetic testing criteria but do not have a pathogenic variant identified in either
• ≥2 family members (first- or second-degree relatives of each other) with gastric cancer regardless of age of diagnosis, with at least one of these individuals with confirmed DGC;
• ≥1 family member with DGC at any age and ≥1 different family member with LBC diagnosed at age <70 years (first- or second-degree relatives of each other).
## Option 1
For an introduction to multigene panels click
## Option 2
Molecular Genetic Testing Used in Diffuse Gastric and Lobular Breast Cancer Syndrome
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
Individuals who meet consensus genetic testing criteria but do not have a pathogenic variant identified in either
## Clinical Characteristics
Diffuse gastric and lobular breast cancer syndrome (DGLBCS) is characterized by an increased risk of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Cleft lip with or without cleft palate has been reported in some individuals with
Diffuse Gastric and Lobular Breast Cancer Syndrome: Frequency of Select Features
NR = not reported to date
Initial estimates of gastric cancer risk were established based on a few families, including some high-risk groups, and were possibly influenced by small sample sizes and sampling bias. In addition, inclusion of all gastric cancers (e.g., occult stage 1A) identified at the time of prophylactic gastrectomy resulted in higher risk estimates by approximately twofold (7%-10% to 13%-19%) [Ryan et 2024].
Breast cancer risks from
Cleft lip/palate has been described in at least one individual in 19% of families with
Signet ring cancer cells are often identified at the initial endoscopy in individuals with a germline
Symptoms of DGC are nonspecific in the early stages and consequently tend to be dismissed both by affected individuals and physicians. Intramucosal occult signet ring cell carcinomas have been identified in prophylactic gastrectomy specimens from women with a history of LBC despite not having a personal or family history of gastric cancer [
DGC is characterized by the presence of multiple gastric intramucosal signet ring cell carcinomas (SRCC) with abnormal or absent E-cadherin immunohistochemistry. This distinctive signet ring appearance is caused by an accumulation of intracellular mucin that pushes the nucleus to one side. A clearly defined preneoplastic lesion is not seen in DGC. A progression model for DGC developed from studying prophylactic total gastrectomy (PTG) specimens from individuals with a germline
The penetrance of DGLBCS is reduced.
In a second study not exclusively selected based on strict DGLBC criteria, the cumulative incidence of gastric cancer including DGC by age 80 years was 42% (95% CI: 30%-56%) for males and 33% (95% CI: 21%-43%) for females with a
A recent analysis of 70 individuals from 11 families from northern Portugal with a
In a recent study involving a North American cohort of 7,323 individuals from 213 families with
Approximately 7% of individuals with DGC have been found to have a germline
Invasive LBC represents 5%-15% of all invasive breast cancers. In two large studies, a germline
• DGC is characterized by the presence of multiple gastric intramucosal signet ring cell carcinomas (SRCC) with abnormal or absent E-cadherin immunohistochemistry. This distinctive signet ring appearance is caused by an accumulation of intracellular mucin that pushes the nucleus to one side. A clearly defined preneoplastic lesion is not seen in DGC. A progression model for DGC developed from studying prophylactic total gastrectomy (PTG) specimens from individuals with a germline
## Clinical Description
Diffuse gastric and lobular breast cancer syndrome (DGLBCS) is characterized by an increased risk of diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Cleft lip with or without cleft palate has been reported in some individuals with
Diffuse Gastric and Lobular Breast Cancer Syndrome: Frequency of Select Features
NR = not reported to date
Initial estimates of gastric cancer risk were established based on a few families, including some high-risk groups, and were possibly influenced by small sample sizes and sampling bias. In addition, inclusion of all gastric cancers (e.g., occult stage 1A) identified at the time of prophylactic gastrectomy resulted in higher risk estimates by approximately twofold (7%-10% to 13%-19%) [Ryan et 2024].
Breast cancer risks from
Cleft lip/palate has been described in at least one individual in 19% of families with
Signet ring cancer cells are often identified at the initial endoscopy in individuals with a germline
Symptoms of DGC are nonspecific in the early stages and consequently tend to be dismissed both by affected individuals and physicians. Intramucosal occult signet ring cell carcinomas have been identified in prophylactic gastrectomy specimens from women with a history of LBC despite not having a personal or family history of gastric cancer [
DGC is characterized by the presence of multiple gastric intramucosal signet ring cell carcinomas (SRCC) with abnormal or absent E-cadherin immunohistochemistry. This distinctive signet ring appearance is caused by an accumulation of intracellular mucin that pushes the nucleus to one side. A clearly defined preneoplastic lesion is not seen in DGC. A progression model for DGC developed from studying prophylactic total gastrectomy (PTG) specimens from individuals with a germline
• DGC is characterized by the presence of multiple gastric intramucosal signet ring cell carcinomas (SRCC) with abnormal or absent E-cadherin immunohistochemistry. This distinctive signet ring appearance is caused by an accumulation of intracellular mucin that pushes the nucleus to one side. A clearly defined preneoplastic lesion is not seen in DGC. A progression model for DGC developed from studying prophylactic total gastrectomy (PTG) specimens from individuals with a germline
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
## Penetrance
The penetrance of DGLBCS is reduced.
In a second study not exclusively selected based on strict DGLBC criteria, the cumulative incidence of gastric cancer including DGC by age 80 years was 42% (95% CI: 30%-56%) for males and 33% (95% CI: 21%-43%) for females with a
A recent analysis of 70 individuals from 11 families from northern Portugal with a
In a recent study involving a North American cohort of 7,323 individuals from 213 families with
## Prevalence
Approximately 7% of individuals with DGC have been found to have a germline
Invasive LBC represents 5%-15% of all invasive breast cancers. In two large studies, a germline
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
Somatic
## Differential Diagnosis
An estimated 5%-10% of all gastric cancers are thought to present familial clustering [
Identification of individuals at risk for diffuse gastric and lobular breast cancer syndrome (DGLBCS) is complicated by several factors:
DGLBCS is one of several hereditary cancer syndromes characterized by gastric and breast cancer and associated premalignant lesions.
Risk of a hereditary cancer syndrome with an overlapping tumor spectrum may not be apparent in an individual with an unknown/unreported family history presenting with isolated gastric or breast cancer detected at early age [
Detailed histologic classification of gastric (diffuse vs non-diffuse) and breast (lobular vs non-lobular) cancers is necessary to identify individuals and families at risk for DGLBCS and to facilitate appropriate genetic testing.
Cancer predisposition syndromes that include gastric and/or breast cancer as part of their disease spectrum (despite not being the primary associated cancers) are listed in
Cancer Predisposition Syndromes in the Differential Diagnosis of Diffuse Gastric and Lobular Breast Cancer Syndrome
Gastric cancer often differs histologically from DGC.
CRC is the most commonly assoc cancer.
Adenomatous gastrointestinal polyps
Additional physical features (dental anomalies, CHRPE, osteomas)
Breast cancer
Gastric cancer
GIST
Risk of other cancers (paragangliomas, pheochromocytomas, renal clear cell)
Pulmonary chondromas
Gastric cancer (≤20% is DGC in those w/Lynch syndrome)
Breast cancer
Gastric cancer often differs histologically from DGC.
CRC is the most commonly assoc cancer.
Risk of other cancers (endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain)
Colonic adenomatous polyps
CRC is the most commonly assoc cancer.
Gastric cancer
Breast cancer
Risk of other cancers (thyroid, kidney, endometrium)
Physical features (macrocephaly, trichilemmomas, & papillomatous papules)
Gastric cancer
Breast cancer
Risk of epithelial malignancies (CRC, gastric, pancreatic, breast, & ovarian cancers)
Gastrointestinal polyposis
Mucocutaneous pigmentation
Breast cancer
Gastric cancer
Risk of many cancer types, most commonly adrenocortical, breast, CNS, osteosarcomas, & soft-tissue sarcomas
AD = autosomal dominant; AR = autosomal recessive; CHRPE = congenital hypertrophy of the retinal pigment epithelium; CNS = central nervous system; CRC = colorectal cancer; DGC = diffuse gastric cancer; DGLBCS = diffuse gastric and lobular breast cancer syndrome; GIST = gastrointestinal stromal tumor; MOI = mode of inheritance
A higher incidence of gastric cancer is reported in individuals with Lynch syndrome younger than age 40 years in Asian kindreds.
See gene-specific cancer risks in
• DGLBCS is one of several hereditary cancer syndromes characterized by gastric and breast cancer and associated premalignant lesions.
• Risk of a hereditary cancer syndrome with an overlapping tumor spectrum may not be apparent in an individual with an unknown/unreported family history presenting with isolated gastric or breast cancer detected at early age [
• Gastric cancer often differs histologically from DGC.
• CRC is the most commonly assoc cancer.
• Adenomatous gastrointestinal polyps
• Additional physical features (dental anomalies, CHRPE, osteomas)
• Breast cancer
• Gastric cancer
• GIST
• Risk of other cancers (paragangliomas, pheochromocytomas, renal clear cell)
• Pulmonary chondromas
• Gastric cancer (≤20% is DGC in those w/Lynch syndrome)
• Breast cancer
• Gastric cancer often differs histologically from DGC.
• CRC is the most commonly assoc cancer.
• Risk of other cancers (endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain)
• Colonic adenomatous polyps
• CRC is the most commonly assoc cancer.
• Gastric cancer
• Breast cancer
• Risk of other cancers (thyroid, kidney, endometrium)
• Physical features (macrocephaly, trichilemmomas, & papillomatous papules)
• Gastric cancer
• Breast cancer
• Risk of epithelial malignancies (CRC, gastric, pancreatic, breast, & ovarian cancers)
• Gastrointestinal polyposis
• Mucocutaneous pigmentation
• Breast cancer
• Gastric cancer
• Risk of many cancer types, most commonly adrenocortical, breast, CNS, osteosarcomas, & soft-tissue sarcomas
## Management
Clinical practice guidelines for diffuse gastric and lobular breast cancer syndrome (DGLBCS) have been published [
To establish the extent of disease and needs in an individual diagnosed with DGLBCS, the evaluations summarized in
Diffuse Gastric and Lobular Breast Cancer Syndrome: Recommended Evaluations Following Initial Diagnosis
Referral to a DGC center of expertise for screening
Endoscopy w/multiple gastric biopsies to assess for macroscopic tumor & microscopic pre-malignant or malignant lesions
Eval for
For those w/
For those w/suspected DGLBCS of unknown cause, beginning at age 40 yrs or 5-10 yrs prior to earliest gastric cancer case in family, w/minimum age of 18 yrs
Referral to high-risk breast cancer clinic
Clinical breast exam in those age ≥20 yrs
Breast MRI in those age 30-40 yrs
Breast MRI combined w/mammography in those age ≥40 yrs
Mammography alone is inadequate to identify LBC; if MRI is unavailable, consider incl breast ultrasound.
Note: (1) Recommended for those w/
DGC = diffuse gastric cancer; DGLBCS = diffuse gastric and lobular breast cancer syndrome; LBC = lobular breast cancer; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
DGLBCS-related
DGLBCS-related
Note: In individuals with an unclear risk of DGC (e.g., DGLBCS of unknown genetic cause [HDGC-like],
Total prophylactic gastrectomy involves a multidisciplinary team including gastric surgery, gastroenterology, pathology, nutrition, oncology, and palliative care for preoperative and postoperative care. The multidisciplinary team members can counsel individuals on the risks and benefits of total gastrectomy. In determining whether to undergo total gastrectomy, the individual and treating physicians should consider the following:
Individuals that opt for prophylactic total gastrectomy are initially tested and treated (if identified) for
Current guidelines suggest that individuals with
In a young, healthy adult, the risk of mortality with prophylactic total gastrectomy in an experienced surgeon's hands is less than 1% [
The morbidity from prophylactic total gastrectomy is 100% [
Individuals who have undergone prophylactic total gastrectomy in expert centers express minimal to no regret, emphasizing that the perceived benefits outweigh the associated risks [
Prophylactic total gastrectomy in young children is not recommended until full physical maturity is reached and should be avoided in adolescents due to its high risk of complications.
Prophylactic total gastrectomy is not typically recommended for individuals older than age 70 years.
Following total gastrectomy, surveillance with laboratory examinations and clinical, nutritional, and psychological monitoring is recommended. Laboratory assessments should include a complete blood count, electrolyte levels, blood urea nitrogen, creatinine, and evaluations of liver function. Annual endoscopy to survey the anastomosis may be considered. Vitamin and mineral supplementation are required due to the increased risk of nutrient deficiency (e.g., vitamin B
An intrauterine device or alternative form of contraception that does not require gastrointestinal absorption is recommended in women with
Supportive care to improve quality of life, maximize function, and reduce complications by a multidisciplinary team comprising those with expertise in gastric and breast surgery, gastroenterology, nutrition, plastic surgery, oncology, and palliative care is recommended.
Diffuse Gastric and Lobular Breast Cancer Syndrome: Treatment of Manifestations
Treatment includes surgery, hormonal therapy, & perioperative &/or adjuvant chemotherapy depending on LBC stage, overall individual health, tumor aggressiveness, & predictive biomarkers for targeted therapies.
Mastectomy is the preferred treatment. The timing for breast reconstruction should be discussed.
Risk-reducing contralateral mastectomy may be considered.
Chemoprevention can be considered (e.g., selective estrogen receptor modulators or aromatase inhibitors), but due to the significant side effects, long-term applicability is limited.
DGC = diffuse gastric cancer; LBC = lobular breast cancer
In those with
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Thorough ≥30-minute exam
Targeted biopsies of all suspicious lesions
Followed by random biopsies from specific anatomic regions using IGCLC Cambridge
Every 6-12 mos beginning at age 40 yrs (or 5-10 yrs prior to earliest gastric cancer diagnosis in family), w/minimum age of 18 yrs
Note: (1) For individuals w/unclear risk of DGC, the interval between endoscopies can be increased after 2 consecutive normal endoscopies at discretion of a DGC specialist based on endoscopy findings & family history. (2) Choosing endoscopy surveillance vs prophylactic gastrectomy is challenging; it is difficult to determine if intramucosal lesions identified on endoscopy will remain indolent &/or become aggressive. The efficacy of endoscopic surveillance performed at expert centers to detect early DGC has been reported.
Clinical breast exams
Education on clinical features of breast cancer (e.g., thickening, indrawn nipple, or change in breast skin)
Bilateral breast MRI w/contrast
Mammogram
Note: Include breast ultrasound w/mammogram if breast MRI is not available.
Audiology eval
Speech eval
DGC = diffuse gastric cancer; IGCLC = International Gastric Cancer Linkage Consortium; LBC = lobular breast cancer
IGCLC Cambridge method recommends a thorough high-definition white light examination of at least 30 minutes in a center of expertise. The session should begin with targeted biopsies from all suspicious lesions, followed by five random biopsies from six specific anatomic regions (prepyloric, antrum, transitional zone, body, fundus, and cardia) [
Bethesda protocol recommends endoscopic examination with a comprehensive assessment of 22 specific anatomic locations, each of which is meticulously photographed. Four non-targeted biopsies are obtained from each of these 22 sites; any abnormal findings are subjected to biopsy.
When comparing the detection rates per endoscopy, the false-negative rates for detection using the Cambridge method and the Bethesda protocol were 80% (12/15) and 37.7% (17/45), respectively [
Three independent prospective longitudinal studies of endoscopic surveillance with multiple biopsies in individuals with DGLBCS showed that endoscopic surveillance, performed in reference centers, may be a reasonable alternative to prophylactic total gastrectomy [
Currently, there are ongoing trials to investigate the utility of probe-based confocal laser endomicroscopy (pCLE) for DGC diagnosis, particularly in identifying early signet ring cell carcinoma lesions [
In females w/
Mammography has a low sensitivity for detecting lobular breast cancer (LBC) due to its subtle and slow-growing nature. Breast imaging radiologists must be aware of the atypical and subtle mammographic patterns of invasive LBC, which include spiculated masses, architectural distortion, and poorly defined asymmetric densities. Breast MRI can detect tumor margins, size, and multifocality more accurately than ultrasound and mammography.
A novel diagnostic approach known as contrast-enhanced spectral mammography (CESM) offers accurate detection similar to breast MRI [
Suspected Diffuse Gastric and Lobular Breast Cancer Syndrome of Unknown Genetic Cause:
Thorough ≥30-minute exam
Targeted biopsies of all suspicious lesions
Followed by random biopsies from specific anatomic regions using IGCLC Cambridge
Annually for ≥2 yrs, beginning at age 40 yrs or 10 yrs prior to earliest gastric cancer diagnosis in family, w/minimum age of 18 yrs
Note: The likelihood of a positive biopsy is highest w/initial endoscopy & surveillance intervals can be extended at discretion of endoscopist after 2 yrs. This decision should be based on individual findings from previous endoscopies & family history.
Clinical breast exams
Education on clinical features of LBC (e.g., thickening, indrawn nipple, or change in breast skin)
Bilateral breast MRI w/contrast
Bilateral breast MRI combined w/mammography & breast ultrasound
Frequency should be based on personalized breast cancer risk assessment by experienced team.
Consider MRI in addition to conventional mammography & breast ultrasound for improved results w/LBC diagnosis.
DGC = diffuse gastric cancer; IGCLC = International Gastric Cancer Linkage Consortium; LBC = lobular breast cancer
Also referred to as HDGC-like
IGCLC Cambridge method recommends a thorough high-definition white light examination of at least 30 minutes in a center of expertise. The session should begin with targeted biopsies from all suspicious lesions, followed by five random biopsies from six specific anatomic regions (prepyloric, antrum, transitional zone, body, fundus, and cardia) [
Bethesda protocol recommends endoscopic examination with a comprehensive assessment of 22 specific anatomic locations, each of which is meticulously photographed. Four non-targeted biopsies are obtained from each of these 22 sites; any abnormal findings are subjected to biopsy.
When comparing the detection rates per endoscopy, the false-negative rates for detection using the Cambridge method and the Bethesda protocol were 80% (12/15) and 37.7% (17/45), respectively [
Three independent prospective longitudinal studies of endoscopic surveillance with multiple biopsies in individuals with DGLBCS showed that endoscopic surveillance, performed in reference centers, may be a reasonable alternative to prophylactic total gastrectomy [
Currently, there are ongoing trials to investigate the utility of probe-based confocal laser endomicroscopy (pCLE) for DGC diagnosis, particularly in identifying early signet ring cell carcinoma lesions [
Mammography has a low sensitivity for detecting lobular breast cancer (LBC) due to its subtle and slow-growing nature. Breast imaging radiologists must be aware of the atypical and subtle mammographic patterns of invasive LBC, which include spiculated masses, architectural distortion, and poorly defined asymmetric densities. Breast MRI can detect tumor margins, size, and multifocality more accurately than ultrasound and mammography.
A novel diagnostic approach known as contrast-enhanced spectral mammography (CESM) offers accurate detection similar to breast MRI [
See
Nutritional consequences of total gastrectomy should be discussed before and during pregnancy. Pregnancy should be delayed at least six to 12 months after total gastrectomy, to allow for weight stabilization and nutritional recovery.
Clinical trials, targeted therapies, and predictive markers of therapy response directed to DGC or LBC are scarce.
Ongoing studies are mainly investigating alternate medication doses and combining therapeutic agents that are approved for sporadic gastric cancer and other solid tumors (e.g., platinum compounds, fluropyrimidines, and topoisomerase I inhibitors). Immunotherapy for anti-HER2, anti-VEGDR2, and anti-PD1 have been approved for treatment of gastric adenocarcinoma; however, treatment data for DGC is weak.
The MONO study (
There are active clinical trials for individuals with invasive LBC or enriched in individuals with lobular histology. These studies are testing small molecules including tyrosine kinase ROS1 inhibition, CDK4/6 inhibition, endocrine therapy strategies, immunotherapy with checkpoint inhibition, and inhibition of HER2 in individuals with HER2 alterations [
Search
• Referral to a DGC center of expertise for screening
• Endoscopy w/multiple gastric biopsies to assess for macroscopic tumor & microscopic pre-malignant or malignant lesions
• Eval for
• For those w/
• For those w/suspected DGLBCS of unknown cause, beginning at age 40 yrs or 5-10 yrs prior to earliest gastric cancer case in family, w/minimum age of 18 yrs
• Referral to high-risk breast cancer clinic
• Clinical breast exam in those age ≥20 yrs
• Breast MRI in those age 30-40 yrs
• Breast MRI combined w/mammography in those age ≥40 yrs
• Mammography alone is inadequate to identify LBC; if MRI is unavailable, consider incl breast ultrasound.
• Note: (1) Recommended for those w/
• DGLBCS-related
• DGLBCS-related
• Individuals that opt for prophylactic total gastrectomy are initially tested and treated (if identified) for
• Current guidelines suggest that individuals with
• In a young, healthy adult, the risk of mortality with prophylactic total gastrectomy in an experienced surgeon's hands is less than 1% [
• The morbidity from prophylactic total gastrectomy is 100% [
• Individuals who have undergone prophylactic total gastrectomy in expert centers express minimal to no regret, emphasizing that the perceived benefits outweigh the associated risks [
• Prophylactic total gastrectomy in young children is not recommended until full physical maturity is reached and should be avoided in adolescents due to its high risk of complications.
• Prophylactic total gastrectomy is not typically recommended for individuals older than age 70 years.
• Following total gastrectomy, surveillance with laboratory examinations and clinical, nutritional, and psychological monitoring is recommended. Laboratory assessments should include a complete blood count, electrolyte levels, blood urea nitrogen, creatinine, and evaluations of liver function. Annual endoscopy to survey the anastomosis may be considered. Vitamin and mineral supplementation are required due to the increased risk of nutrient deficiency (e.g., vitamin B
• An intrauterine device or alternative form of contraception that does not require gastrointestinal absorption is recommended in women with
• Treatment includes surgery, hormonal therapy, & perioperative &/or adjuvant chemotherapy depending on LBC stage, overall individual health, tumor aggressiveness, & predictive biomarkers for targeted therapies.
• Mastectomy is the preferred treatment. The timing for breast reconstruction should be discussed.
• Risk-reducing contralateral mastectomy may be considered.
• Chemoprevention can be considered (e.g., selective estrogen receptor modulators or aromatase inhibitors), but due to the significant side effects, long-term applicability is limited.
• Thorough ≥30-minute exam
• Targeted biopsies of all suspicious lesions
• Followed by random biopsies from specific anatomic regions using IGCLC Cambridge
• Every 6-12 mos beginning at age 40 yrs (or 5-10 yrs prior to earliest gastric cancer diagnosis in family), w/minimum age of 18 yrs
• Note: (1) For individuals w/unclear risk of DGC, the interval between endoscopies can be increased after 2 consecutive normal endoscopies at discretion of a DGC specialist based on endoscopy findings & family history. (2) Choosing endoscopy surveillance vs prophylactic gastrectomy is challenging; it is difficult to determine if intramucosal lesions identified on endoscopy will remain indolent &/or become aggressive. The efficacy of endoscopic surveillance performed at expert centers to detect early DGC has been reported.
• Clinical breast exams
• Education on clinical features of breast cancer (e.g., thickening, indrawn nipple, or change in breast skin)
• Bilateral breast MRI w/contrast
• Mammogram
• Note: Include breast ultrasound w/mammogram if breast MRI is not available.
• Audiology eval
• Speech eval
• Thorough ≥30-minute exam
• Targeted biopsies of all suspicious lesions
• Followed by random biopsies from specific anatomic regions using IGCLC Cambridge
• Annually for ≥2 yrs, beginning at age 40 yrs or 10 yrs prior to earliest gastric cancer diagnosis in family, w/minimum age of 18 yrs
• Note: The likelihood of a positive biopsy is highest w/initial endoscopy & surveillance intervals can be extended at discretion of endoscopist after 2 yrs. This decision should be based on individual findings from previous endoscopies & family history.
• Clinical breast exams
• Education on clinical features of LBC (e.g., thickening, indrawn nipple, or change in breast skin)
• Bilateral breast MRI w/contrast
• Bilateral breast MRI combined w/mammography & breast ultrasound
• Frequency should be based on personalized breast cancer risk assessment by experienced team.
• Consider MRI in addition to conventional mammography & breast ultrasound for improved results w/LBC diagnosis.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with DGLBCS, the evaluations summarized in
Diffuse Gastric and Lobular Breast Cancer Syndrome: Recommended Evaluations Following Initial Diagnosis
Referral to a DGC center of expertise for screening
Endoscopy w/multiple gastric biopsies to assess for macroscopic tumor & microscopic pre-malignant or malignant lesions
Eval for
For those w/
For those w/suspected DGLBCS of unknown cause, beginning at age 40 yrs or 5-10 yrs prior to earliest gastric cancer case in family, w/minimum age of 18 yrs
Referral to high-risk breast cancer clinic
Clinical breast exam in those age ≥20 yrs
Breast MRI in those age 30-40 yrs
Breast MRI combined w/mammography in those age ≥40 yrs
Mammography alone is inadequate to identify LBC; if MRI is unavailable, consider incl breast ultrasound.
Note: (1) Recommended for those w/
DGC = diffuse gastric cancer; DGLBCS = diffuse gastric and lobular breast cancer syndrome; LBC = lobular breast cancer; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Referral to a DGC center of expertise for screening
• Endoscopy w/multiple gastric biopsies to assess for macroscopic tumor & microscopic pre-malignant or malignant lesions
• Eval for
• For those w/
• For those w/suspected DGLBCS of unknown cause, beginning at age 40 yrs or 5-10 yrs prior to earliest gastric cancer case in family, w/minimum age of 18 yrs
• Referral to high-risk breast cancer clinic
• Clinical breast exam in those age ≥20 yrs
• Breast MRI in those age 30-40 yrs
• Breast MRI combined w/mammography in those age ≥40 yrs
• Mammography alone is inadequate to identify LBC; if MRI is unavailable, consider incl breast ultrasound.
• Note: (1) Recommended for those w/
## Treatment of Manifestations
DGLBCS-related
DGLBCS-related
Note: In individuals with an unclear risk of DGC (e.g., DGLBCS of unknown genetic cause [HDGC-like],
Total prophylactic gastrectomy involves a multidisciplinary team including gastric surgery, gastroenterology, pathology, nutrition, oncology, and palliative care for preoperative and postoperative care. The multidisciplinary team members can counsel individuals on the risks and benefits of total gastrectomy. In determining whether to undergo total gastrectomy, the individual and treating physicians should consider the following:
Individuals that opt for prophylactic total gastrectomy are initially tested and treated (if identified) for
Current guidelines suggest that individuals with
In a young, healthy adult, the risk of mortality with prophylactic total gastrectomy in an experienced surgeon's hands is less than 1% [
The morbidity from prophylactic total gastrectomy is 100% [
Individuals who have undergone prophylactic total gastrectomy in expert centers express minimal to no regret, emphasizing that the perceived benefits outweigh the associated risks [
Prophylactic total gastrectomy in young children is not recommended until full physical maturity is reached and should be avoided in adolescents due to its high risk of complications.
Prophylactic total gastrectomy is not typically recommended for individuals older than age 70 years.
Following total gastrectomy, surveillance with laboratory examinations and clinical, nutritional, and psychological monitoring is recommended. Laboratory assessments should include a complete blood count, electrolyte levels, blood urea nitrogen, creatinine, and evaluations of liver function. Annual endoscopy to survey the anastomosis may be considered. Vitamin and mineral supplementation are required due to the increased risk of nutrient deficiency (e.g., vitamin B
An intrauterine device or alternative form of contraception that does not require gastrointestinal absorption is recommended in women with
Supportive care to improve quality of life, maximize function, and reduce complications by a multidisciplinary team comprising those with expertise in gastric and breast surgery, gastroenterology, nutrition, plastic surgery, oncology, and palliative care is recommended.
Diffuse Gastric and Lobular Breast Cancer Syndrome: Treatment of Manifestations
Treatment includes surgery, hormonal therapy, & perioperative &/or adjuvant chemotherapy depending on LBC stage, overall individual health, tumor aggressiveness, & predictive biomarkers for targeted therapies.
Mastectomy is the preferred treatment. The timing for breast reconstruction should be discussed.
Risk-reducing contralateral mastectomy may be considered.
Chemoprevention can be considered (e.g., selective estrogen receptor modulators or aromatase inhibitors), but due to the significant side effects, long-term applicability is limited.
DGC = diffuse gastric cancer; LBC = lobular breast cancer
In those with
• DGLBCS-related
• DGLBCS-related
• Individuals that opt for prophylactic total gastrectomy are initially tested and treated (if identified) for
• Current guidelines suggest that individuals with
• In a young, healthy adult, the risk of mortality with prophylactic total gastrectomy in an experienced surgeon's hands is less than 1% [
• The morbidity from prophylactic total gastrectomy is 100% [
• Individuals who have undergone prophylactic total gastrectomy in expert centers express minimal to no regret, emphasizing that the perceived benefits outweigh the associated risks [
• Prophylactic total gastrectomy in young children is not recommended until full physical maturity is reached and should be avoided in adolescents due to its high risk of complications.
• Prophylactic total gastrectomy is not typically recommended for individuals older than age 70 years.
• Following total gastrectomy, surveillance with laboratory examinations and clinical, nutritional, and psychological monitoring is recommended. Laboratory assessments should include a complete blood count, electrolyte levels, blood urea nitrogen, creatinine, and evaluations of liver function. Annual endoscopy to survey the anastomosis may be considered. Vitamin and mineral supplementation are required due to the increased risk of nutrient deficiency (e.g., vitamin B
• An intrauterine device or alternative form of contraception that does not require gastrointestinal absorption is recommended in women with
• Treatment includes surgery, hormonal therapy, & perioperative &/or adjuvant chemotherapy depending on LBC stage, overall individual health, tumor aggressiveness, & predictive biomarkers for targeted therapies.
• Mastectomy is the preferred treatment. The timing for breast reconstruction should be discussed.
• Risk-reducing contralateral mastectomy may be considered.
• Chemoprevention can be considered (e.g., selective estrogen receptor modulators or aromatase inhibitors), but due to the significant side effects, long-term applicability is limited.
## Targeted Therapy
DGLBCS-related
DGLBCS-related
Note: In individuals with an unclear risk of DGC (e.g., DGLBCS of unknown genetic cause [HDGC-like],
Total prophylactic gastrectomy involves a multidisciplinary team including gastric surgery, gastroenterology, pathology, nutrition, oncology, and palliative care for preoperative and postoperative care. The multidisciplinary team members can counsel individuals on the risks and benefits of total gastrectomy. In determining whether to undergo total gastrectomy, the individual and treating physicians should consider the following:
Individuals that opt for prophylactic total gastrectomy are initially tested and treated (if identified) for
Current guidelines suggest that individuals with
In a young, healthy adult, the risk of mortality with prophylactic total gastrectomy in an experienced surgeon's hands is less than 1% [
The morbidity from prophylactic total gastrectomy is 100% [
Individuals who have undergone prophylactic total gastrectomy in expert centers express minimal to no regret, emphasizing that the perceived benefits outweigh the associated risks [
Prophylactic total gastrectomy in young children is not recommended until full physical maturity is reached and should be avoided in adolescents due to its high risk of complications.
Prophylactic total gastrectomy is not typically recommended for individuals older than age 70 years.
Following total gastrectomy, surveillance with laboratory examinations and clinical, nutritional, and psychological monitoring is recommended. Laboratory assessments should include a complete blood count, electrolyte levels, blood urea nitrogen, creatinine, and evaluations of liver function. Annual endoscopy to survey the anastomosis may be considered. Vitamin and mineral supplementation are required due to the increased risk of nutrient deficiency (e.g., vitamin B
An intrauterine device or alternative form of contraception that does not require gastrointestinal absorption is recommended in women with
• DGLBCS-related
• DGLBCS-related
• Individuals that opt for prophylactic total gastrectomy are initially tested and treated (if identified) for
• Current guidelines suggest that individuals with
• In a young, healthy adult, the risk of mortality with prophylactic total gastrectomy in an experienced surgeon's hands is less than 1% [
• The morbidity from prophylactic total gastrectomy is 100% [
• Individuals who have undergone prophylactic total gastrectomy in expert centers express minimal to no regret, emphasizing that the perceived benefits outweigh the associated risks [
• Prophylactic total gastrectomy in young children is not recommended until full physical maturity is reached and should be avoided in adolescents due to its high risk of complications.
• Prophylactic total gastrectomy is not typically recommended for individuals older than age 70 years.
• Following total gastrectomy, surveillance with laboratory examinations and clinical, nutritional, and psychological monitoring is recommended. Laboratory assessments should include a complete blood count, electrolyte levels, blood urea nitrogen, creatinine, and evaluations of liver function. Annual endoscopy to survey the anastomosis may be considered. Vitamin and mineral supplementation are required due to the increased risk of nutrient deficiency (e.g., vitamin B
• An intrauterine device or alternative form of contraception that does not require gastrointestinal absorption is recommended in women with
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications by a multidisciplinary team comprising those with expertise in gastric and breast surgery, gastroenterology, nutrition, plastic surgery, oncology, and palliative care is recommended.
Diffuse Gastric and Lobular Breast Cancer Syndrome: Treatment of Manifestations
Treatment includes surgery, hormonal therapy, & perioperative &/or adjuvant chemotherapy depending on LBC stage, overall individual health, tumor aggressiveness, & predictive biomarkers for targeted therapies.
Mastectomy is the preferred treatment. The timing for breast reconstruction should be discussed.
Risk-reducing contralateral mastectomy may be considered.
Chemoprevention can be considered (e.g., selective estrogen receptor modulators or aromatase inhibitors), but due to the significant side effects, long-term applicability is limited.
DGC = diffuse gastric cancer; LBC = lobular breast cancer
In those with
• Treatment includes surgery, hormonal therapy, & perioperative &/or adjuvant chemotherapy depending on LBC stage, overall individual health, tumor aggressiveness, & predictive biomarkers for targeted therapies.
• Mastectomy is the preferred treatment. The timing for breast reconstruction should be discussed.
• Risk-reducing contralateral mastectomy may be considered.
• Chemoprevention can be considered (e.g., selective estrogen receptor modulators or aromatase inhibitors), but due to the significant side effects, long-term applicability is limited.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Thorough ≥30-minute exam
Targeted biopsies of all suspicious lesions
Followed by random biopsies from specific anatomic regions using IGCLC Cambridge
Every 6-12 mos beginning at age 40 yrs (or 5-10 yrs prior to earliest gastric cancer diagnosis in family), w/minimum age of 18 yrs
Note: (1) For individuals w/unclear risk of DGC, the interval between endoscopies can be increased after 2 consecutive normal endoscopies at discretion of a DGC specialist based on endoscopy findings & family history. (2) Choosing endoscopy surveillance vs prophylactic gastrectomy is challenging; it is difficult to determine if intramucosal lesions identified on endoscopy will remain indolent &/or become aggressive. The efficacy of endoscopic surveillance performed at expert centers to detect early DGC has been reported.
Clinical breast exams
Education on clinical features of breast cancer (e.g., thickening, indrawn nipple, or change in breast skin)
Bilateral breast MRI w/contrast
Mammogram
Note: Include breast ultrasound w/mammogram if breast MRI is not available.
Audiology eval
Speech eval
DGC = diffuse gastric cancer; IGCLC = International Gastric Cancer Linkage Consortium; LBC = lobular breast cancer
IGCLC Cambridge method recommends a thorough high-definition white light examination of at least 30 minutes in a center of expertise. The session should begin with targeted biopsies from all suspicious lesions, followed by five random biopsies from six specific anatomic regions (prepyloric, antrum, transitional zone, body, fundus, and cardia) [
Bethesda protocol recommends endoscopic examination with a comprehensive assessment of 22 specific anatomic locations, each of which is meticulously photographed. Four non-targeted biopsies are obtained from each of these 22 sites; any abnormal findings are subjected to biopsy.
When comparing the detection rates per endoscopy, the false-negative rates for detection using the Cambridge method and the Bethesda protocol were 80% (12/15) and 37.7% (17/45), respectively [
Three independent prospective longitudinal studies of endoscopic surveillance with multiple biopsies in individuals with DGLBCS showed that endoscopic surveillance, performed in reference centers, may be a reasonable alternative to prophylactic total gastrectomy [
Currently, there are ongoing trials to investigate the utility of probe-based confocal laser endomicroscopy (pCLE) for DGC diagnosis, particularly in identifying early signet ring cell carcinoma lesions [
In females w/
Mammography has a low sensitivity for detecting lobular breast cancer (LBC) due to its subtle and slow-growing nature. Breast imaging radiologists must be aware of the atypical and subtle mammographic patterns of invasive LBC, which include spiculated masses, architectural distortion, and poorly defined asymmetric densities. Breast MRI can detect tumor margins, size, and multifocality more accurately than ultrasound and mammography.
A novel diagnostic approach known as contrast-enhanced spectral mammography (CESM) offers accurate detection similar to breast MRI [
Suspected Diffuse Gastric and Lobular Breast Cancer Syndrome of Unknown Genetic Cause:
Thorough ≥30-minute exam
Targeted biopsies of all suspicious lesions
Followed by random biopsies from specific anatomic regions using IGCLC Cambridge
Annually for ≥2 yrs, beginning at age 40 yrs or 10 yrs prior to earliest gastric cancer diagnosis in family, w/minimum age of 18 yrs
Note: The likelihood of a positive biopsy is highest w/initial endoscopy & surveillance intervals can be extended at discretion of endoscopist after 2 yrs. This decision should be based on individual findings from previous endoscopies & family history.
Clinical breast exams
Education on clinical features of LBC (e.g., thickening, indrawn nipple, or change in breast skin)
Bilateral breast MRI w/contrast
Bilateral breast MRI combined w/mammography & breast ultrasound
Frequency should be based on personalized breast cancer risk assessment by experienced team.
Consider MRI in addition to conventional mammography & breast ultrasound for improved results w/LBC diagnosis.
DGC = diffuse gastric cancer; IGCLC = International Gastric Cancer Linkage Consortium; LBC = lobular breast cancer
Also referred to as HDGC-like
IGCLC Cambridge method recommends a thorough high-definition white light examination of at least 30 minutes in a center of expertise. The session should begin with targeted biopsies from all suspicious lesions, followed by five random biopsies from six specific anatomic regions (prepyloric, antrum, transitional zone, body, fundus, and cardia) [
Bethesda protocol recommends endoscopic examination with a comprehensive assessment of 22 specific anatomic locations, each of which is meticulously photographed. Four non-targeted biopsies are obtained from each of these 22 sites; any abnormal findings are subjected to biopsy.
When comparing the detection rates per endoscopy, the false-negative rates for detection using the Cambridge method and the Bethesda protocol were 80% (12/15) and 37.7% (17/45), respectively [
Three independent prospective longitudinal studies of endoscopic surveillance with multiple biopsies in individuals with DGLBCS showed that endoscopic surveillance, performed in reference centers, may be a reasonable alternative to prophylactic total gastrectomy [
Currently, there are ongoing trials to investigate the utility of probe-based confocal laser endomicroscopy (pCLE) for DGC diagnosis, particularly in identifying early signet ring cell carcinoma lesions [
Mammography has a low sensitivity for detecting lobular breast cancer (LBC) due to its subtle and slow-growing nature. Breast imaging radiologists must be aware of the atypical and subtle mammographic patterns of invasive LBC, which include spiculated masses, architectural distortion, and poorly defined asymmetric densities. Breast MRI can detect tumor margins, size, and multifocality more accurately than ultrasound and mammography.
A novel diagnostic approach known as contrast-enhanced spectral mammography (CESM) offers accurate detection similar to breast MRI [
• Thorough ≥30-minute exam
• Targeted biopsies of all suspicious lesions
• Followed by random biopsies from specific anatomic regions using IGCLC Cambridge
• Every 6-12 mos beginning at age 40 yrs (or 5-10 yrs prior to earliest gastric cancer diagnosis in family), w/minimum age of 18 yrs
• Note: (1) For individuals w/unclear risk of DGC, the interval between endoscopies can be increased after 2 consecutive normal endoscopies at discretion of a DGC specialist based on endoscopy findings & family history. (2) Choosing endoscopy surveillance vs prophylactic gastrectomy is challenging; it is difficult to determine if intramucosal lesions identified on endoscopy will remain indolent &/or become aggressive. The efficacy of endoscopic surveillance performed at expert centers to detect early DGC has been reported.
• Clinical breast exams
• Education on clinical features of breast cancer (e.g., thickening, indrawn nipple, or change in breast skin)
• Bilateral breast MRI w/contrast
• Mammogram
• Note: Include breast ultrasound w/mammogram if breast MRI is not available.
• Audiology eval
• Speech eval
• Thorough ≥30-minute exam
• Targeted biopsies of all suspicious lesions
• Followed by random biopsies from specific anatomic regions using IGCLC Cambridge
• Annually for ≥2 yrs, beginning at age 40 yrs or 10 yrs prior to earliest gastric cancer diagnosis in family, w/minimum age of 18 yrs
• Note: The likelihood of a positive biopsy is highest w/initial endoscopy & surveillance intervals can be extended at discretion of endoscopist after 2 yrs. This decision should be based on individual findings from previous endoscopies & family history.
• Clinical breast exams
• Education on clinical features of LBC (e.g., thickening, indrawn nipple, or change in breast skin)
• Bilateral breast MRI w/contrast
• Bilateral breast MRI combined w/mammography & breast ultrasound
• Frequency should be based on personalized breast cancer risk assessment by experienced team.
• Consider MRI in addition to conventional mammography & breast ultrasound for improved results w/LBC diagnosis.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Nutritional consequences of total gastrectomy should be discussed before and during pregnancy. Pregnancy should be delayed at least six to 12 months after total gastrectomy, to allow for weight stabilization and nutritional recovery.
## Therapies Under Investigation
Clinical trials, targeted therapies, and predictive markers of therapy response directed to DGC or LBC are scarce.
Ongoing studies are mainly investigating alternate medication doses and combining therapeutic agents that are approved for sporadic gastric cancer and other solid tumors (e.g., platinum compounds, fluropyrimidines, and topoisomerase I inhibitors). Immunotherapy for anti-HER2, anti-VEGDR2, and anti-PD1 have been approved for treatment of gastric adenocarcinoma; however, treatment data for DGC is weak.
The MONO study (
There are active clinical trials for individuals with invasive LBC or enriched in individuals with lobular histology. These studies are testing small molecules including tyrosine kinase ROS1 inhibition, CDK4/6 inhibition, endocrine therapy strategies, immunotherapy with checkpoint inhibition, and inhibition of HER2 in individuals with HER2 alterations [
Search
## Genetic Counseling
Diffuse gastric and lobular breast cancer syndrome (DGLBCS) is inherited in an autosomal dominant manner.
The majority of individuals diagnosed with
Some individuals with DGLBCS have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing of the parents for the DGLBCS-related
If the DGLBCS-related pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
The family history of an individual with DGLBCS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has confirmed that neither parent is heterozygous for the DGLBCS-related pathogenic variant identified in the proband.
If a parent of the proband is affected and/or known to have a DGLBCS-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and having DGLBCS is 50%.
Because DGLBCS is associated with reduced
If the DGLBCS-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
The absence of DGLBCS-related manifestations in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
See Management,
Predictive testing for at-risk relatives is possible if a DGLBCS-related pathogenic variant has been identified in an affected family member.
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Predictive testing is not possible for family members of a proband with suspected DGLBCS of unknown genetic cause (i.e., a proband with clinical features and a family history consistent with DGLBCS in whom molecular genetic testing has not identified a pathogenic variant in
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Counseling about nutritional consequences of prophylactic gastrectomy should be discussed before and during pregnancy (see
If the DGLBCS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and in families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The majority of individuals diagnosed with
• Some individuals with DGLBCS have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing of the parents for the DGLBCS-related
• If the DGLBCS-related pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of an individual with DGLBCS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has confirmed that neither parent is heterozygous for the DGLBCS-related pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or known to have a DGLBCS-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and having DGLBCS is 50%.
• Because DGLBCS is associated with reduced
• If the DGLBCS-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
• The absence of DGLBCS-related manifestations in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
• Predictive testing for at-risk relatives is possible if a DGLBCS-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Counseling about nutritional consequences of prophylactic gastrectomy should be discussed before and during pregnancy (see
## Mode of Inheritance
Diffuse gastric and lobular breast cancer syndrome (DGLBCS) is inherited in an autosomal dominant manner.
## Risk to Family Members – Proband with a DGLBCS-Related
The majority of individuals diagnosed with
Some individuals with DGLBCS have the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing of the parents for the DGLBCS-related
If the DGLBCS-related pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
The family history of an individual with DGLBCS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has confirmed that neither parent is heterozygous for the DGLBCS-related pathogenic variant identified in the proband.
If a parent of the proband is affected and/or known to have a DGLBCS-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and having DGLBCS is 50%.
Because DGLBCS is associated with reduced
If the DGLBCS-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
The absence of DGLBCS-related manifestations in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
• The majority of individuals diagnosed with
• Some individuals with DGLBCS have the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing of the parents for the DGLBCS-related
• If the DGLBCS-related pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of an individual with DGLBCS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has confirmed that neither parent is heterozygous for the DGLBCS-related pathogenic variant identified in the proband.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or known to have a DGLBCS-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant and having DGLBCS is 50%.
• Because DGLBCS is associated with reduced
• If the DGLBCS-related pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [
• The absence of DGLBCS-related manifestations in parents whose genetic status is unknown cannot be used to predict risk to sibs of a proband because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.
## Related Genetic Counseling Issues
See Management,
Predictive testing for at-risk relatives is possible if a DGLBCS-related pathogenic variant has been identified in an affected family member.
Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Predictive testing is not possible for family members of a proband with suspected DGLBCS of unknown genetic cause (i.e., a proband with clinical features and a family history consistent with DGLBCS in whom molecular genetic testing has not identified a pathogenic variant in
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Counseling about nutritional consequences of prophylactic gastrectomy should be discussed before and during pregnancy (see
• Predictive testing for at-risk relatives is possible if a DGLBCS-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Counseling about nutritional consequences of prophylactic gastrectomy should be discussed before and during pregnancy (see
## Prenatal Testing and Preimplantation Genetic Testing
If the DGLBCS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and in families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Diffuse Gastric and Lobular Breast Cancer Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Diffuse Gastric and Lobular Breast Cancer Syndrome (
E-cadherin (epithelial cadherin; also known as cadherin-1) is a transmembrane glycoprotein that is predominantly expressed at the basolateral membrane of epithelial cells, where it exerts calcium-dependent cell-cell adhesion and invasion-suppression functions [
Somatic inactivation or down-regulation
The activity of E-cadherin in cell adhesion is dependent on its association with the actin cytoskeleton via undercoat proteins called catenins (α-, β-, and γ-) [
Catenin alpha-1 (also known as alpha E-catenin), encoded by
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
DNA nucleotide change introduces a new splice site and does not result in the predicted protein change p.Ala634Val. Cryptic splicing causes a 37-bp deletion in exon 12 and premature truncation [
## Molecular Pathogenesis
E-cadherin (epithelial cadherin; also known as cadherin-1) is a transmembrane glycoprotein that is predominantly expressed at the basolateral membrane of epithelial cells, where it exerts calcium-dependent cell-cell adhesion and invasion-suppression functions [
Somatic inactivation or down-regulation
The activity of E-cadherin in cell adhesion is dependent on its association with the actin cytoskeleton via undercoat proteins called catenins (α-, β-, and γ-) [
Catenin alpha-1 (also known as alpha E-catenin), encoded by
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
DNA nucleotide change introduces a new splice site and does not result in the predicted protein change p.Ala634Val. Cryptic splicing causes a 37-bp deletion in exon 12 and premature truncation [
## Chapter Notes
Rita Barbosa-Matos, BSc, PhD (2024-present)Lilian Córdova, MD (2024-present)David G Huntsman, MD; University of British Columbia (2002-2024)Pardeep Kaurah, MSc, PhD; University of British Columbia (2002-2024)Carla Oliveira, PhD (2024-present)Kasmintan Schrader, MBBS, PhD (2024-present)
10 October 2024 (sw) Comprehensive update posted live
22 March 2018 (sw) Comprehensive update posted live
31 July 2014 (me) Comprehensive update posted live
21 June 2011 (me) Comprehensive update posted live
13 December 2004 (me) Comprehensive update posted live
4 November 2002 (me) Review posted live
5 April 2002 (pk) Original submission
• 10 October 2024 (sw) Comprehensive update posted live
• 22 March 2018 (sw) Comprehensive update posted live
• 31 July 2014 (me) Comprehensive update posted live
• 21 June 2011 (me) Comprehensive update posted live
• 13 December 2004 (me) Comprehensive update posted live
• 4 November 2002 (me) Review posted live
• 5 April 2002 (pk) Original submission
## Author History
Rita Barbosa-Matos, BSc, PhD (2024-present)Lilian Córdova, MD (2024-present)David G Huntsman, MD; University of British Columbia (2002-2024)Pardeep Kaurah, MSc, PhD; University of British Columbia (2002-2024)Carla Oliveira, PhD (2024-present)Kasmintan Schrader, MBBS, PhD (2024-present)
## Revision History
10 October 2024 (sw) Comprehensive update posted live
22 March 2018 (sw) Comprehensive update posted live
31 July 2014 (me) Comprehensive update posted live
21 June 2011 (me) Comprehensive update posted live
13 December 2004 (me) Comprehensive update posted live
4 November 2002 (me) Review posted live
5 April 2002 (pk) Original submission
• 10 October 2024 (sw) Comprehensive update posted live
• 22 March 2018 (sw) Comprehensive update posted live
• 31 July 2014 (me) Comprehensive update posted live
• 21 June 2011 (me) Comprehensive update posted live
• 13 December 2004 (me) Comprehensive update posted live
• 4 November 2002 (me) Review posted live
• 5 April 2002 (pk) Original submission
## Key Sections in This
## References
Blair VR, McLeod M, Carneiro F, Coit DG, D'Addario JL, van Dieren JM, Harris KL, Hoogerbrugge N, Oliveira C, van der Post RS, Arnold J, Benusiglio PR, Bisseling TM, Boussioutas A, Cats A, Charlton A, Schreiber KEC, Davis JL, Pietro MD, Fitzgerald RC, Ford JM, Gamet K, Gullo I, Hardwick RH, Huntsman DG, Kaurah P, Kupfer SS, Latchford A, Mansfield PF, Nakajima T, Parry S, Rossaak J, Sugimura H, Svrcek M, Tischkowitz M, Ushijima T, Yamada H, Yang HK, Claydon A, Figueiredo J, Paringatai K, Seruca R, Bougen-Zhukov N, Brew T, Busija S, Carneiro P, DeGregorio L, Fisher H, Gardner E, Godwin TD, Holm KN, Humar B, Lintott CJ, Monroe EC, Muller MD, Norero E, Nouri Y, Paredes J, Sanches JM, Schulpen E, Ribeiro AS, Sporle A, Whitworth J, Zhang L, Reeve AE, Guilford P. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. 2020;21:e386-e397. [
• Blair VR, McLeod M, Carneiro F, Coit DG, D'Addario JL, van Dieren JM, Harris KL, Hoogerbrugge N, Oliveira C, van der Post RS, Arnold J, Benusiglio PR, Bisseling TM, Boussioutas A, Cats A, Charlton A, Schreiber KEC, Davis JL, Pietro MD, Fitzgerald RC, Ford JM, Gamet K, Gullo I, Hardwick RH, Huntsman DG, Kaurah P, Kupfer SS, Latchford A, Mansfield PF, Nakajima T, Parry S, Rossaak J, Sugimura H, Svrcek M, Tischkowitz M, Ushijima T, Yamada H, Yang HK, Claydon A, Figueiredo J, Paringatai K, Seruca R, Bougen-Zhukov N, Brew T, Busija S, Carneiro P, DeGregorio L, Fisher H, Gardner E, Godwin TD, Holm KN, Humar B, Lintott CJ, Monroe EC, Muller MD, Norero E, Nouri Y, Paredes J, Sanches JM, Schulpen E, Ribeiro AS, Sporle A, Whitworth J, Zhang L, Reeve AE, Guilford P. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. 2020;21:e386-e397. [
## Published Guidelines / Consensus Statements
Blair VR, McLeod M, Carneiro F, Coit DG, D'Addario JL, van Dieren JM, Harris KL, Hoogerbrugge N, Oliveira C, van der Post RS, Arnold J, Benusiglio PR, Bisseling TM, Boussioutas A, Cats A, Charlton A, Schreiber KEC, Davis JL, Pietro MD, Fitzgerald RC, Ford JM, Gamet K, Gullo I, Hardwick RH, Huntsman DG, Kaurah P, Kupfer SS, Latchford A, Mansfield PF, Nakajima T, Parry S, Rossaak J, Sugimura H, Svrcek M, Tischkowitz M, Ushijima T, Yamada H, Yang HK, Claydon A, Figueiredo J, Paringatai K, Seruca R, Bougen-Zhukov N, Brew T, Busija S, Carneiro P, DeGregorio L, Fisher H, Gardner E, Godwin TD, Holm KN, Humar B, Lintott CJ, Monroe EC, Muller MD, Norero E, Nouri Y, Paredes J, Sanches JM, Schulpen E, Ribeiro AS, Sporle A, Whitworth J, Zhang L, Reeve AE, Guilford P. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. 2020;21:e386-e397. [
• Blair VR, McLeod M, Carneiro F, Coit DG, D'Addario JL, van Dieren JM, Harris KL, Hoogerbrugge N, Oliveira C, van der Post RS, Arnold J, Benusiglio PR, Bisseling TM, Boussioutas A, Cats A, Charlton A, Schreiber KEC, Davis JL, Pietro MD, Fitzgerald RC, Ford JM, Gamet K, Gullo I, Hardwick RH, Huntsman DG, Kaurah P, Kupfer SS, Latchford A, Mansfield PF, Nakajima T, Parry S, Rossaak J, Sugimura H, Svrcek M, Tischkowitz M, Ushijima T, Yamada H, Yang HK, Claydon A, Figueiredo J, Paringatai K, Seruca R, Bougen-Zhukov N, Brew T, Busija S, Carneiro P, DeGregorio L, Fisher H, Gardner E, Godwin TD, Holm KN, Humar B, Lintott CJ, Monroe EC, Muller MD, Norero E, Nouri Y, Paredes J, Sanches JM, Schulpen E, Ribeiro AS, Sporle A, Whitworth J, Zhang L, Reeve AE, Guilford P. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. 2020;21:e386-e397. [
## Literature Cited
|
[] |
4/11/2002
|
10/10/2024
|
31/8/2006
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
hgps
|
hgps
|
[
"Hutchinson-Gilford Progeria Syndrome, Nonclassic Genotypes",
"Hutchinson-Gilford Progeria Syndrome, Classic Genotype",
"Prelamin-A/C",
"LMNA",
"Hutchinson-Gilford Progeria Syndrome"
] |
Hutchinson-Gilford Progeria Syndrome
|
Leslie B Gordon, W Ted Brown, Francis S Collins
|
Summary Hutchinson-Gilford progeria syndrome (HGPS) is characterized in the first year of life by growth deficiency, lagophthalmos, hair loss, delayed and incomplete primary tooth eruption, subcutaneous fat loss, and areas of abnormal skin (tightness, stippling, and/or small outpouchings over the abdomen and upper thighs). Motor and mental development is normal. Children have profound growth failure, subcutaneous lipodystrophy, total alopecia, high-pitched voice, nail dystrophy, horse-riding stance, coxa valga with possible hip dislocations, narrowed upper thorax, and progressive joint contractures. Characteristic facial features include disproportionately large head for the face, narrow nasal ridge, narrow nasal tip, thin vermilion of the lips, small mouth, retro- and micrognathia, delayed loss of primary teeth, and partial secondary tooth eruption. Additional features include low-frequency conductive hearing loss, dry eye with risk of exposure keratitis, and premature and accelerated atherosclerosis with cerebrovascular and cardiovascular disease. Without lonafarnib treatment death occurs at an average age of 14.5 years (range: 6-20 years). With lonafarnib treatment average life span is extended to approximately 18.7 years. The diagnosis of classic or nonclassic genotype HGPS is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in HGPS is an autosomal dominant disorder. Ninety-eight percent of individuals with HGPS have the disorder as the result of a
|
Hutchinson-Gilford progeria syndrome, classic genotype
Hutchinson-Gilford progeria syndrome, nonclassic genotypes
For synonyms and outdated names see
• Hutchinson-Gilford progeria syndrome, classic genotype
• Hutchinson-Gilford progeria syndrome, nonclassic genotypes
## Diagnosis
The clinical diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) can be established in a proband when characteristic pathognomonic features emerge. Molecular testing should accompany a clinical diagnosis (see
HGPS
Typically postnatal onset during first two years of life
Short stature (<3rd centile)
Poor weight gain (<3rd centile); weight distinctly low for height
Diminished subcutaneous body fat globally, along with low serum leptin levels
Head disproportionately large for face
Long, narrow nose (narrow nasal ridge and narrow nasal tip)
Thin vermilion of the upper and lower lips
Small mouth, retrognathia, and micrognathia
Dental. Delayed eruption and delayed loss of primary teeth, partial secondary tooth eruption, tooth misalignment
Skin. Taut, variably pigmented, sclerodermatous skin outpouchings over lower abdomen and/or proximal thighs, any of which can be the first signs of disease in infancy
Hair. Total alopecia that develops in the first two years of life, sometimes with very sparse, downy, immature hair remaining; loss of eyebrows
Dystrophic nails develop at variable ages in childhood.
Coxa valga develops within the first three years, with wide-based, shuffling gait, sometimes accompanied by avascular necrosis of the femoral head.
Osteolysis of the distal phalanges
Short clavicles with distal resorption/tapering (distal clavicular osteolysis)
Pear-shaped thorax
Normal or mildly low bone density z scores when normalized for height and age
Joint contractures are present in all individuals; can be present at birth or present later in childhood; locations vary
Nocturnal lagophthalmos (the inability to fully close the eyes while sleeping) is an almost uniform finding and can occur from birth.
Normal intellectual development
High-pitched voice
Low-frequency conductive hearing loss
Secondary sexual characteristics do not fully develop. Menstruation is variable in females.
The clinical diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) can be established in a proband when characteristic pathognomonic features emerge. These include, at a minimum, one of the skin findings, severe growth failure, alopecia, global lipodystrophy, and small clavicles, all present in the setting of normal intellectual development and within the first two years of life. Although these findings can establish the clinical diagnosis of HGPS, the lack of or delay in these findings does not exclude the diagnosis, as nonclassic and classic genotype HGPS can vary in the onset of these findings. Molecular testing should accompany a clinical diagnosis.
Four major categories help to define
Progerin-producing classic genotype HGPS
Progerin-producing nonclassic genotype HGPS
Non-progerin-producing progeroid laminopathies (see
Heterozygous or biallelic
Pathogenic variants in
Non-progeroid laminopathies (See
HGPS is caused by the production of an abnormal form of lamin A protein called progerin. Progerin results from increased spliceosome binding ratio between an
The diagnosis of
The diagnosis of
Molecular genetic testing approaches can include a combination of
Targeted analysis for classic and nonclassic HGPS can be performed by sequencing exon 11 and at least the first seven bases of intron 11. This span of bases should be standard for an exon 11 gene sequencing request. A search for the classic
Sequence analysis of the entire
If no
Note: To date,
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by a progeroid phenotype,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hutchinson-Gilford Progeria Syndrome
See
See
About 90% of individuals with typical clinical features of HGPS will have the classic genotype (heterozygous
Sequence analysis should include intron 11. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
An individual with somatic mosaicism has been identified using deep sequencing, whereby a child likely manifested two progerin-producing variants in different cells [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Typically postnatal onset during first two years of life
• Short stature (<3rd centile)
• Poor weight gain (<3rd centile); weight distinctly low for height
• Diminished subcutaneous body fat globally, along with low serum leptin levels
• Head disproportionately large for face
• Long, narrow nose (narrow nasal ridge and narrow nasal tip)
• Thin vermilion of the upper and lower lips
• Small mouth, retrognathia, and micrognathia
• Dental. Delayed eruption and delayed loss of primary teeth, partial secondary tooth eruption, tooth misalignment
• Skin. Taut, variably pigmented, sclerodermatous skin outpouchings over lower abdomen and/or proximal thighs, any of which can be the first signs of disease in infancy
• Hair. Total alopecia that develops in the first two years of life, sometimes with very sparse, downy, immature hair remaining; loss of eyebrows
• Dystrophic nails develop at variable ages in childhood.
• Coxa valga develops within the first three years, with wide-based, shuffling gait, sometimes accompanied by avascular necrosis of the femoral head.
• Osteolysis of the distal phalanges
• Short clavicles with distal resorption/tapering (distal clavicular osteolysis)
• Pear-shaped thorax
• Normal or mildly low bone density z scores when normalized for height and age
• Joint contractures are present in all individuals; can be present at birth or present later in childhood; locations vary
• Nocturnal lagophthalmos (the inability to fully close the eyes while sleeping) is an almost uniform finding and can occur from birth.
• Normal intellectual development
• High-pitched voice
• Low-frequency conductive hearing loss
• Secondary sexual characteristics do not fully develop. Menstruation is variable in females.
• Progerin-producing classic genotype HGPS
• Progerin-producing nonclassic genotype HGPS
• Non-progerin-producing progeroid laminopathies (see
• Heterozygous or biallelic
• Pathogenic variants in
• Heterozygous or biallelic
• Pathogenic variants in
• Non-progeroid laminopathies (See
• Heterozygous or biallelic
• Pathogenic variants in
• Targeted analysis for classic and nonclassic HGPS can be performed by sequencing exon 11 and at least the first seven bases of intron 11. This span of bases should be standard for an exon 11 gene sequencing request. A search for the classic
• Sequence analysis of the entire
• If no
## Suggestive Findings
HGPS
Typically postnatal onset during first two years of life
Short stature (<3rd centile)
Poor weight gain (<3rd centile); weight distinctly low for height
Diminished subcutaneous body fat globally, along with low serum leptin levels
Head disproportionately large for face
Long, narrow nose (narrow nasal ridge and narrow nasal tip)
Thin vermilion of the upper and lower lips
Small mouth, retrognathia, and micrognathia
Dental. Delayed eruption and delayed loss of primary teeth, partial secondary tooth eruption, tooth misalignment
Skin. Taut, variably pigmented, sclerodermatous skin outpouchings over lower abdomen and/or proximal thighs, any of which can be the first signs of disease in infancy
Hair. Total alopecia that develops in the first two years of life, sometimes with very sparse, downy, immature hair remaining; loss of eyebrows
Dystrophic nails develop at variable ages in childhood.
Coxa valga develops within the first three years, with wide-based, shuffling gait, sometimes accompanied by avascular necrosis of the femoral head.
Osteolysis of the distal phalanges
Short clavicles with distal resorption/tapering (distal clavicular osteolysis)
Pear-shaped thorax
Normal or mildly low bone density z scores when normalized for height and age
Joint contractures are present in all individuals; can be present at birth or present later in childhood; locations vary
Nocturnal lagophthalmos (the inability to fully close the eyes while sleeping) is an almost uniform finding and can occur from birth.
Normal intellectual development
High-pitched voice
Low-frequency conductive hearing loss
Secondary sexual characteristics do not fully develop. Menstruation is variable in females.
• Typically postnatal onset during first two years of life
• Short stature (<3rd centile)
• Poor weight gain (<3rd centile); weight distinctly low for height
• Diminished subcutaneous body fat globally, along with low serum leptin levels
• Head disproportionately large for face
• Long, narrow nose (narrow nasal ridge and narrow nasal tip)
• Thin vermilion of the upper and lower lips
• Small mouth, retrognathia, and micrognathia
• Dental. Delayed eruption and delayed loss of primary teeth, partial secondary tooth eruption, tooth misalignment
• Skin. Taut, variably pigmented, sclerodermatous skin outpouchings over lower abdomen and/or proximal thighs, any of which can be the first signs of disease in infancy
• Hair. Total alopecia that develops in the first two years of life, sometimes with very sparse, downy, immature hair remaining; loss of eyebrows
• Dystrophic nails develop at variable ages in childhood.
• Coxa valga develops within the first three years, with wide-based, shuffling gait, sometimes accompanied by avascular necrosis of the femoral head.
• Osteolysis of the distal phalanges
• Short clavicles with distal resorption/tapering (distal clavicular osteolysis)
• Pear-shaped thorax
• Normal or mildly low bone density z scores when normalized for height and age
• Joint contractures are present in all individuals; can be present at birth or present later in childhood; locations vary
• Nocturnal lagophthalmos (the inability to fully close the eyes while sleeping) is an almost uniform finding and can occur from birth.
• Normal intellectual development
• High-pitched voice
• Low-frequency conductive hearing loss
• Secondary sexual characteristics do not fully develop. Menstruation is variable in females.
## Establishing the Diagnosis
The clinical diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) can be established in a proband when characteristic pathognomonic features emerge. These include, at a minimum, one of the skin findings, severe growth failure, alopecia, global lipodystrophy, and small clavicles, all present in the setting of normal intellectual development and within the first two years of life. Although these findings can establish the clinical diagnosis of HGPS, the lack of or delay in these findings does not exclude the diagnosis, as nonclassic and classic genotype HGPS can vary in the onset of these findings. Molecular testing should accompany a clinical diagnosis.
Four major categories help to define
Progerin-producing classic genotype HGPS
Progerin-producing nonclassic genotype HGPS
Non-progerin-producing progeroid laminopathies (see
Heterozygous or biallelic
Pathogenic variants in
Non-progeroid laminopathies (See
HGPS is caused by the production of an abnormal form of lamin A protein called progerin. Progerin results from increased spliceosome binding ratio between an
The diagnosis of
The diagnosis of
Molecular genetic testing approaches can include a combination of
Targeted analysis for classic and nonclassic HGPS can be performed by sequencing exon 11 and at least the first seven bases of intron 11. This span of bases should be standard for an exon 11 gene sequencing request. A search for the classic
Sequence analysis of the entire
If no
Note: To date,
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by a progeroid phenotype,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hutchinson-Gilford Progeria Syndrome
See
See
About 90% of individuals with typical clinical features of HGPS will have the classic genotype (heterozygous
Sequence analysis should include intron 11. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
An individual with somatic mosaicism has been identified using deep sequencing, whereby a child likely manifested two progerin-producing variants in different cells [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Progerin-producing classic genotype HGPS
• Progerin-producing nonclassic genotype HGPS
• Non-progerin-producing progeroid laminopathies (see
• Heterozygous or biallelic
• Pathogenic variants in
• Heterozygous or biallelic
• Pathogenic variants in
• Non-progeroid laminopathies (See
• Heterozygous or biallelic
• Pathogenic variants in
• Targeted analysis for classic and nonclassic HGPS can be performed by sequencing exon 11 and at least the first seven bases of intron 11. This span of bases should be standard for an exon 11 gene sequencing request. A search for the classic
• Sequence analysis of the entire
• If no
## Clinical Diagnosis
The clinical diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) can be established in a proband when characteristic pathognomonic features emerge. These include, at a minimum, one of the skin findings, severe growth failure, alopecia, global lipodystrophy, and small clavicles, all present in the setting of normal intellectual development and within the first two years of life. Although these findings can establish the clinical diagnosis of HGPS, the lack of or delay in these findings does not exclude the diagnosis, as nonclassic and classic genotype HGPS can vary in the onset of these findings. Molecular testing should accompany a clinical diagnosis.
## Molecular Diagnosis
Four major categories help to define
Progerin-producing classic genotype HGPS
Progerin-producing nonclassic genotype HGPS
Non-progerin-producing progeroid laminopathies (see
Heterozygous or biallelic
Pathogenic variants in
Non-progeroid laminopathies (See
HGPS is caused by the production of an abnormal form of lamin A protein called progerin. Progerin results from increased spliceosome binding ratio between an
The diagnosis of
The diagnosis of
Molecular genetic testing approaches can include a combination of
Targeted analysis for classic and nonclassic HGPS can be performed by sequencing exon 11 and at least the first seven bases of intron 11. This span of bases should be standard for an exon 11 gene sequencing request. A search for the classic
Sequence analysis of the entire
If no
Note: To date,
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by a progeroid phenotype,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hutchinson-Gilford Progeria Syndrome
See
See
About 90% of individuals with typical clinical features of HGPS will have the classic genotype (heterozygous
Sequence analysis should include intron 11. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
An individual with somatic mosaicism has been identified using deep sequencing, whereby a child likely manifested two progerin-producing variants in different cells [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
• Progerin-producing classic genotype HGPS
• Progerin-producing nonclassic genotype HGPS
• Non-progerin-producing progeroid laminopathies (see
• Heterozygous or biallelic
• Pathogenic variants in
• Heterozygous or biallelic
• Pathogenic variants in
• Non-progeroid laminopathies (See
• Heterozygous or biallelic
• Pathogenic variants in
• Targeted analysis for classic and nonclassic HGPS can be performed by sequencing exon 11 and at least the first seven bases of intron 11. This span of bases should be standard for an exon 11 gene sequencing request. A search for the classic
• Sequence analysis of the entire
• If no
##
Targeted analysis for classic and nonclassic HGPS can be performed by sequencing exon 11 and at least the first seven bases of intron 11. This span of bases should be standard for an exon 11 gene sequencing request. A search for the classic
Sequence analysis of the entire
If no
Note: To date,
For an introduction to multigene panels click
• Targeted analysis for classic and nonclassic HGPS can be performed by sequencing exon 11 and at least the first seven bases of intron 11. This span of bases should be standard for an exon 11 gene sequencing request. A search for the classic
• Sequence analysis of the entire
• If no
##
When the phenotype is indistinguishable from many other inherited disorders characterized by a progeroid phenotype,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hutchinson-Gilford Progeria Syndrome
See
See
About 90% of individuals with typical clinical features of HGPS will have the classic genotype (heterozygous
Sequence analysis should include intron 11. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
An individual with somatic mosaicism has been identified using deep sequencing, whereby a child likely manifested two progerin-producing variants in different cells [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
## Clinical Characteristics
Classic and nonclassic genotype Hutchinson-Gilford progeria syndrome (HGPS) are characterized by growth deficiency, characteristic facial features, dental anomalies, sclerodermatous skin findings, alopecia, lipodystrophy, dystrophic nails, musculoskeletal manifestations, infertility, severe early-onset atherosclerosis, hearing loss, and nocturnal lagophthalmos. Children with progeria usually appear normal at birth and in early infancy.
Systolic dysfunction is usually present in the setting of advanced disease, with or without identified coronary vascular insufficiency. Clinical symptoms of angina, dyspnea on exertion, or overt heart failure appear as late findings in the course of disease.
Transient ischemic attacks, silent strokes, or symptomatic strokes have occurred as early as age four years [
Raynaud phenomenon in fingers occurs in a minority of affected individuals.
Without lonafarnib treatment, death typically occurs as a result of complications of cardiac or cerebrovascular disease. More than 80% of deaths are due to heart failure and/or myocardial infarction, most often between ages six and 20 years, with an average life span of approximately 14.5 years [
Liver, kidney, gastrointestinal, neurologic, strength-for-size, and cognitive functions are normal.
Tumor rate is not increased over that of the general population.
Other changes associated with normal aging such as nearsightedness or farsightedness, arcus senilis, senile personality changes, or Alzheimer disease have not been documented.
Children with HGPS appear to have a normal immune system; they respond as well as the general population when subjected to various infections. Wound healing is normal.
Classic and Nonclassic Genotype HGPS: Causative
HGPS = Hutchinson-Gilford progeria syndrome; PRF = Progeria Research Foundation
Activation of the cryptic splice donor is not 100% efficient, so the amino acid change occurs in nonsynonymous variants in the proportion of the RNA that has followed the normal splicing pattern.
There is a spectrum of severity for classic genotype HGPS, and most individuals with nonclassic genotype HGPS fall within that spectrum. Comparisons with classic genotype HGPS are based on the midrange of severity for classic genotype HGPS. Note that it is possible for a listed pathogenic variant to yield a spectrum of disease severity among different affected individuals.
Individuals with
Penetrance is complete.
HGPS is also referred to as the Hutchinson-Gilford syndrome or progeria.
HGPS is an ultra-rare disease. The prevalence of children with HGPS per total population is one in 20 million living individuals, with an estimated 400 affected individuals worldwide [
The estimated birth incidence for HGPS is one in four million births, with no observed differences based on sex or ethnic background [
• Liver, kidney, gastrointestinal, neurologic, strength-for-size, and cognitive functions are normal.
• Tumor rate is not increased over that of the general population.
• Other changes associated with normal aging such as nearsightedness or farsightedness, arcus senilis, senile personality changes, or Alzheimer disease have not been documented.
• Children with HGPS appear to have a normal immune system; they respond as well as the general population when subjected to various infections. Wound healing is normal.
## Clinical Description
Classic and nonclassic genotype Hutchinson-Gilford progeria syndrome (HGPS) are characterized by growth deficiency, characteristic facial features, dental anomalies, sclerodermatous skin findings, alopecia, lipodystrophy, dystrophic nails, musculoskeletal manifestations, infertility, severe early-onset atherosclerosis, hearing loss, and nocturnal lagophthalmos. Children with progeria usually appear normal at birth and in early infancy.
Systolic dysfunction is usually present in the setting of advanced disease, with or without identified coronary vascular insufficiency. Clinical symptoms of angina, dyspnea on exertion, or overt heart failure appear as late findings in the course of disease.
Transient ischemic attacks, silent strokes, or symptomatic strokes have occurred as early as age four years [
Raynaud phenomenon in fingers occurs in a minority of affected individuals.
Without lonafarnib treatment, death typically occurs as a result of complications of cardiac or cerebrovascular disease. More than 80% of deaths are due to heart failure and/or myocardial infarction, most often between ages six and 20 years, with an average life span of approximately 14.5 years [
Liver, kidney, gastrointestinal, neurologic, strength-for-size, and cognitive functions are normal.
Tumor rate is not increased over that of the general population.
Other changes associated with normal aging such as nearsightedness or farsightedness, arcus senilis, senile personality changes, or Alzheimer disease have not been documented.
Children with HGPS appear to have a normal immune system; they respond as well as the general population when subjected to various infections. Wound healing is normal.
• Liver, kidney, gastrointestinal, neurologic, strength-for-size, and cognitive functions are normal.
• Tumor rate is not increased over that of the general population.
• Other changes associated with normal aging such as nearsightedness or farsightedness, arcus senilis, senile personality changes, or Alzheimer disease have not been documented.
• Children with HGPS appear to have a normal immune system; they respond as well as the general population when subjected to various infections. Wound healing is normal.
## Genotype-Phenotype Correlations
Classic and Nonclassic Genotype HGPS: Causative
HGPS = Hutchinson-Gilford progeria syndrome; PRF = Progeria Research Foundation
Activation of the cryptic splice donor is not 100% efficient, so the amino acid change occurs in nonsynonymous variants in the proportion of the RNA that has followed the normal splicing pattern.
There is a spectrum of severity for classic genotype HGPS, and most individuals with nonclassic genotype HGPS fall within that spectrum. Comparisons with classic genotype HGPS are based on the midrange of severity for classic genotype HGPS. Note that it is possible for a listed pathogenic variant to yield a spectrum of disease severity among different affected individuals.
Individuals with
## Penetrance
Penetrance is complete.
## Nomenclature
HGPS is also referred to as the Hutchinson-Gilford syndrome or progeria.
## Prevalence
HGPS is an ultra-rare disease. The prevalence of children with HGPS per total population is one in 20 million living individuals, with an estimated 400 affected individuals worldwide [
The estimated birth incidence for HGPS is one in four million births, with no observed differences based on sex or ethnic background [
## Genetically Related (Allelic) Disorders
Many distinguishably different genetic conditions with nucleotide variants in
Selected non-progeroid laminopathies caused by pathogenic
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
See also OMIM
Some features of premature aging are seen in
## Differential Diagnosis
Progeroid Syndromes in the Differential Diagnosis of Hutchinson-Gilford Progeria Syndrome
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Biallelic pathogenic variants in
## Management
Comprehensive clinical practice guidelines for Hutchinson-Gilford progeria syndrome (HGPS) have been published (see
To establish the extent of disease and needs in an individual diagnosed with HGPS, the evaluations summarized in
Hutchinson-Gilford Progeria Syndrome: Recommended Evaluations Following Initial Diagnosis
Weight & height plotted on standard growth charts to evaluate growth over time
Nutritional assessment
Orthopedic eval for progressive coxa valga &/or avascular necrosis
DXA scan to assess bone mineral density
Skeletal radiographs to evaluate for acroosteolysis, clavicular resorption, coxa valga, & extraskeletal soft tissue calcifications
OT & PT assessments, incl 6-minute walk test, goniometry to assess joint mobility, & assessment of ADL
EKG
Echocardiogram
Carotid artery duplex scans to evaluate size of lumen & intimal thickness to establish baseline vascular status
MRI/MRA of brain & neck
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; HGPS = Hutchinson-Gilford progeria syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
This must be normalized for height age [
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Hutchinson-Gilford Progeria Syndrome: Treatment of Manifestations
Frequent small meals to maximize caloric intake
Daily multivitamin
Medication dosages should be based on body weight or body surface area & not on age. Anesthetics should be used w/particular caution.
Fluoride supplement in areas where the water supply does not contain fluoride
Extraction of primary teeth may be required to avoid dental crowding.
Since secondary teeth may erupt slowly or not at all, pulling primary teeth to make room for secondary teeth should be performed after secondary teeth have fully or almost fully erupted or descended.
Once the primary tooth has been extracted, the secondary tooth often moves into the appropriate position w/time.
Use of sunscreen on all exposed areas of skin, incl the head, for outdoor activities
Encourage sun-protective clothing incl hat
Conservative mgmt w/PT & body bracing when possible
Surgical correction if essential, w/special attention to intubation & anesthesia guidelines
Reconstructive hip surgery can be performed for repeated dislocations causing pain & significant decrease in quality of life.
PT/OT to maintain range of motion in large & small joints
Active stretching & strengthening
Hydrotherapy
Healthy diet
Maintain regular physical activity as tolerated.
Maintain optimal hydration esp during hot weather & airplane travel.
Physical activity should account for limitations related to restricted joint mobility & hip problems incl osteoarthritis & hip dislocation.
As the vasculature becomes less pliable & risk of CV disease ↑ over time, adequate oral hydration is esp important.
Based on evidence from adult studies that low-dose aspirin may prevent heart attacks & strokes.
Anticoagulants other than aspirin may be warranted if vascular blockage, transient ischemic attacks, stroke, angina, or myocardial infarction occur.
Modified transcatheter aortic valve replacement (TAVR)
Modified apico-aortic valve placement (AAC)
Sitting at the front of the classroom can be helpful.
Hearing aids as needed
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports.
ADL = activities of daily living; HGPS = Hutchinson-Gilford progeria syndrome; OT = occupational therapy; PT = physical therapy
If chicken pox or influenza is prevalent in the community, consider discontinuing the aspirin during that time because of the increased risk of Reye syndrome.
To date, two persons have undergone modified TAVR; one was successfully treated and the other experienced intra- & perisurgical cardiac death [
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Hutchinson-Gilford Progeria Syndrome: Recommended Surveillance
Orthopedic eval for avascular necrosis of hip, progressive coxa valga, & hip dislocation w/radiographs as needed
OT & PT assessments incl 6-minute walk test, goniometry to assess joint mobility, & assessment of ADL
Blood pressure measurement w/appropriately sized cuff
EKG
Echocardiogram
Carotid duplex scan
Lipid profile
Neurologic assessment for headaches & manifestations of stroke
Head & neck MRI/MRA to assess for vascular changes & silent strokes
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
Children may experience severe carotid artery atherosclerotic blockage prior to any significant EKG changes.
Children should avoid being in the midst of large crowds with much taller and larger peers because of the increased risk of injury.
Physical activity should be self-limited. Avoid uneven surfaces that could aggravate hip dysplasia, such as trampolines and bouncy houses. Avoid being carried by underage peers.
Avoid dehydration due to increased risk of stroke.
Avoid anemia and high fever, particularly in individuals with advanced cardiovascular disease.
Avoid calcium supplementation, due to the potential for aggravating extraskeletal calcification formation and hypothetically aggravating vascular plaque status.
See
Search HGPS or progeria within
A clinical treatment trial administering lonafarnib monotherapy (see
A clinical treatment trial administering progerinin, an oral small molecule inhibitor of progerin / lamin A binding, is currently being conducted [
A clinical treatment trial administering lonafarnib (see
A clinical treatment trial administering lonafarnib in combination with pravastatin and zoledronate demonstrated evidence of increased bone mineral density but no other improvements over that of lonafarnib monotherapy [
• Weight & height plotted on standard growth charts to evaluate growth over time
• Nutritional assessment
• Orthopedic eval for progressive coxa valga &/or avascular necrosis
• DXA scan to assess bone mineral density
• Skeletal radiographs to evaluate for acroosteolysis, clavicular resorption, coxa valga, & extraskeletal soft tissue calcifications
• OT & PT assessments, incl 6-minute walk test, goniometry to assess joint mobility, & assessment of ADL
• EKG
• Echocardiogram
• Carotid artery duplex scans to evaluate size of lumen & intimal thickness to establish baseline vascular status
• MRI/MRA of brain & neck
• Community or
• Social work involvement for parental support
• Home nursing referral
• Frequent small meals to maximize caloric intake
• Daily multivitamin
• Medication dosages should be based on body weight or body surface area & not on age. Anesthetics should be used w/particular caution.
• Fluoride supplement in areas where the water supply does not contain fluoride
• Extraction of primary teeth may be required to avoid dental crowding.
• Since secondary teeth may erupt slowly or not at all, pulling primary teeth to make room for secondary teeth should be performed after secondary teeth have fully or almost fully erupted or descended.
• Once the primary tooth has been extracted, the secondary tooth often moves into the appropriate position w/time.
• Use of sunscreen on all exposed areas of skin, incl the head, for outdoor activities
• Encourage sun-protective clothing incl hat
• Conservative mgmt w/PT & body bracing when possible
• Surgical correction if essential, w/special attention to intubation & anesthesia guidelines
• Reconstructive hip surgery can be performed for repeated dislocations causing pain & significant decrease in quality of life.
• PT/OT to maintain range of motion in large & small joints
• Active stretching & strengthening
• Hydrotherapy
• Healthy diet
• Maintain regular physical activity as tolerated.
• Maintain optimal hydration esp during hot weather & airplane travel.
• Physical activity should account for limitations related to restricted joint mobility & hip problems incl osteoarthritis & hip dislocation.
• As the vasculature becomes less pliable & risk of CV disease ↑ over time, adequate oral hydration is esp important.
• Based on evidence from adult studies that low-dose aspirin may prevent heart attacks & strokes.
• Anticoagulants other than aspirin may be warranted if vascular blockage, transient ischemic attacks, stroke, angina, or myocardial infarction occur.
• Modified transcatheter aortic valve replacement (TAVR)
• Modified apico-aortic valve placement (AAC)
• Sitting at the front of the classroom can be helpful.
• Hearing aids as needed
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports.
• Orthopedic eval for avascular necrosis of hip, progressive coxa valga, & hip dislocation w/radiographs as needed
• OT & PT assessments incl 6-minute walk test, goniometry to assess joint mobility, & assessment of ADL
• Blood pressure measurement w/appropriately sized cuff
• EKG
• Echocardiogram
• Carotid duplex scan
• Lipid profile
• Neurologic assessment for headaches & manifestations of stroke
• Head & neck MRI/MRA to assess for vascular changes & silent strokes
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with HGPS, the evaluations summarized in
Hutchinson-Gilford Progeria Syndrome: Recommended Evaluations Following Initial Diagnosis
Weight & height plotted on standard growth charts to evaluate growth over time
Nutritional assessment
Orthopedic eval for progressive coxa valga &/or avascular necrosis
DXA scan to assess bone mineral density
Skeletal radiographs to evaluate for acroosteolysis, clavicular resorption, coxa valga, & extraskeletal soft tissue calcifications
OT & PT assessments, incl 6-minute walk test, goniometry to assess joint mobility, & assessment of ADL
EKG
Echocardiogram
Carotid artery duplex scans to evaluate size of lumen & intimal thickness to establish baseline vascular status
MRI/MRA of brain & neck
Community or
Social work involvement for parental support
Home nursing referral
ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; HGPS = Hutchinson-Gilford progeria syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
This must be normalized for height age [
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Weight & height plotted on standard growth charts to evaluate growth over time
• Nutritional assessment
• Orthopedic eval for progressive coxa valga &/or avascular necrosis
• DXA scan to assess bone mineral density
• Skeletal radiographs to evaluate for acroosteolysis, clavicular resorption, coxa valga, & extraskeletal soft tissue calcifications
• OT & PT assessments, incl 6-minute walk test, goniometry to assess joint mobility, & assessment of ADL
• EKG
• Echocardiogram
• Carotid artery duplex scans to evaluate size of lumen & intimal thickness to establish baseline vascular status
• MRI/MRA of brain & neck
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Hutchinson-Gilford Progeria Syndrome: Treatment of Manifestations
Frequent small meals to maximize caloric intake
Daily multivitamin
Medication dosages should be based on body weight or body surface area & not on age. Anesthetics should be used w/particular caution.
Fluoride supplement in areas where the water supply does not contain fluoride
Extraction of primary teeth may be required to avoid dental crowding.
Since secondary teeth may erupt slowly or not at all, pulling primary teeth to make room for secondary teeth should be performed after secondary teeth have fully or almost fully erupted or descended.
Once the primary tooth has been extracted, the secondary tooth often moves into the appropriate position w/time.
Use of sunscreen on all exposed areas of skin, incl the head, for outdoor activities
Encourage sun-protective clothing incl hat
Conservative mgmt w/PT & body bracing when possible
Surgical correction if essential, w/special attention to intubation & anesthesia guidelines
Reconstructive hip surgery can be performed for repeated dislocations causing pain & significant decrease in quality of life.
PT/OT to maintain range of motion in large & small joints
Active stretching & strengthening
Hydrotherapy
Healthy diet
Maintain regular physical activity as tolerated.
Maintain optimal hydration esp during hot weather & airplane travel.
Physical activity should account for limitations related to restricted joint mobility & hip problems incl osteoarthritis & hip dislocation.
As the vasculature becomes less pliable & risk of CV disease ↑ over time, adequate oral hydration is esp important.
Based on evidence from adult studies that low-dose aspirin may prevent heart attacks & strokes.
Anticoagulants other than aspirin may be warranted if vascular blockage, transient ischemic attacks, stroke, angina, or myocardial infarction occur.
Modified transcatheter aortic valve replacement (TAVR)
Modified apico-aortic valve placement (AAC)
Sitting at the front of the classroom can be helpful.
Hearing aids as needed
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports.
ADL = activities of daily living; HGPS = Hutchinson-Gilford progeria syndrome; OT = occupational therapy; PT = physical therapy
If chicken pox or influenza is prevalent in the community, consider discontinuing the aspirin during that time because of the increased risk of Reye syndrome.
To date, two persons have undergone modified TAVR; one was successfully treated and the other experienced intra- & perisurgical cardiac death [
• Frequent small meals to maximize caloric intake
• Daily multivitamin
• Medication dosages should be based on body weight or body surface area & not on age. Anesthetics should be used w/particular caution.
• Fluoride supplement in areas where the water supply does not contain fluoride
• Extraction of primary teeth may be required to avoid dental crowding.
• Since secondary teeth may erupt slowly or not at all, pulling primary teeth to make room for secondary teeth should be performed after secondary teeth have fully or almost fully erupted or descended.
• Once the primary tooth has been extracted, the secondary tooth often moves into the appropriate position w/time.
• Use of sunscreen on all exposed areas of skin, incl the head, for outdoor activities
• Encourage sun-protective clothing incl hat
• Conservative mgmt w/PT & body bracing when possible
• Surgical correction if essential, w/special attention to intubation & anesthesia guidelines
• Reconstructive hip surgery can be performed for repeated dislocations causing pain & significant decrease in quality of life.
• PT/OT to maintain range of motion in large & small joints
• Active stretching & strengthening
• Hydrotherapy
• Healthy diet
• Maintain regular physical activity as tolerated.
• Maintain optimal hydration esp during hot weather & airplane travel.
• Physical activity should account for limitations related to restricted joint mobility & hip problems incl osteoarthritis & hip dislocation.
• As the vasculature becomes less pliable & risk of CV disease ↑ over time, adequate oral hydration is esp important.
• Based on evidence from adult studies that low-dose aspirin may prevent heart attacks & strokes.
• Anticoagulants other than aspirin may be warranted if vascular blockage, transient ischemic attacks, stroke, angina, or myocardial infarction occur.
• Modified transcatheter aortic valve replacement (TAVR)
• Modified apico-aortic valve placement (AAC)
• Sitting at the front of the classroom can be helpful.
• Hearing aids as needed
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports.
## Targeted Therapy
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Hutchinson-Gilford Progeria Syndrome: Treatment of Manifestations
Frequent small meals to maximize caloric intake
Daily multivitamin
Medication dosages should be based on body weight or body surface area & not on age. Anesthetics should be used w/particular caution.
Fluoride supplement in areas where the water supply does not contain fluoride
Extraction of primary teeth may be required to avoid dental crowding.
Since secondary teeth may erupt slowly or not at all, pulling primary teeth to make room for secondary teeth should be performed after secondary teeth have fully or almost fully erupted or descended.
Once the primary tooth has been extracted, the secondary tooth often moves into the appropriate position w/time.
Use of sunscreen on all exposed areas of skin, incl the head, for outdoor activities
Encourage sun-protective clothing incl hat
Conservative mgmt w/PT & body bracing when possible
Surgical correction if essential, w/special attention to intubation & anesthesia guidelines
Reconstructive hip surgery can be performed for repeated dislocations causing pain & significant decrease in quality of life.
PT/OT to maintain range of motion in large & small joints
Active stretching & strengthening
Hydrotherapy
Healthy diet
Maintain regular physical activity as tolerated.
Maintain optimal hydration esp during hot weather & airplane travel.
Physical activity should account for limitations related to restricted joint mobility & hip problems incl osteoarthritis & hip dislocation.
As the vasculature becomes less pliable & risk of CV disease ↑ over time, adequate oral hydration is esp important.
Based on evidence from adult studies that low-dose aspirin may prevent heart attacks & strokes.
Anticoagulants other than aspirin may be warranted if vascular blockage, transient ischemic attacks, stroke, angina, or myocardial infarction occur.
Modified transcatheter aortic valve replacement (TAVR)
Modified apico-aortic valve placement (AAC)
Sitting at the front of the classroom can be helpful.
Hearing aids as needed
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports.
ADL = activities of daily living; HGPS = Hutchinson-Gilford progeria syndrome; OT = occupational therapy; PT = physical therapy
If chicken pox or influenza is prevalent in the community, consider discontinuing the aspirin during that time because of the increased risk of Reye syndrome.
To date, two persons have undergone modified TAVR; one was successfully treated and the other experienced intra- & perisurgical cardiac death [
• Frequent small meals to maximize caloric intake
• Daily multivitamin
• Medication dosages should be based on body weight or body surface area & not on age. Anesthetics should be used w/particular caution.
• Fluoride supplement in areas where the water supply does not contain fluoride
• Extraction of primary teeth may be required to avoid dental crowding.
• Since secondary teeth may erupt slowly or not at all, pulling primary teeth to make room for secondary teeth should be performed after secondary teeth have fully or almost fully erupted or descended.
• Once the primary tooth has been extracted, the secondary tooth often moves into the appropriate position w/time.
• Use of sunscreen on all exposed areas of skin, incl the head, for outdoor activities
• Encourage sun-protective clothing incl hat
• Conservative mgmt w/PT & body bracing when possible
• Surgical correction if essential, w/special attention to intubation & anesthesia guidelines
• Reconstructive hip surgery can be performed for repeated dislocations causing pain & significant decrease in quality of life.
• PT/OT to maintain range of motion in large & small joints
• Active stretching & strengthening
• Hydrotherapy
• Healthy diet
• Maintain regular physical activity as tolerated.
• Maintain optimal hydration esp during hot weather & airplane travel.
• Physical activity should account for limitations related to restricted joint mobility & hip problems incl osteoarthritis & hip dislocation.
• As the vasculature becomes less pliable & risk of CV disease ↑ over time, adequate oral hydration is esp important.
• Based on evidence from adult studies that low-dose aspirin may prevent heart attacks & strokes.
• Anticoagulants other than aspirin may be warranted if vascular blockage, transient ischemic attacks, stroke, angina, or myocardial infarction occur.
• Modified transcatheter aortic valve replacement (TAVR)
• Modified apico-aortic valve placement (AAC)
• Sitting at the front of the classroom can be helpful.
• Hearing aids as needed
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Hutchinson-Gilford Progeria Syndrome: Recommended Surveillance
Orthopedic eval for avascular necrosis of hip, progressive coxa valga, & hip dislocation w/radiographs as needed
OT & PT assessments incl 6-minute walk test, goniometry to assess joint mobility, & assessment of ADL
Blood pressure measurement w/appropriately sized cuff
EKG
Echocardiogram
Carotid duplex scan
Lipid profile
Neurologic assessment for headaches & manifestations of stroke
Head & neck MRI/MRA to assess for vascular changes & silent strokes
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
Children may experience severe carotid artery atherosclerotic blockage prior to any significant EKG changes.
• Orthopedic eval for avascular necrosis of hip, progressive coxa valga, & hip dislocation w/radiographs as needed
• OT & PT assessments incl 6-minute walk test, goniometry to assess joint mobility, & assessment of ADL
• Blood pressure measurement w/appropriately sized cuff
• EKG
• Echocardiogram
• Carotid duplex scan
• Lipid profile
• Neurologic assessment for headaches & manifestations of stroke
• Head & neck MRI/MRA to assess for vascular changes & silent strokes
## Agents/Circumstances to Avoid
Children should avoid being in the midst of large crowds with much taller and larger peers because of the increased risk of injury.
Physical activity should be self-limited. Avoid uneven surfaces that could aggravate hip dysplasia, such as trampolines and bouncy houses. Avoid being carried by underage peers.
Avoid dehydration due to increased risk of stroke.
Avoid anemia and high fever, particularly in individuals with advanced cardiovascular disease.
Avoid calcium supplementation, due to the potential for aggravating extraskeletal calcification formation and hypothetically aggravating vascular plaque status.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search HGPS or progeria within
A clinical treatment trial administering lonafarnib monotherapy (see
A clinical treatment trial administering progerinin, an oral small molecule inhibitor of progerin / lamin A binding, is currently being conducted [
A clinical treatment trial administering lonafarnib (see
A clinical treatment trial administering lonafarnib in combination with pravastatin and zoledronate demonstrated evidence of increased bone mineral density but no other improvements over that of lonafarnib monotherapy [
## Genetic Counseling
Hutchinson-Gilford progeria syndrome (HGPS) is an autosomal dominant disorder typically caused by a
Ninety-eight percent of individuals reported to date with HGPS whose parents have undergone molecular genetic testing have the disorder as the result of a
The parental origin of the
A study of paternal age effect found that on average the father's age was significantly increased by about five years [
Approximately 2% of currently living individuals with the classic genotype HGPS identified through the Progeria Research Foundation
Parents of individuals with HGPS are not affected.
The risk to the sibs of the proband depends on the genetic status of the proband's parents. Because HGPS is typically caused by a
Of the 214 known individuals with classic genotype HGPS in the Progeria Research Foundation
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Ninety-eight percent of individuals reported to date with HGPS whose parents have undergone molecular genetic testing have the disorder as the result of a
• The parental origin of the
• A study of paternal age effect found that on average the father's age was significantly increased by about five years [
• The parental origin of the
• A study of paternal age effect found that on average the father's age was significantly increased by about five years [
• Approximately 2% of currently living individuals with the classic genotype HGPS identified through the Progeria Research Foundation
• Parents of individuals with HGPS are not affected.
• The parental origin of the
• A study of paternal age effect found that on average the father's age was significantly increased by about five years [
• The risk to the sibs of the proband depends on the genetic status of the proband's parents. Because HGPS is typically caused by a
• Of the 214 known individuals with classic genotype HGPS in the Progeria Research Foundation
## Mode of Inheritance
Hutchinson-Gilford progeria syndrome (HGPS) is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Ninety-eight percent of individuals reported to date with HGPS whose parents have undergone molecular genetic testing have the disorder as the result of a
The parental origin of the
A study of paternal age effect found that on average the father's age was significantly increased by about five years [
Approximately 2% of currently living individuals with the classic genotype HGPS identified through the Progeria Research Foundation
Parents of individuals with HGPS are not affected.
The risk to the sibs of the proband depends on the genetic status of the proband's parents. Because HGPS is typically caused by a
Of the 214 known individuals with classic genotype HGPS in the Progeria Research Foundation
• Ninety-eight percent of individuals reported to date with HGPS whose parents have undergone molecular genetic testing have the disorder as the result of a
• The parental origin of the
• A study of paternal age effect found that on average the father's age was significantly increased by about five years [
• The parental origin of the
• A study of paternal age effect found that on average the father's age was significantly increased by about five years [
• Approximately 2% of currently living individuals with the classic genotype HGPS identified through the Progeria Research Foundation
• Parents of individuals with HGPS are not affected.
• The parental origin of the
• A study of paternal age effect found that on average the father's age was significantly increased by about five years [
• The risk to the sibs of the proband depends on the genetic status of the proband's parents. Because HGPS is typically caused by a
• Of the 214 known individuals with classic genotype HGPS in the Progeria Research Foundation
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Patient Information and Assistance Programs
•
•
•
• Patient Information and Assistance Programs
•
•
•
•
•
•
•
## Molecular Genetics
Hutchinson-Gilford Progeria Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hutchinson-Gilford Progeria Syndrome (
The nuclear lamina is a protein-containing layer attached to the inner nuclear membrane. It is composed of a family of polypeptides, with the major components being the lamins A, B1, B2, and C. Lamins A and C are formed by alternative splicing of the
Lamin A is normally synthesized as a precursor molecule (prelamin A) and undergoes four major post-translational processing steps. First, because prelamin A contains a CAAX (cysteine / aliphatic / aliphatic / any amino acid) box at its carboxyl terminus, it is modified by farnesylation. Following farnesylation, cleavage of the last three amino acids, methylation of the C terminus, and internal proteolytic cleavage by the ZMPSTE24 protease occurs. Removal of the last 15 coding amino acids along with the CAAX box and farnesyl group generates mature lamin A with 646 amino acids.
The classic
Other
Variants listed in the table have been provided by the authors.
Pathogenic variant results in activation of a cryptic splice site.
The nucleotide substitution affects the donor splice site of intron 11.
## Molecular Pathogenesis
The nuclear lamina is a protein-containing layer attached to the inner nuclear membrane. It is composed of a family of polypeptides, with the major components being the lamins A, B1, B2, and C. Lamins A and C are formed by alternative splicing of the
Lamin A is normally synthesized as a precursor molecule (prelamin A) and undergoes four major post-translational processing steps. First, because prelamin A contains a CAAX (cysteine / aliphatic / aliphatic / any amino acid) box at its carboxyl terminus, it is modified by farnesylation. Following farnesylation, cleavage of the last three amino acids, methylation of the C terminus, and internal proteolytic cleavage by the ZMPSTE24 protease occurs. Removal of the last 15 coding amino acids along with the CAAX box and farnesyl group generates mature lamin A with 646 amino acids.
The classic
Other
Variants listed in the table have been provided by the authors.
Pathogenic variant results in activation of a cryptic splice site.
The nucleotide substitution affects the donor splice site of intron 11.
## Chapter Notes
Dr Gordon is an investigator for progeria clinical treatment trials being conducted at Boston Children's Hospital. She leads the Progeria Research Foundation's International Progeria Patient Registry and Diagnostic Testing Program. She is interested in hearing from patients, patient families, and clinicians with questions about progeria or patients with suspected progeria. She is also interested in hearing from families or clinicians who are considering treatment with lonafarnib. For more information, contact Dr Gordon at
We are grateful to all those with progeria and their families who have contributed to the medical and research progress on progeria. We thank the Progeria Research Foundation and the Boston Children's Hospital progeria clinical trial team members for advancing progeria natural history studies, treatments, and clinical care.
13 March 2025 (sw) Comprehensive update posted live
17 January 2019 (sw) Comprehensive update posted live
8 January 2015 (me) Comprehensive update posted live
6 January 2011 (me) Comprehensive update posted live
10 August 2006 (me) Comprehensive update posted live
12 December 2003 (me) Review posted live
31 July 2003 (wtb) Original submission
• 13 March 2025 (sw) Comprehensive update posted live
• 17 January 2019 (sw) Comprehensive update posted live
• 8 January 2015 (me) Comprehensive update posted live
• 6 January 2011 (me) Comprehensive update posted live
• 10 August 2006 (me) Comprehensive update posted live
• 12 December 2003 (me) Review posted live
• 31 July 2003 (wtb) Original submission
## Author Notes
Dr Gordon is an investigator for progeria clinical treatment trials being conducted at Boston Children's Hospital. She leads the Progeria Research Foundation's International Progeria Patient Registry and Diagnostic Testing Program. She is interested in hearing from patients, patient families, and clinicians with questions about progeria or patients with suspected progeria. She is also interested in hearing from families or clinicians who are considering treatment with lonafarnib. For more information, contact Dr Gordon at
## Acknowledgments
We are grateful to all those with progeria and their families who have contributed to the medical and research progress on progeria. We thank the Progeria Research Foundation and the Boston Children's Hospital progeria clinical trial team members for advancing progeria natural history studies, treatments, and clinical care.
## Revision History
13 March 2025 (sw) Comprehensive update posted live
17 January 2019 (sw) Comprehensive update posted live
8 January 2015 (me) Comprehensive update posted live
6 January 2011 (me) Comprehensive update posted live
10 August 2006 (me) Comprehensive update posted live
12 December 2003 (me) Review posted live
31 July 2003 (wtb) Original submission
• 13 March 2025 (sw) Comprehensive update posted live
• 17 January 2019 (sw) Comprehensive update posted live
• 8 January 2015 (me) Comprehensive update posted live
• 6 January 2011 (me) Comprehensive update posted live
• 10 August 2006 (me) Comprehensive update posted live
• 12 December 2003 (me) Review posted live
• 31 July 2003 (wtb) Original submission
## Key Sections in this
## References
Progeria Research Foundation. The Progeria Handbook: A Guide for Families & Health Care Providers of Children with Progeria. Includes genetic testing guidelines. Available
• Progeria Research Foundation. The Progeria Handbook: A Guide for Families & Health Care Providers of Children with Progeria. Includes genetic testing guidelines. Available
## Published Guidelines / Consensus Statements
Progeria Research Foundation. The Progeria Handbook: A Guide for Families & Health Care Providers of Children with Progeria. Includes genetic testing guidelines. Available
• Progeria Research Foundation. The Progeria Handbook: A Guide for Families & Health Care Providers of Children with Progeria. Includes genetic testing guidelines. Available
## Literature Cited
Female age 11 years and male age six years with Hutchinson-Gilford progeria syndrome displaying characteristic facial features, with total alopecia, lipodystrophy, long, narrow nose with narrow nasal ridge and narrow nasal tip, small mouth, and retrognathia
Photo courtesy of the Progeria Research Foundation
Clinical, imaging, and growth features of Hutchinson-Gilford progeria syndrome (HGPS)
A. Girl age three months
B. Girl age 2.2 years
C. Boy age 8.5 years
D. Boy age 16 years
E. Carotid artery MRI scan with contrast in a child age four years demonstrates patency on the right and 100% occlusion on the left (white arrow).
F. Boy age seven years with truncal skin showing areas of discoloration, stippled pigmentation, tightened areas that can restrict movement, and areas of the dorsal trunk with small (1 to 2 cm), soft, bulging skin.
G. Knee joint restriction in a boy age 12 years
H. Nail dystrophy and distal phalangeal tufting in a boy age ten years
I-K. Typical radiograph findings: acro-osteolysis of the distal phalange (I); clavicular shortening (J); coxa valga (K)
L. Growth characteristics showing normal birth weight and length, followed by poor weight gain and growth deficiency. Average length (blue) and weight (green) for age for ten girls from birth to age 12 months (left) and age two to eight years (right). Standard deviation is less than 6% for each data point. Data for boys are not significantly different from those of girls (P <0.005; data not shown).
Reproduced with permission from
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[] |
12/12/2003
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13/3/2025
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19/10/2023
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GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
hhhs
|
hhhs
|
[
"HHH Syndrome, ORNT1 Deficiency",
"HHH Syndrome",
"ORNT1 Deficiency",
"Mitochondrial ornithine transporter 1",
"SLC25A15",
"Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome"
] |
Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome
|
Jose Camacho, Natalia Rioseco-Camacho
|
Summary Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway. Clinical manifestations and age of onset vary among individuals even in the same family. Chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits, and/or unexplained seizures); Acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and Chronic liver dysfunction (unexplained elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance). Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia. The biochemical diagnosis of HHH syndrome is established in a proband with the classic metabolic triad of episodic or postprandial hyperammonemia, persistent hyperornithinemia, and urinary excretion of homocitrulline. The molecular diagnosis of HHH syndrome is established in a symptomatic individual with or without suggestive metabolic/biochemical findings by identification of biallelic pathogenic variants in HHH syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the
|
## Diagnosis
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome should be suspected in symptomatic individuals with the following age-related clinical, laboratory, and neuroimaging findings.
Note: (1) In HHH syndrome the degree of hyperammonemia is usually significantly less than in other urea cycle disorders such as OTC, ASS, or CPS-I deficiency (see
Plasma Ammonia Concentrations Observed in HHH Syndrome by Age of Diagnosis
Based on 64 of 120 individuals with HHH syndrome [
SD = standard deviation
The upper limit of normal plasma ammonia can vary among laboratories. Values of 40 μmol/L or less are usually considered normal for most infants, children, and adults; however, the upper limit of normal in neonates is 100 μmol/L (see
Note: While plasma concentration of ornithine decreases significantly with a protein-restricted diet, it very rarely normalizes.
Note: Homocitrulline may be found in infant formulas due to the carbamylation of lysine during manufacture and, thus, may cause a false positive result.
Of note, in neonates, the classic metabolic triad of hyperammonemia, hyperornithinemia, and homocitrullinuria may be absent or subtle; alternatively, it may be obscured by the abnormal plasma amino acid profile and aminoaciduria characteristic of hepatic dysfunction and prematurity [
At initial presentation brain MRI of a previously undiagnosed male age 36 years demonstrated multiple foci of subcortical white matter gliosis and moderate atrophy of the frontoparietal opercula and cerebellar hemispheres [
The initial brain MRI findings (pre-diagnosis of HHH syndrome) in a male age 48 years were normal; seven months after extended treatment for hyperammonemic coma requiring dialysis, brain MRI showed evidence of severe hyperammonemic encephalopathy: brain gliosis, widespread hemorrhagic necrosis in the tips of the temporal lobes, and widened horns of the lateral ventricles [
The biochemical diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome
The molecular diagnosis of HHH syndrome is established in a symptomatic individual with or without suggestive metabolic/biochemical findings by identification of biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches that depend on the clinical and biochemical findings can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive laboratory findings of HHH syndrome described in
French-Canadian founder variant
Accounts for 28% of individuals with HHH syndrome [
Japanese and Middle Eastern founder variant
Accounts for 16% of individuals with HHH syndrome [
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One exon-intron deletion (~4.5 kb) has been reported [
• At initial presentation brain MRI of a previously undiagnosed male age 36 years demonstrated multiple foci of subcortical white matter gliosis and moderate atrophy of the frontoparietal opercula and cerebellar hemispheres [
• The initial brain MRI findings (pre-diagnosis of HHH syndrome) in a male age 48 years were normal; seven months after extended treatment for hyperammonemic coma requiring dialysis, brain MRI showed evidence of severe hyperammonemic encephalopathy: brain gliosis, widespread hemorrhagic necrosis in the tips of the temporal lobes, and widened horns of the lateral ventricles [
• French-Canadian founder variant
• Accounts for 28% of individuals with HHH syndrome [
• French-Canadian founder variant
• Accounts for 28% of individuals with HHH syndrome [
• Japanese and Middle Eastern founder variant
• Accounts for 16% of individuals with HHH syndrome [
• Japanese and Middle Eastern founder variant
• Accounts for 16% of individuals with HHH syndrome [
• French-Canadian founder variant
• Accounts for 28% of individuals with HHH syndrome [
• Japanese and Middle Eastern founder variant
• Accounts for 16% of individuals with HHH syndrome [
## Suggestive Findings
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome should be suspected in symptomatic individuals with the following age-related clinical, laboratory, and neuroimaging findings.
Note: (1) In HHH syndrome the degree of hyperammonemia is usually significantly less than in other urea cycle disorders such as OTC, ASS, or CPS-I deficiency (see
Plasma Ammonia Concentrations Observed in HHH Syndrome by Age of Diagnosis
Based on 64 of 120 individuals with HHH syndrome [
SD = standard deviation
The upper limit of normal plasma ammonia can vary among laboratories. Values of 40 μmol/L or less are usually considered normal for most infants, children, and adults; however, the upper limit of normal in neonates is 100 μmol/L (see
Note: While plasma concentration of ornithine decreases significantly with a protein-restricted diet, it very rarely normalizes.
Note: Homocitrulline may be found in infant formulas due to the carbamylation of lysine during manufacture and, thus, may cause a false positive result.
Of note, in neonates, the classic metabolic triad of hyperammonemia, hyperornithinemia, and homocitrullinuria may be absent or subtle; alternatively, it may be obscured by the abnormal plasma amino acid profile and aminoaciduria characteristic of hepatic dysfunction and prematurity [
At initial presentation brain MRI of a previously undiagnosed male age 36 years demonstrated multiple foci of subcortical white matter gliosis and moderate atrophy of the frontoparietal opercula and cerebellar hemispheres [
The initial brain MRI findings (pre-diagnosis of HHH syndrome) in a male age 48 years were normal; seven months after extended treatment for hyperammonemic coma requiring dialysis, brain MRI showed evidence of severe hyperammonemic encephalopathy: brain gliosis, widespread hemorrhagic necrosis in the tips of the temporal lobes, and widened horns of the lateral ventricles [
• At initial presentation brain MRI of a previously undiagnosed male age 36 years demonstrated multiple foci of subcortical white matter gliosis and moderate atrophy of the frontoparietal opercula and cerebellar hemispheres [
• The initial brain MRI findings (pre-diagnosis of HHH syndrome) in a male age 48 years were normal; seven months after extended treatment for hyperammonemic coma requiring dialysis, brain MRI showed evidence of severe hyperammonemic encephalopathy: brain gliosis, widespread hemorrhagic necrosis in the tips of the temporal lobes, and widened horns of the lateral ventricles [
## Clinical Findings
## Laboratory Findings
Note: (1) In HHH syndrome the degree of hyperammonemia is usually significantly less than in other urea cycle disorders such as OTC, ASS, or CPS-I deficiency (see
Plasma Ammonia Concentrations Observed in HHH Syndrome by Age of Diagnosis
Based on 64 of 120 individuals with HHH syndrome [
SD = standard deviation
The upper limit of normal plasma ammonia can vary among laboratories. Values of 40 μmol/L or less are usually considered normal for most infants, children, and adults; however, the upper limit of normal in neonates is 100 μmol/L (see
Note: While plasma concentration of ornithine decreases significantly with a protein-restricted diet, it very rarely normalizes.
Note: Homocitrulline may be found in infant formulas due to the carbamylation of lysine during manufacture and, thus, may cause a false positive result.
Of note, in neonates, the classic metabolic triad of hyperammonemia, hyperornithinemia, and homocitrullinuria may be absent or subtle; alternatively, it may be obscured by the abnormal plasma amino acid profile and aminoaciduria characteristic of hepatic dysfunction and prematurity [
At initial presentation brain MRI of a previously undiagnosed male age 36 years demonstrated multiple foci of subcortical white matter gliosis and moderate atrophy of the frontoparietal opercula and cerebellar hemispheres [
The initial brain MRI findings (pre-diagnosis of HHH syndrome) in a male age 48 years were normal; seven months after extended treatment for hyperammonemic coma requiring dialysis, brain MRI showed evidence of severe hyperammonemic encephalopathy: brain gliosis, widespread hemorrhagic necrosis in the tips of the temporal lobes, and widened horns of the lateral ventricles [
• At initial presentation brain MRI of a previously undiagnosed male age 36 years demonstrated multiple foci of subcortical white matter gliosis and moderate atrophy of the frontoparietal opercula and cerebellar hemispheres [
• The initial brain MRI findings (pre-diagnosis of HHH syndrome) in a male age 48 years were normal; seven months after extended treatment for hyperammonemic coma requiring dialysis, brain MRI showed evidence of severe hyperammonemic encephalopathy: brain gliosis, widespread hemorrhagic necrosis in the tips of the temporal lobes, and widened horns of the lateral ventricles [
## Establishing the Diagnosis
The biochemical diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome
The molecular diagnosis of HHH syndrome is established in a symptomatic individual with or without suggestive metabolic/biochemical findings by identification of biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches that depend on the clinical and biochemical findings can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive laboratory findings of HHH syndrome described in
French-Canadian founder variant
Accounts for 28% of individuals with HHH syndrome [
Japanese and Middle Eastern founder variant
Accounts for 16% of individuals with HHH syndrome [
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One exon-intron deletion (~4.5 kb) has been reported [
• French-Canadian founder variant
• Accounts for 28% of individuals with HHH syndrome [
• French-Canadian founder variant
• Accounts for 28% of individuals with HHH syndrome [
• Japanese and Middle Eastern founder variant
• Accounts for 16% of individuals with HHH syndrome [
• Japanese and Middle Eastern founder variant
• Accounts for 16% of individuals with HHH syndrome [
• French-Canadian founder variant
• Accounts for 28% of individuals with HHH syndrome [
• Japanese and Middle Eastern founder variant
• Accounts for 16% of individuals with HHH syndrome [
## Biochemical Diagnosis
The biochemical diagnosis of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome
## Molecular Diagnosis
The molecular diagnosis of HHH syndrome is established in a symptomatic individual with or without suggestive metabolic/biochemical findings by identification of biallelic pathogenic (or likely pathogenic) variants in
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [
Molecular genetic testing approaches that depend on the clinical and biochemical findings can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive laboratory findings of HHH syndrome described in
French-Canadian founder variant
Accounts for 28% of individuals with HHH syndrome [
Japanese and Middle Eastern founder variant
Accounts for 16% of individuals with HHH syndrome [
For an introduction to multigene panels click
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
One exon-intron deletion (~4.5 kb) has been reported [
• French-Canadian founder variant
• Accounts for 28% of individuals with HHH syndrome [
• French-Canadian founder variant
• Accounts for 28% of individuals with HHH syndrome [
• Japanese and Middle Eastern founder variant
• Accounts for 16% of individuals with HHH syndrome [
• Japanese and Middle Eastern founder variant
• Accounts for 16% of individuals with HHH syndrome [
• French-Canadian founder variant
• Accounts for 28% of individuals with HHH syndrome [
• Japanese and Middle Eastern founder variant
• Accounts for 16% of individuals with HHH syndrome [
## Clinical Characteristics
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is characterized by variable clinical presentation and age of onset ranging from the neonatal period to adulthood. Those with neonatal onset are normal for the first 24-48 hours, followed by onset of symptoms related to hyperammonemia (poor feeding, vomiting, lethargy, low temperature, rapid breathing). Those with later onset may present with chronic neurocognitive deficits and/or unexplained seizures, spasticity, acute encephalopathy secondary to hyperammonemic crisis, or chronic liver dysfunction. Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia.
Unless otherwise indicated, the data used in this chapter are from a total of 122 individuals with HHH syndrome: Martinelli et al 2015 (n=111), six subsequent case reports [
Selected Clinical Findings in Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome
The overall survival rate in individuals with HHH syndrome is 94% (109/116). Of the 21% (13/62) of individuals with HHH syndrome who manifested in the neonatal period, the mortality rate is 15% (2/13). Treatment with a protein-restricted diet resolves hepatic dysfunction (elevated transaminases and coagulopathy). Since hyperammonemia in HHH syndrome responds quickly to treatment, early diagnosis leads to an overall improved long-term outcome regardless of the age of onset.
The long-term neurodevelopmental outcome usually (but not always) correlates with the severity and duration of the hyperammonemic insult.
Pyramidal tract findings and intellectual disability, which range from mild to severe, are generally evident by childhood since almost 70% of HHH syndrome manifests in infancy and childhood [
Given the small number of case studies published to date, little is known about the long-term outcome of individuals with neonatal onset of HHH syndrome. One child died from hyperammonemic encephalopathy at birth and another at age two months. Survivors ranged in age from one to 23 years – one demonstrated normal development at age six years, four had progressive pyramidal signs, and one with significant neuromotor impairment underwent liver transplantation at age seven years. In eight survivors with neonatal onset, cognitive abilities in four ranged from normal to mild deficiency, three exhibited severe cognitive impairment, and one was a recently reported premature infant [
Click
Unique case studies include an affected individual who presented with fulminant hepatic failure and a recent example of the clinical progression of symptoms in an undiagnosed infant.
Click
A salient characteristic of affected individuals diagnosed in childhood who have the same
Click
Liver dysfunction, a predominant feature at time of diagnosis, generally manifests as mild coagulopathy and elevated liver enzymes (AST and ALT) with or without hyperammonemia. In a few reports acute liver failure prompted consideration of liver transplantation [
Despite early detection and adequate metabolic control (i.e., absence of hyperammonemia), some individuals with HHH syndrome continue to worsen neurologically with pyramidal tract involvement and cognitive decline [
The Urea Cycle Disorders Consortium reported developmental quotients (DQ) in four preschool children (age 4-5 years) with HHH syndrome: two were in the normal range and two were <71. Two also exhibited anxiety and acting out behaviors [
Individuals diagnosed in adolescence/adulthood may present with recurrent encephalopathy secondary to hyperammonemia (lethargy, disorientation, episodic confusion, unexplained seizures), intellectual disabilities, recurrent vomiting, chronic behavioral problems, cerebellar signs (dizziness, loss of balance, poor coordination, abnormal gait/posture), and pyramidal tract dysfunction (inability to perform fine movements, positive Babinski reflex, muscle weakness, ataxia, hyperreflexia, and spasticity).
Click
The Urea Cycle Disorder Consortium reported findings of two successive neurocognitive evaluations given to one adult with HHH syndrome: full scale IQ was 100 and 84 at ages 21 years and 26 years, respectively; performance was significantly diminished across all neuropsychological tests. No cognitive or behavioral issues were noted [
Mildly elevated plasma glutamine concentration (1.5- to 2-fold the upper limits of control values)
Plasma lysine can range from normal to moderately decreased
Increased urinary excretion of:
Orotic acid (2.5- to 12-fold the upper limit of control values)
Organic acids. An increase in the urinary excretion of components of the Krebs cycle (succinate, citrate, fumaric, α-ketoglutaric), methylcitrate, and lactate has been documented in a few reports [
Statistically significant elevation of AFP and pronounced liver ultrasound abnormalities at follow up [
The
The name "hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome" was coined by Vivian Shih, MD in 1969 for the disorder in which a "block in the ornithine metabolic pathway" has biochemical findings "not concordant with those in patients with proven
In 1999 after
HHH syndrome may also be referred to as "ornithine transporter deficiency" or "ornithine translocase deficiency."
Since the description of the first individual with HHH syndrome by
The incidence of HHH syndrome is highest in individuals of French-Canadian ancestry because of the
Another common pathogenic variant,
• Mildly elevated plasma glutamine concentration (1.5- to 2-fold the upper limits of control values)
• Plasma lysine can range from normal to moderately decreased
• Increased urinary excretion of:
• Orotic acid (2.5- to 12-fold the upper limit of control values)
• Organic acids. An increase in the urinary excretion of components of the Krebs cycle (succinate, citrate, fumaric, α-ketoglutaric), methylcitrate, and lactate has been documented in a few reports [
• Orotic acid (2.5- to 12-fold the upper limit of control values)
• Organic acids. An increase in the urinary excretion of components of the Krebs cycle (succinate, citrate, fumaric, α-ketoglutaric), methylcitrate, and lactate has been documented in a few reports [
• Statistically significant elevation of AFP and pronounced liver ultrasound abnormalities at follow up [
• Orotic acid (2.5- to 12-fold the upper limit of control values)
• Organic acids. An increase in the urinary excretion of components of the Krebs cycle (succinate, citrate, fumaric, α-ketoglutaric), methylcitrate, and lactate has been documented in a few reports [
## Clinical Description
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is characterized by variable clinical presentation and age of onset ranging from the neonatal period to adulthood. Those with neonatal onset are normal for the first 24-48 hours, followed by onset of symptoms related to hyperammonemia (poor feeding, vomiting, lethargy, low temperature, rapid breathing). Those with later onset may present with chronic neurocognitive deficits and/or unexplained seizures, spasticity, acute encephalopathy secondary to hyperammonemic crisis, or chronic liver dysfunction. Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia.
Unless otherwise indicated, the data used in this chapter are from a total of 122 individuals with HHH syndrome: Martinelli et al 2015 (n=111), six subsequent case reports [
Selected Clinical Findings in Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome
The overall survival rate in individuals with HHH syndrome is 94% (109/116). Of the 21% (13/62) of individuals with HHH syndrome who manifested in the neonatal period, the mortality rate is 15% (2/13). Treatment with a protein-restricted diet resolves hepatic dysfunction (elevated transaminases and coagulopathy). Since hyperammonemia in HHH syndrome responds quickly to treatment, early diagnosis leads to an overall improved long-term outcome regardless of the age of onset.
The long-term neurodevelopmental outcome usually (but not always) correlates with the severity and duration of the hyperammonemic insult.
Pyramidal tract findings and intellectual disability, which range from mild to severe, are generally evident by childhood since almost 70% of HHH syndrome manifests in infancy and childhood [
Given the small number of case studies published to date, little is known about the long-term outcome of individuals with neonatal onset of HHH syndrome. One child died from hyperammonemic encephalopathy at birth and another at age two months. Survivors ranged in age from one to 23 years – one demonstrated normal development at age six years, four had progressive pyramidal signs, and one with significant neuromotor impairment underwent liver transplantation at age seven years. In eight survivors with neonatal onset, cognitive abilities in four ranged from normal to mild deficiency, three exhibited severe cognitive impairment, and one was a recently reported premature infant [
Click
Unique case studies include an affected individual who presented with fulminant hepatic failure and a recent example of the clinical progression of symptoms in an undiagnosed infant.
Click
A salient characteristic of affected individuals diagnosed in childhood who have the same
Click
Liver dysfunction, a predominant feature at time of diagnosis, generally manifests as mild coagulopathy and elevated liver enzymes (AST and ALT) with or without hyperammonemia. In a few reports acute liver failure prompted consideration of liver transplantation [
Despite early detection and adequate metabolic control (i.e., absence of hyperammonemia), some individuals with HHH syndrome continue to worsen neurologically with pyramidal tract involvement and cognitive decline [
The Urea Cycle Disorders Consortium reported developmental quotients (DQ) in four preschool children (age 4-5 years) with HHH syndrome: two were in the normal range and two were <71. Two also exhibited anxiety and acting out behaviors [
Individuals diagnosed in adolescence/adulthood may present with recurrent encephalopathy secondary to hyperammonemia (lethargy, disorientation, episodic confusion, unexplained seizures), intellectual disabilities, recurrent vomiting, chronic behavioral problems, cerebellar signs (dizziness, loss of balance, poor coordination, abnormal gait/posture), and pyramidal tract dysfunction (inability to perform fine movements, positive Babinski reflex, muscle weakness, ataxia, hyperreflexia, and spasticity).
Click
The Urea Cycle Disorder Consortium reported findings of two successive neurocognitive evaluations given to one adult with HHH syndrome: full scale IQ was 100 and 84 at ages 21 years and 26 years, respectively; performance was significantly diminished across all neuropsychological tests. No cognitive or behavioral issues were noted [
Mildly elevated plasma glutamine concentration (1.5- to 2-fold the upper limits of control values)
Plasma lysine can range from normal to moderately decreased
Increased urinary excretion of:
Orotic acid (2.5- to 12-fold the upper limit of control values)
Organic acids. An increase in the urinary excretion of components of the Krebs cycle (succinate, citrate, fumaric, α-ketoglutaric), methylcitrate, and lactate has been documented in a few reports [
Statistically significant elevation of AFP and pronounced liver ultrasound abnormalities at follow up [
• Mildly elevated plasma glutamine concentration (1.5- to 2-fold the upper limits of control values)
• Plasma lysine can range from normal to moderately decreased
• Increased urinary excretion of:
• Orotic acid (2.5- to 12-fold the upper limit of control values)
• Organic acids. An increase in the urinary excretion of components of the Krebs cycle (succinate, citrate, fumaric, α-ketoglutaric), methylcitrate, and lactate has been documented in a few reports [
• Orotic acid (2.5- to 12-fold the upper limit of control values)
• Organic acids. An increase in the urinary excretion of components of the Krebs cycle (succinate, citrate, fumaric, α-ketoglutaric), methylcitrate, and lactate has been documented in a few reports [
• Statistically significant elevation of AFP and pronounced liver ultrasound abnormalities at follow up [
• Orotic acid (2.5- to 12-fold the upper limit of control values)
• Organic acids. An increase in the urinary excretion of components of the Krebs cycle (succinate, citrate, fumaric, α-ketoglutaric), methylcitrate, and lactate has been documented in a few reports [
## Genotype-Phenotype Correlations
The
## Nomenclature
The name "hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome" was coined by Vivian Shih, MD in 1969 for the disorder in which a "block in the ornithine metabolic pathway" has biochemical findings "not concordant with those in patients with proven
In 1999 after
HHH syndrome may also be referred to as "ornithine transporter deficiency" or "ornithine translocase deficiency."
## Prevalence
Since the description of the first individual with HHH syndrome by
The incidence of HHH syndrome is highest in individuals of French-Canadian ancestry because of the
Another common pathogenic variant,
## Genetically Related (Allelic) Disorders
No clinical or biochemical phenotypes other than those discussed in this
## Differential Diagnosis
Most commonly, neonates with hyperammonemia and neonatal-onset HHH syndrome are initially suspected of having sepsis. See
Like other urea cycle disorders (UCDs), HHH syndrome should be included in the differential diagnosis of any individual with hyperammonemia, including women who experience hyperammonemia during or following pregnancy. The onset and severity of findings in HHH syndrome are more variable and less severe when compared to UCDs like
A complete chemistry panel (CMP), CBC and differential, lactate determination, arterial blood gases, serum creatine kinase (CK), and urinalysis (to check for ketonuria) should always be included in the evaluation of any person with an elevated plasma ammonia concentration to evaluate for conditions including the following:
The only other condition that causes chronic elevations in plasma ornithine concentration is deficiency of ornithine amino transferase (OAT) (OMIM
Homocitrulline is a by-product of canned milk production that arises from the reaction of cyanate and the terminal ε-amino group of lysine. In canned formulas, cyanate is produced from heat-induced urea breakdown. When homocitrulline is consumed in the diet from sources such as these, it is absorbed in the small intestine via a transport system similar to that of cationic amino acids and excreted in the urine. In contrast, homocitrullinuria detected in neonates given IV glucose only (and no dietary source of protein) indicates the presence of a metabolic disorder.
Some individuals with
In those individuals with early-childhood onset HHH syndrome in whom gait abnormalities and spasticity predominate, the differential diagnosis should also include early-onset inherited spastic paraplegia (see
## Hyperammonemia
Most commonly, neonates with hyperammonemia and neonatal-onset HHH syndrome are initially suspected of having sepsis. See
Like other urea cycle disorders (UCDs), HHH syndrome should be included in the differential diagnosis of any individual with hyperammonemia, including women who experience hyperammonemia during or following pregnancy. The onset and severity of findings in HHH syndrome are more variable and less severe when compared to UCDs like
A complete chemistry panel (CMP), CBC and differential, lactate determination, arterial blood gases, serum creatine kinase (CK), and urinalysis (to check for ketonuria) should always be included in the evaluation of any person with an elevated plasma ammonia concentration to evaluate for conditions including the following:
## Hyperornithinemia
The only other condition that causes chronic elevations in plasma ornithine concentration is deficiency of ornithine amino transferase (OAT) (OMIM
## Homocitrullinuria
Homocitrulline is a by-product of canned milk production that arises from the reaction of cyanate and the terminal ε-amino group of lysine. In canned formulas, cyanate is produced from heat-induced urea breakdown. When homocitrulline is consumed in the diet from sources such as these, it is absorbed in the small intestine via a transport system similar to that of cationic amino acids and excreted in the urine. In contrast, homocitrullinuria detected in neonates given IV glucose only (and no dietary source of protein) indicates the presence of a metabolic disorder.
Some individuals with
## Neurologic Findings
In those individuals with early-childhood onset HHH syndrome in whom gait abnormalities and spasticity predominate, the differential diagnosis should also include early-onset inherited spastic paraplegia (see
## Management
To establish the extent of disease and needs of an individual diagnosed with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome
Baseline evaluation of persons w/significant neurologic impairment
Evaluation of persons who develop hyperammonemic coma
Community or
Social work involvement for parental support
Consultation w/genetic counselor to address genetic counseling issues
Social worker can help w/school IEP, access to low-protein foods, & social services assistance.
ADHD = attention-deficit/hyperactivity disorder; BARS = Brief Ataxia Rating Scale; HC = head circumference; HT = height; ICARS= International Co-operative Ataxia Rating Scale; ID = intellectual disability; IEP = individualized educational plan; OT = occupational therapist; PT = physical therapist; SARA= Scale for the Assessment and Rating of Ataxia; US = ultrasound; WT = weight
It is critical that the acute and long-term management of individuals with HHH syndrome be performed in conjunction with a metabolic specialist. Of primary importance is the rapid control of acute hyperammonemic episodes that may result from changes in diet (e.g., protein intake), infection, dehydration, fasting, injury, or unknown cause. Long-term management focuses on prevention of postprandial hyperammonemia and acute hyperammonemic episodes and efforts to lower the plasma ornithine concentration.
Plasma ammonia concentrations ≥80 μmol/L (~2x control value) should be treated immediately.
Discontinue all oral intake until the affected individual is stabilized to stop all protein intake (a cornerstone of acute treatment) and to reduce the risk of vomiting from hyperammonemia and/or nitrogen-scavenging medications. Of note, use of the recently approved ammonia-scavenging medication glycerol phenylbutyrate (RAVICTI
Provide intravenous fluid with dextrose and intralipids to reverse catabolism while optimizing caloric intake:
Initial intravenous infusion should be 10% dextrose (with 1/4 normal saline and 20 mEq/L KCl) at twice maintenance; ammonia and glucose/Na/K/Cl/CO
It is important to maintain an approximate glucose infusion rate (GIR) between 10 to 15 mg/kg/min in order to prevent catabolism (protein sparring effect) and maintain adequate blood glucose levels between 100 and 150 mg/dL. The concentration of glucose may need to be increased (12.5% to 15%) to prevent fluid overload, particularly when secondary brain edema is present. As the affected individual's metabolic condition stabilizes, it is important to keep a stable GIR and not decrease or stop infusion rate in response to hyperglycemia (>150 mg/dL). An insulin drip should be used to maintain blood glucose at ~150-160 mg/dL during the critical phase of the hyperammonemic event and may be quickly withdrawn or reduced in rate if hypoglycemia develops.
The use of IV intralipids (2-3 g/kg/day) is an additional source of energy used in individuals with prolonged episodes of hyperammonemia common during periods of infection.
An individual with HHH syndrome is more likely to respond to the initial IV infusion of dextrose and to normalize the individual's plasma ammonia concentration when compared to an individual with a urea cycle disorder such as OTC deficiency or ASS deficiency. If clinical status does not improve, infusion of supplemental arginine and ammonia removal drugs is added to the regimen.
Of note, as clinical manifestations often do not correlate with rising plasma ammonia concentrations, treatment decisions should consider both plasma ammonia concentration and neurologic status.
Follow published protocols for treatment of acute hyperammonemic episodes similar to those instituted for OTC deficiency (see
The New England Consortium of Metabolic Programs complete set of treatment protocols for
It is important to note that unless the affected individual is transferred to a specialized metabolic center, treatment with scavenging agents to remove excess nitrogen and ammonia from the blood will depend on availability of medications.
An initial priming dose of arginine, benzoate, and phenylacetate is given (see
Initial Priming Dose of Arginine, Benzoate, and Phenylacetate by Age Group
Mix solutions of arginine, benzoate, and phenylacetate in a 10% dextrose solution at a dose of 25 mL of 10% dextrose/kg and infuse over
If ammonia levels stabilize, the same arginine, benzoate, and phenylacetate solution is infused over 24 hrs.
Sodium phenylbutyrate (sodium phenylacetate prodrug) may be given either by mouth or by nasogastric tube (Buphenyl
Dose of sodium phenylbutyrate:
≤25 kg: 550-600 mg/kg/day
>25 kg: 9.9-13.0 g/m
Mechanisms of Drug Action in Treatment of Hyperammonemia
Raises insulin levels
Induces anabolic state
Causes protein sparing effect from skeletal muscle amino acids
Needs to be supplemented in those w/a urea cycle disorder
Stimulates secretion of insulin
Plays a role in 1st step of creatine synthesis
Forms benzoate-glycine (hippurate) via the benzoylCoA:glycine acyltransferase reaction
Eliminates 1 amino group in the urine
Forms a phenylacetate-glutamine compound via the phenylacetateCoA:glutamine acetyl-transferase reaction
Eliminates 2 amino groups in the urine
A nonessential amino acid in humans
Interruption in the synthesis of brain creatine secondary to hyperammonemia has been proposed as a contributing factor to the neurologic findings in affected individuals.
Initially esterified to its CoA-ester via the medium-chain fatty acid enzyme acyl-CoA ligase
Reaction takes place in the mitochondrial matrix (liver and kidney) [
Concurrent with the above, the trigger for the hyperammonemic event (most commonly infection or internal bleeding) should be identified and treated to prevent ongoing protein catabolism and allow for the metabolic stabilization of the affected individual.
Need for dialysis (CRRT) falls into one of the following three categories based on age and plasma ammonia level [
Unlikely: <200 µmol/L
Possible: ≥200-300 µmol/L if no response within four hours
Definitely: >400-500 µmol/L
Dialysis may be prolonged if the catabolic state (e.g., infection) persists.
The recommended amount of total protein, calories, and fluids consumed per day varies with age. The ratio of natural protein to essential amino acids is approximately 60:40. The Ross Manual [
Dietary supplementation with Cyclinex
Caloric supplements such as ProPhree
UCD-Trio
Citrulline supplementation at 0.17 g/kg/day or 3.8 g/m
Sodium phenylbutyrate (Buphenyl
Effective January 2019, the FDA approved the use of glycerol phenylbutyrate (RAVICTI
Lysine supplementation is indicated when plasma lysine concentrations are low. Low plasma lysine concentrations have been associated with delayed growth and development.
Creatine supplementation has also been recommended in HHH syndrome and urea cycle disorders such as OTC and ASS deficiencies [
Carnitine supplementation may be necessary due to carnitine deficiency secondary to dietary restriction (e.g., meat) and/or conjugation of carnitine with ammonia removal drug metabolites (phenylacetate).
Plasma concentrations of ammonia, glutamine, arginine, ornithine, and essential amino acids (in particular lysine, isoleucine, leucine, and valine) should be maintained within the normal range.
Three individuals with HHH syndrome who had acute fulminant hepatic failure and coagulopathy rapidly stabilized after protein restriction and arginine or citrulline supplementation [
Two instances of liver transplantation for HHH syndrome were reported:
A child age six years with a history of continued biochemical abnormalities, protein intolerance, developmental delay, and abnormal posture [
A child age seven years with poor metabolic control who had presented at age four weeks with hyperammonemic coma (plasma ammonia 2,300 µmol/L) [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
All surveillance of individuals with HHH syndrome (
Recommended Surveillance for Individuals with Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome
From time of diagnosis until adolescence
During pre-school years: follow WT, HT & HC in conjunction w/PCP even when not seen in metabolic clinic.
Plasma ammonia & amino acids
Urine amino acids, organic acids, & orotic acid
Age:
<1 yr: every mo
1-2 yrs: every 2-3 mos
>2 yrs: every 3-4 mos
History of adherence
History of metabolic decompensation
Incl changes in eating habits, motor skills, & behavior
In children age ≤3 yrs, especially in flu season or hot/humid weather
ADD = attention-deficit disorder; ADHD = attention-deficit/hyperactivity disorder; BMI = body mass index; HC = head circumference; HT = height; PCP = primary care provider; WT = weight
Low plasma concentrations of essential amino acids (isoleucine, leucine, valine, and arginine) could trigger a catabolic state, requiring readjustment of diet/formulas and/or supplements.
Low plasma concentrations of lysine may lead to delays in growth and development in infants.
Poor school performance may lead to low self-esteem and/or behavioral problems that could influence adherence to a protein-restricted diet.
Avoid the following:
Excess dietary protein intake
Nonprescribed protein supplements such as those used to increase size of skeletal muscle during exercise regimens
Prolonged fasting during an illness or weight loss
Use of oral and intravenous steroids
Valproic acid, which induces and exacerbates hyperammonemia in urea cycle disorders
Exposure to communicable diseases
Testing of at-risk sibs is warranted to allow for early diagnosis and treatment.
If the
See
Delivery by cesarean section is recommended in order to optimize metabolic control.
One woman experienced mild hyperammonemia at the end of the first trimester of her first pregnancy. In her second pregnancy, she experienced metabolic decompensation (ammonia 295 µmol/L) prior to the second trimester and responded well to emergency treatment with Ammonul
A second woman experienced mild hyperammonemia at the end of the first trimester of her first pregnancy, and developed petit mal seizures in the second trimester and elevations in ammonia (21-103 µmol/L) post partum. In her second pregnancy, she experienced hyperammonemia ten hours post-C-section delivery that responded to treatment with oral sodium benzoate and IV arginine. During her third pregnancy, she had a seizure.
A third woman experienced mild elevation of plasma ammonia (43-126 µmol/L) during labor.
Normal pregnancy and delivery were documented in two women with HHH syndrome.
One, diagnosed with HHH syndrome at age 13 years in the course of evaluation of an affected sib, was clinically asymptomatic before pregnancy. During the pregnancy, she was maintained on citrulline and an appropriate protein-restricted diet [Rebecca Mardach, MD, Kaiser Permanente, personal communication].
The other, a woman age 22 years with no neurologic findings, had learned to self-restrict protein intake after severe protein intolerance in infancy [
One female had intrauterine growth restriction (IUGR); development at age two years was normal.
One of the neonates who had normal development at birth experienced transient respiratory distress requiring mechanical ventilation.
There are no well-controlled epidemiologic studies of the fetal effects of sodium benzoate, phenylacetate, or phenylbutyrate during human pregnancy, although there are several case reports.
In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years.
In the second pregnancy, emergency treatment with Ammonul
Although the mother responded well to emergency treatment, the baby experienced IUGR and remained in the NICU due to prematurity and low birth weight. At age two years the child exhibited speech delay and autism.
How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known.
See
Search
• Baseline evaluation of persons w/significant neurologic impairment
• Evaluation of persons who develop hyperammonemic coma
• Community or
• Social work involvement for parental support
• Consultation w/genetic counselor to address genetic counseling issues
• Social worker can help w/school IEP, access to low-protein foods, & social services assistance.
• Initial intravenous infusion should be 10% dextrose (with 1/4 normal saline and 20 mEq/L KCl) at twice maintenance; ammonia and glucose/Na/K/Cl/CO
• It is important to maintain an approximate glucose infusion rate (GIR) between 10 to 15 mg/kg/min in order to prevent catabolism (protein sparring effect) and maintain adequate blood glucose levels between 100 and 150 mg/dL. The concentration of glucose may need to be increased (12.5% to 15%) to prevent fluid overload, particularly when secondary brain edema is present. As the affected individual's metabolic condition stabilizes, it is important to keep a stable GIR and not decrease or stop infusion rate in response to hyperglycemia (>150 mg/dL). An insulin drip should be used to maintain blood glucose at ~150-160 mg/dL during the critical phase of the hyperammonemic event and may be quickly withdrawn or reduced in rate if hypoglycemia develops.
• The use of IV intralipids (2-3 g/kg/day) is an additional source of energy used in individuals with prolonged episodes of hyperammonemia common during periods of infection.
• An individual with HHH syndrome is more likely to respond to the initial IV infusion of dextrose and to normalize the individual's plasma ammonia concentration when compared to an individual with a urea cycle disorder such as OTC deficiency or ASS deficiency. If clinical status does not improve, infusion of supplemental arginine and ammonia removal drugs is added to the regimen.
• Sodium phenylbutyrate (sodium phenylacetate prodrug) may be given either by mouth or by nasogastric tube (Buphenyl
• Dose of sodium phenylbutyrate:
• ≤25 kg: 550-600 mg/kg/day
• >25 kg: 9.9-13.0 g/m
• ≤25 kg: 550-600 mg/kg/day
• >25 kg: 9.9-13.0 g/m
• ≤25 kg: 550-600 mg/kg/day
• >25 kg: 9.9-13.0 g/m
• Raises insulin levels
• Induces anabolic state
• Causes protein sparing effect from skeletal muscle amino acids
• Needs to be supplemented in those w/a urea cycle disorder
• Stimulates secretion of insulin
• Plays a role in 1st step of creatine synthesis
• Forms benzoate-glycine (hippurate) via the benzoylCoA:glycine acyltransferase reaction
• Eliminates 1 amino group in the urine
• Forms a phenylacetate-glutamine compound via the phenylacetateCoA:glutamine acetyl-transferase reaction
• Eliminates 2 amino groups in the urine
•
• Unlikely: <200 µmol/L
• Possible: ≥200-300 µmol/L if no response within four hours
• Definitely: >400-500 µmol/L
• Unlikely: <200 µmol/L
• Possible: ≥200-300 µmol/L if no response within four hours
• Definitely: >400-500 µmol/L
• Unlikely: <200 µmol/L
• Possible: ≥200-300 µmol/L if no response within four hours
• Definitely: >400-500 µmol/L
• Dietary supplementation with Cyclinex
• Caloric supplements such as ProPhree
• UCD-Trio
• Citrulline supplementation at 0.17 g/kg/day or 3.8 g/m
• Sodium phenylbutyrate (Buphenyl
• Effective January 2019, the FDA approved the use of glycerol phenylbutyrate (RAVICTI
• Lysine supplementation is indicated when plasma lysine concentrations are low. Low plasma lysine concentrations have been associated with delayed growth and development.
• Creatine supplementation has also been recommended in HHH syndrome and urea cycle disorders such as OTC and ASS deficiencies [
• Carnitine supplementation may be necessary due to carnitine deficiency secondary to dietary restriction (e.g., meat) and/or conjugation of carnitine with ammonia removal drug metabolites (phenylacetate).
• Plasma concentrations of ammonia, glutamine, arginine, ornithine, and essential amino acids (in particular lysine, isoleucine, leucine, and valine) should be maintained within the normal range.
• A child age six years with a history of continued biochemical abnormalities, protein intolerance, developmental delay, and abnormal posture [
• A child age seven years with poor metabolic control who had presented at age four weeks with hyperammonemic coma (plasma ammonia 2,300 µmol/L) [
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• From time of diagnosis until adolescence
• During pre-school years: follow WT, HT & HC in conjunction w/PCP even when not seen in metabolic clinic.
• Plasma ammonia & amino acids
• Urine amino acids, organic acids, & orotic acid
• Age:
• <1 yr: every mo
• 1-2 yrs: every 2-3 mos
• >2 yrs: every 3-4 mos
• History of adherence
• History of metabolic decompensation
• Incl changes in eating habits, motor skills, & behavior
• In children age ≤3 yrs, especially in flu season or hot/humid weather
• Excess dietary protein intake
• Nonprescribed protein supplements such as those used to increase size of skeletal muscle during exercise regimens
• Prolonged fasting during an illness or weight loss
• Use of oral and intravenous steroids
• Valproic acid, which induces and exacerbates hyperammonemia in urea cycle disorders
• Exposure to communicable diseases
• One woman experienced mild hyperammonemia at the end of the first trimester of her first pregnancy. In her second pregnancy, she experienced metabolic decompensation (ammonia 295 µmol/L) prior to the second trimester and responded well to emergency treatment with Ammonul
• A second woman experienced mild hyperammonemia at the end of the first trimester of her first pregnancy, and developed petit mal seizures in the second trimester and elevations in ammonia (21-103 µmol/L) post partum. In her second pregnancy, she experienced hyperammonemia ten hours post-C-section delivery that responded to treatment with oral sodium benzoate and IV arginine. During her third pregnancy, she had a seizure.
• A third woman experienced mild elevation of plasma ammonia (43-126 µmol/L) during labor.
• One, diagnosed with HHH syndrome at age 13 years in the course of evaluation of an affected sib, was clinically asymptomatic before pregnancy. During the pregnancy, she was maintained on citrulline and an appropriate protein-restricted diet [Rebecca Mardach, MD, Kaiser Permanente, personal communication].
• The other, a woman age 22 years with no neurologic findings, had learned to self-restrict protein intake after severe protein intolerance in infancy [
• One female had intrauterine growth restriction (IUGR); development at age two years was normal.
• One of the neonates who had normal development at birth experienced transient respiratory distress requiring mechanical ventilation.
• In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years.
• In the second pregnancy, emergency treatment with Ammonul
• Although the mother responded well to emergency treatment, the baby experienced IUGR and remained in the NICU due to prematurity and low birth weight. At age two years the child exhibited speech delay and autism.
• How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known.
• In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years.
• In the second pregnancy, emergency treatment with Ammonul
• Although the mother responded well to emergency treatment, the baby experienced IUGR and remained in the NICU due to prematurity and low birth weight. At age two years the child exhibited speech delay and autism.
• How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known.
• In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years.
• In the second pregnancy, emergency treatment with Ammonul
• Although the mother responded well to emergency treatment, the baby experienced IUGR and remained in the NICU due to prematurity and low birth weight. At age two years the child exhibited speech delay and autism.
• How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome
Baseline evaluation of persons w/significant neurologic impairment
Evaluation of persons who develop hyperammonemic coma
Community or
Social work involvement for parental support
Consultation w/genetic counselor to address genetic counseling issues
Social worker can help w/school IEP, access to low-protein foods, & social services assistance.
ADHD = attention-deficit/hyperactivity disorder; BARS = Brief Ataxia Rating Scale; HC = head circumference; HT = height; ICARS= International Co-operative Ataxia Rating Scale; ID = intellectual disability; IEP = individualized educational plan; OT = occupational therapist; PT = physical therapist; SARA= Scale for the Assessment and Rating of Ataxia; US = ultrasound; WT = weight
• Baseline evaluation of persons w/significant neurologic impairment
• Evaluation of persons who develop hyperammonemic coma
• Community or
• Social work involvement for parental support
• Consultation w/genetic counselor to address genetic counseling issues
• Social worker can help w/school IEP, access to low-protein foods, & social services assistance.
## Treatment of Manifestations
It is critical that the acute and long-term management of individuals with HHH syndrome be performed in conjunction with a metabolic specialist. Of primary importance is the rapid control of acute hyperammonemic episodes that may result from changes in diet (e.g., protein intake), infection, dehydration, fasting, injury, or unknown cause. Long-term management focuses on prevention of postprandial hyperammonemia and acute hyperammonemic episodes and efforts to lower the plasma ornithine concentration.
Plasma ammonia concentrations ≥80 μmol/L (~2x control value) should be treated immediately.
Discontinue all oral intake until the affected individual is stabilized to stop all protein intake (a cornerstone of acute treatment) and to reduce the risk of vomiting from hyperammonemia and/or nitrogen-scavenging medications. Of note, use of the recently approved ammonia-scavenging medication glycerol phenylbutyrate (RAVICTI
Provide intravenous fluid with dextrose and intralipids to reverse catabolism while optimizing caloric intake:
Initial intravenous infusion should be 10% dextrose (with 1/4 normal saline and 20 mEq/L KCl) at twice maintenance; ammonia and glucose/Na/K/Cl/CO
It is important to maintain an approximate glucose infusion rate (GIR) between 10 to 15 mg/kg/min in order to prevent catabolism (protein sparring effect) and maintain adequate blood glucose levels between 100 and 150 mg/dL. The concentration of glucose may need to be increased (12.5% to 15%) to prevent fluid overload, particularly when secondary brain edema is present. As the affected individual's metabolic condition stabilizes, it is important to keep a stable GIR and not decrease or stop infusion rate in response to hyperglycemia (>150 mg/dL). An insulin drip should be used to maintain blood glucose at ~150-160 mg/dL during the critical phase of the hyperammonemic event and may be quickly withdrawn or reduced in rate if hypoglycemia develops.
The use of IV intralipids (2-3 g/kg/day) is an additional source of energy used in individuals with prolonged episodes of hyperammonemia common during periods of infection.
An individual with HHH syndrome is more likely to respond to the initial IV infusion of dextrose and to normalize the individual's plasma ammonia concentration when compared to an individual with a urea cycle disorder such as OTC deficiency or ASS deficiency. If clinical status does not improve, infusion of supplemental arginine and ammonia removal drugs is added to the regimen.
Of note, as clinical manifestations often do not correlate with rising plasma ammonia concentrations, treatment decisions should consider both plasma ammonia concentration and neurologic status.
Follow published protocols for treatment of acute hyperammonemic episodes similar to those instituted for OTC deficiency (see
The New England Consortium of Metabolic Programs complete set of treatment protocols for
It is important to note that unless the affected individual is transferred to a specialized metabolic center, treatment with scavenging agents to remove excess nitrogen and ammonia from the blood will depend on availability of medications.
An initial priming dose of arginine, benzoate, and phenylacetate is given (see
Initial Priming Dose of Arginine, Benzoate, and Phenylacetate by Age Group
Mix solutions of arginine, benzoate, and phenylacetate in a 10% dextrose solution at a dose of 25 mL of 10% dextrose/kg and infuse over
If ammonia levels stabilize, the same arginine, benzoate, and phenylacetate solution is infused over 24 hrs.
Sodium phenylbutyrate (sodium phenylacetate prodrug) may be given either by mouth or by nasogastric tube (Buphenyl
Dose of sodium phenylbutyrate:
≤25 kg: 550-600 mg/kg/day
>25 kg: 9.9-13.0 g/m
Mechanisms of Drug Action in Treatment of Hyperammonemia
Raises insulin levels
Induces anabolic state
Causes protein sparing effect from skeletal muscle amino acids
Needs to be supplemented in those w/a urea cycle disorder
Stimulates secretion of insulin
Plays a role in 1st step of creatine synthesis
Forms benzoate-glycine (hippurate) via the benzoylCoA:glycine acyltransferase reaction
Eliminates 1 amino group in the urine
Forms a phenylacetate-glutamine compound via the phenylacetateCoA:glutamine acetyl-transferase reaction
Eliminates 2 amino groups in the urine
A nonessential amino acid in humans
Interruption in the synthesis of brain creatine secondary to hyperammonemia has been proposed as a contributing factor to the neurologic findings in affected individuals.
Initially esterified to its CoA-ester via the medium-chain fatty acid enzyme acyl-CoA ligase
Reaction takes place in the mitochondrial matrix (liver and kidney) [
Concurrent with the above, the trigger for the hyperammonemic event (most commonly infection or internal bleeding) should be identified and treated to prevent ongoing protein catabolism and allow for the metabolic stabilization of the affected individual.
Need for dialysis (CRRT) falls into one of the following three categories based on age and plasma ammonia level [
Unlikely: <200 µmol/L
Possible: ≥200-300 µmol/L if no response within four hours
Definitely: >400-500 µmol/L
Dialysis may be prolonged if the catabolic state (e.g., infection) persists.
The recommended amount of total protein, calories, and fluids consumed per day varies with age. The ratio of natural protein to essential amino acids is approximately 60:40. The Ross Manual [
Dietary supplementation with Cyclinex
Caloric supplements such as ProPhree
UCD-Trio
Citrulline supplementation at 0.17 g/kg/day or 3.8 g/m
Sodium phenylbutyrate (Buphenyl
Effective January 2019, the FDA approved the use of glycerol phenylbutyrate (RAVICTI
Lysine supplementation is indicated when plasma lysine concentrations are low. Low plasma lysine concentrations have been associated with delayed growth and development.
Creatine supplementation has also been recommended in HHH syndrome and urea cycle disorders such as OTC and ASS deficiencies [
Carnitine supplementation may be necessary due to carnitine deficiency secondary to dietary restriction (e.g., meat) and/or conjugation of carnitine with ammonia removal drug metabolites (phenylacetate).
Plasma concentrations of ammonia, glutamine, arginine, ornithine, and essential amino acids (in particular lysine, isoleucine, leucine, and valine) should be maintained within the normal range.
Three individuals with HHH syndrome who had acute fulminant hepatic failure and coagulopathy rapidly stabilized after protein restriction and arginine or citrulline supplementation [
Two instances of liver transplantation for HHH syndrome were reported:
A child age six years with a history of continued biochemical abnormalities, protein intolerance, developmental delay, and abnormal posture [
A child age seven years with poor metabolic control who had presented at age four weeks with hyperammonemic coma (plasma ammonia 2,300 µmol/L) [
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Initial intravenous infusion should be 10% dextrose (with 1/4 normal saline and 20 mEq/L KCl) at twice maintenance; ammonia and glucose/Na/K/Cl/CO
• It is important to maintain an approximate glucose infusion rate (GIR) between 10 to 15 mg/kg/min in order to prevent catabolism (protein sparring effect) and maintain adequate blood glucose levels between 100 and 150 mg/dL. The concentration of glucose may need to be increased (12.5% to 15%) to prevent fluid overload, particularly when secondary brain edema is present. As the affected individual's metabolic condition stabilizes, it is important to keep a stable GIR and not decrease or stop infusion rate in response to hyperglycemia (>150 mg/dL). An insulin drip should be used to maintain blood glucose at ~150-160 mg/dL during the critical phase of the hyperammonemic event and may be quickly withdrawn or reduced in rate if hypoglycemia develops.
• The use of IV intralipids (2-3 g/kg/day) is an additional source of energy used in individuals with prolonged episodes of hyperammonemia common during periods of infection.
• An individual with HHH syndrome is more likely to respond to the initial IV infusion of dextrose and to normalize the individual's plasma ammonia concentration when compared to an individual with a urea cycle disorder such as OTC deficiency or ASS deficiency. If clinical status does not improve, infusion of supplemental arginine and ammonia removal drugs is added to the regimen.
• Sodium phenylbutyrate (sodium phenylacetate prodrug) may be given either by mouth or by nasogastric tube (Buphenyl
• Dose of sodium phenylbutyrate:
• ≤25 kg: 550-600 mg/kg/day
• >25 kg: 9.9-13.0 g/m
• ≤25 kg: 550-600 mg/kg/day
• >25 kg: 9.9-13.0 g/m
• ≤25 kg: 550-600 mg/kg/day
• >25 kg: 9.9-13.0 g/m
• Raises insulin levels
• Induces anabolic state
• Causes protein sparing effect from skeletal muscle amino acids
• Needs to be supplemented in those w/a urea cycle disorder
• Stimulates secretion of insulin
• Plays a role in 1st step of creatine synthesis
• Forms benzoate-glycine (hippurate) via the benzoylCoA:glycine acyltransferase reaction
• Eliminates 1 amino group in the urine
• Forms a phenylacetate-glutamine compound via the phenylacetateCoA:glutamine acetyl-transferase reaction
• Eliminates 2 amino groups in the urine
•
• Unlikely: <200 µmol/L
• Possible: ≥200-300 µmol/L if no response within four hours
• Definitely: >400-500 µmol/L
• Unlikely: <200 µmol/L
• Possible: ≥200-300 µmol/L if no response within four hours
• Definitely: >400-500 µmol/L
• Unlikely: <200 µmol/L
• Possible: ≥200-300 µmol/L if no response within four hours
• Definitely: >400-500 µmol/L
• Dietary supplementation with Cyclinex
• Caloric supplements such as ProPhree
• UCD-Trio
• Citrulline supplementation at 0.17 g/kg/day or 3.8 g/m
• Sodium phenylbutyrate (Buphenyl
• Effective January 2019, the FDA approved the use of glycerol phenylbutyrate (RAVICTI
• Lysine supplementation is indicated when plasma lysine concentrations are low. Low plasma lysine concentrations have been associated with delayed growth and development.
• Creatine supplementation has also been recommended in HHH syndrome and urea cycle disorders such as OTC and ASS deficiencies [
• Carnitine supplementation may be necessary due to carnitine deficiency secondary to dietary restriction (e.g., meat) and/or conjugation of carnitine with ammonia removal drug metabolites (phenylacetate).
• Plasma concentrations of ammonia, glutamine, arginine, ornithine, and essential amino acids (in particular lysine, isoleucine, leucine, and valine) should be maintained within the normal range.
• A child age six years with a history of continued biochemical abnormalities, protein intolerance, developmental delay, and abnormal posture [
• A child age seven years with poor metabolic control who had presented at age four weeks with hyperammonemic coma (plasma ammonia 2,300 µmol/L) [
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine if any changes are needed.
As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine if any changes are needed.
• As required by special education law, children should be in the least restricted environment feasible at school and included in general education as much as possible and when appropriate.
• Vision and hearing consultants should be a part of the child’s IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
## Surveillance
All surveillance of individuals with HHH syndrome (
Recommended Surveillance for Individuals with Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome
From time of diagnosis until adolescence
During pre-school years: follow WT, HT & HC in conjunction w/PCP even when not seen in metabolic clinic.
Plasma ammonia & amino acids
Urine amino acids, organic acids, & orotic acid
Age:
<1 yr: every mo
1-2 yrs: every 2-3 mos
>2 yrs: every 3-4 mos
History of adherence
History of metabolic decompensation
Incl changes in eating habits, motor skills, & behavior
In children age ≤3 yrs, especially in flu season or hot/humid weather
ADD = attention-deficit disorder; ADHD = attention-deficit/hyperactivity disorder; BMI = body mass index; HC = head circumference; HT = height; PCP = primary care provider; WT = weight
Low plasma concentrations of essential amino acids (isoleucine, leucine, valine, and arginine) could trigger a catabolic state, requiring readjustment of diet/formulas and/or supplements.
Low plasma concentrations of lysine may lead to delays in growth and development in infants.
Poor school performance may lead to low self-esteem and/or behavioral problems that could influence adherence to a protein-restricted diet.
• From time of diagnosis until adolescence
• During pre-school years: follow WT, HT & HC in conjunction w/PCP even when not seen in metabolic clinic.
• Plasma ammonia & amino acids
• Urine amino acids, organic acids, & orotic acid
• Age:
• <1 yr: every mo
• 1-2 yrs: every 2-3 mos
• >2 yrs: every 3-4 mos
• History of adherence
• History of metabolic decompensation
• Incl changes in eating habits, motor skills, & behavior
• In children age ≤3 yrs, especially in flu season or hot/humid weather
## Agents/Circumstances to Avoid
Avoid the following:
Excess dietary protein intake
Nonprescribed protein supplements such as those used to increase size of skeletal muscle during exercise regimens
Prolonged fasting during an illness or weight loss
Use of oral and intravenous steroids
Valproic acid, which induces and exacerbates hyperammonemia in urea cycle disorders
Exposure to communicable diseases
• Excess dietary protein intake
• Nonprescribed protein supplements such as those used to increase size of skeletal muscle during exercise regimens
• Prolonged fasting during an illness or weight loss
• Use of oral and intravenous steroids
• Valproic acid, which induces and exacerbates hyperammonemia in urea cycle disorders
• Exposure to communicable diseases
## Evaluation of Relatives at Risk
Testing of at-risk sibs is warranted to allow for early diagnosis and treatment.
If the
See
## Pregnancy Management
Delivery by cesarean section is recommended in order to optimize metabolic control.
One woman experienced mild hyperammonemia at the end of the first trimester of her first pregnancy. In her second pregnancy, she experienced metabolic decompensation (ammonia 295 µmol/L) prior to the second trimester and responded well to emergency treatment with Ammonul
A second woman experienced mild hyperammonemia at the end of the first trimester of her first pregnancy, and developed petit mal seizures in the second trimester and elevations in ammonia (21-103 µmol/L) post partum. In her second pregnancy, she experienced hyperammonemia ten hours post-C-section delivery that responded to treatment with oral sodium benzoate and IV arginine. During her third pregnancy, she had a seizure.
A third woman experienced mild elevation of plasma ammonia (43-126 µmol/L) during labor.
Normal pregnancy and delivery were documented in two women with HHH syndrome.
One, diagnosed with HHH syndrome at age 13 years in the course of evaluation of an affected sib, was clinically asymptomatic before pregnancy. During the pregnancy, she was maintained on citrulline and an appropriate protein-restricted diet [Rebecca Mardach, MD, Kaiser Permanente, personal communication].
The other, a woman age 22 years with no neurologic findings, had learned to self-restrict protein intake after severe protein intolerance in infancy [
One female had intrauterine growth restriction (IUGR); development at age two years was normal.
One of the neonates who had normal development at birth experienced transient respiratory distress requiring mechanical ventilation.
There are no well-controlled epidemiologic studies of the fetal effects of sodium benzoate, phenylacetate, or phenylbutyrate during human pregnancy, although there are several case reports.
In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years.
In the second pregnancy, emergency treatment with Ammonul
Although the mother responded well to emergency treatment, the baby experienced IUGR and remained in the NICU due to prematurity and low birth weight. At age two years the child exhibited speech delay and autism.
How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known.
See
• One woman experienced mild hyperammonemia at the end of the first trimester of her first pregnancy. In her second pregnancy, she experienced metabolic decompensation (ammonia 295 µmol/L) prior to the second trimester and responded well to emergency treatment with Ammonul
• A second woman experienced mild hyperammonemia at the end of the first trimester of her first pregnancy, and developed petit mal seizures in the second trimester and elevations in ammonia (21-103 µmol/L) post partum. In her second pregnancy, she experienced hyperammonemia ten hours post-C-section delivery that responded to treatment with oral sodium benzoate and IV arginine. During her third pregnancy, she had a seizure.
• A third woman experienced mild elevation of plasma ammonia (43-126 µmol/L) during labor.
• One, diagnosed with HHH syndrome at age 13 years in the course of evaluation of an affected sib, was clinically asymptomatic before pregnancy. During the pregnancy, she was maintained on citrulline and an appropriate protein-restricted diet [Rebecca Mardach, MD, Kaiser Permanente, personal communication].
• The other, a woman age 22 years with no neurologic findings, had learned to self-restrict protein intake after severe protein intolerance in infancy [
• One female had intrauterine growth restriction (IUGR); development at age two years was normal.
• One of the neonates who had normal development at birth experienced transient respiratory distress requiring mechanical ventilation.
• In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years.
• In the second pregnancy, emergency treatment with Ammonul
• Although the mother responded well to emergency treatment, the baby experienced IUGR and remained in the NICU due to prematurity and low birth weight. At age two years the child exhibited speech delay and autism.
• How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known.
• In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years.
• In the second pregnancy, emergency treatment with Ammonul
• Although the mother responded well to emergency treatment, the baby experienced IUGR and remained in the NICU due to prematurity and low birth weight. At age two years the child exhibited speech delay and autism.
• How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known.
• In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years.
• In the second pregnancy, emergency treatment with Ammonul
• Although the mother responded well to emergency treatment, the baby experienced IUGR and remained in the NICU due to prematurity and low birth weight. At age two years the child exhibited speech delay and autism.
• How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known.
## Therapies Under Investigation
Search
## Genetic Counseling
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing HHH syndrome.
If both parents are known to be heterozygous for a
Marked phenotypic variability is observed among sibs who have the same
Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing HHH syndrome [
Carrier testing for at-risk family members requires prior identification of the
Carrier testing using clinical biochemical parameters is unreliable; heterozygotes (e.g., parents and carrier sibs) do not exhibit biochemical abnormalities in plasma or urine; therefore, molecular genetic testing is the only reliable method of carrier detection.
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing HHH syndrome.
• If both parents are known to be heterozygous for a
• Marked phenotypic variability is observed among sibs who have the same
• Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing HHH syndrome [
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing HHH syndrome.
If both parents are known to be heterozygous for a
Marked phenotypic variability is observed among sibs who have the same
Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing HHH syndrome [
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a
• Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing HHH syndrome.
• If both parents are known to be heterozygous for a
• Marked phenotypic variability is observed among sibs who have the same
• Heterozygotes (carriers) are clinically asymptomatic and are not at risk of developing HHH syndrome [
## Carrier Detection
Carrier testing for at-risk family members requires prior identification of the
Carrier testing using clinical biochemical parameters is unreliable; heterozygotes (e.g., parents and carrier sibs) do not exhibit biochemical abnormalities in plasma or urine; therefore, molecular genetic testing is the only reliable method of carrier detection.
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
Children's National Medical Center
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•
•
•
•
•
•
• United Kingdom
•
•
•
•
•
•
•
•
• Children's National Medical Center
•
## Molecular Genetics
Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a disorder of the urea cycle (UC) and ornithine degradation pathway. The urea cycle (
HHH syndrome is caused by pathogenic variants in
Absence of intramitochondrial ornithine. The UC is disrupted in the liver and hyperammonemia ensues. The toxic effects of ammonia and glutamine (product of ammonia and glutamate) include brain edema and, if not treated, coma. Moreover, effects on astrocytes, which play a key role in long-term memory, may explain "memory problems" that are common in individuals with HHH syndrome [
Disruption of the ornithine amino transferase reaction, the pathway for ornithine catabolism. Ornithine accumulates, leading to hyperornithinemia.
Underused carbamoyl phosphate either reacting with lysine to form homocitrulline or entering the pyrimidine pathway to form orotic acid. Consequently, their accumulation leads to increased urinary excretion of homocitrulline (homocitrullinuria) and orotic acid.
Increased cytosolic ornithine leading to increased polyamine synthesis. Polyamines in excess increase intramitochondrial calcium (promotes apoptosis), mitochondrial autophagy, and cell proliferation [
Inhibition of AGAT, which reduces endogenous creatine synthesis in the cerebrum and cerebellum, increasing the brain’s susceptibility to local ammonia-induced damage [
Two other mitochondrial ornithine transporters, ORNT2 (SLC25A2) and ORNT3 (SLC25A29), exist; ORNT2 has been shown to co-transport citrulline and, thus, may compensate for a defective ORNT1 in the urea cycle. Hence, gene redundancy may in part be responsible for the later onset and less severe clinical presentation in individuals with HHH syndrome [
Chr Yq11.13 (
Chr 21p11.2 (
Chr 22q11.1 (
Chr 13q12.3 (
Chr 13q12.11 (
When performing
Notable
Variants listed in the table have been provided by the authors.
• Absence of intramitochondrial ornithine. The UC is disrupted in the liver and hyperammonemia ensues. The toxic effects of ammonia and glutamine (product of ammonia and glutamate) include brain edema and, if not treated, coma. Moreover, effects on astrocytes, which play a key role in long-term memory, may explain "memory problems" that are common in individuals with HHH syndrome [
• Disruption of the ornithine amino transferase reaction, the pathway for ornithine catabolism. Ornithine accumulates, leading to hyperornithinemia.
• Underused carbamoyl phosphate either reacting with lysine to form homocitrulline or entering the pyrimidine pathway to form orotic acid. Consequently, their accumulation leads to increased urinary excretion of homocitrulline (homocitrullinuria) and orotic acid.
• Increased cytosolic ornithine leading to increased polyamine synthesis. Polyamines in excess increase intramitochondrial calcium (promotes apoptosis), mitochondrial autophagy, and cell proliferation [
• Inhibition of AGAT, which reduces endogenous creatine synthesis in the cerebrum and cerebellum, increasing the brain’s susceptibility to local ammonia-induced damage [
• Chr Yq11.13 (
• Chr 21p11.2 (
• Chr 22q11.1 (
• Chr 13q12.3 (
• Chr 13q12.11 (
## Molecular Pathogenesis
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a disorder of the urea cycle (UC) and ornithine degradation pathway. The urea cycle (
HHH syndrome is caused by pathogenic variants in
Absence of intramitochondrial ornithine. The UC is disrupted in the liver and hyperammonemia ensues. The toxic effects of ammonia and glutamine (product of ammonia and glutamate) include brain edema and, if not treated, coma. Moreover, effects on astrocytes, which play a key role in long-term memory, may explain "memory problems" that are common in individuals with HHH syndrome [
Disruption of the ornithine amino transferase reaction, the pathway for ornithine catabolism. Ornithine accumulates, leading to hyperornithinemia.
Underused carbamoyl phosphate either reacting with lysine to form homocitrulline or entering the pyrimidine pathway to form orotic acid. Consequently, their accumulation leads to increased urinary excretion of homocitrulline (homocitrullinuria) and orotic acid.
Increased cytosolic ornithine leading to increased polyamine synthesis. Polyamines in excess increase intramitochondrial calcium (promotes apoptosis), mitochondrial autophagy, and cell proliferation [
Inhibition of AGAT, which reduces endogenous creatine synthesis in the cerebrum and cerebellum, increasing the brain’s susceptibility to local ammonia-induced damage [
Two other mitochondrial ornithine transporters, ORNT2 (SLC25A2) and ORNT3 (SLC25A29), exist; ORNT2 has been shown to co-transport citrulline and, thus, may compensate for a defective ORNT1 in the urea cycle. Hence, gene redundancy may in part be responsible for the later onset and less severe clinical presentation in individuals with HHH syndrome [
Chr Yq11.13 (
Chr 21p11.2 (
Chr 22q11.1 (
Chr 13q12.3 (
Chr 13q12.11 (
When performing
Notable
Variants listed in the table have been provided by the authors.
• Absence of intramitochondrial ornithine. The UC is disrupted in the liver and hyperammonemia ensues. The toxic effects of ammonia and glutamine (product of ammonia and glutamate) include brain edema and, if not treated, coma. Moreover, effects on astrocytes, which play a key role in long-term memory, may explain "memory problems" that are common in individuals with HHH syndrome [
• Disruption of the ornithine amino transferase reaction, the pathway for ornithine catabolism. Ornithine accumulates, leading to hyperornithinemia.
• Underused carbamoyl phosphate either reacting with lysine to form homocitrulline or entering the pyrimidine pathway to form orotic acid. Consequently, their accumulation leads to increased urinary excretion of homocitrulline (homocitrullinuria) and orotic acid.
• Increased cytosolic ornithine leading to increased polyamine synthesis. Polyamines in excess increase intramitochondrial calcium (promotes apoptosis), mitochondrial autophagy, and cell proliferation [
• Inhibition of AGAT, which reduces endogenous creatine synthesis in the cerebrum and cerebellum, increasing the brain’s susceptibility to local ammonia-induced damage [
• Chr Yq11.13 (
• Chr 21p11.2 (
• Chr 22q11.1 (
• Chr 13q12.3 (
• Chr 13q12.11 (
## Chapter Notes
We would like to acknowledge Drs William Nyhan, Rebecca Mardach, Yong Qu, Kamer Tezcan, Alicia Chan, Esperanza Font-Montgomery, and J Lawrence Merritt for referring or sharing clinical information of patients with HHH syndrome.
Dr José A Camacho's work was previously supported by a Robert Wood Johnson Foundation-Dr Harold Amos Faculty Development Award.
10 April 2025 (aa) Revision: "ORNT1 Deficiency" added as synonym
13 February 2020 (bp) Comprehensive update posted live
31 May 2012 (me) Review posted live
17 June 2011 (jac) Original submission
• 10 April 2025 (aa) Revision: "ORNT1 Deficiency" added as synonym
• 13 February 2020 (bp) Comprehensive update posted live
• 31 May 2012 (me) Review posted live
• 17 June 2011 (jac) Original submission
## Acknowledgments
We would like to acknowledge Drs William Nyhan, Rebecca Mardach, Yong Qu, Kamer Tezcan, Alicia Chan, Esperanza Font-Montgomery, and J Lawrence Merritt for referring or sharing clinical information of patients with HHH syndrome.
Dr José A Camacho's work was previously supported by a Robert Wood Johnson Foundation-Dr Harold Amos Faculty Development Award.
## Revision History
10 April 2025 (aa) Revision: "ORNT1 Deficiency" added as synonym
13 February 2020 (bp) Comprehensive update posted live
31 May 2012 (me) Review posted live
17 June 2011 (jac) Original submission
• 10 April 2025 (aa) Revision: "ORNT1 Deficiency" added as synonym
• 13 February 2020 (bp) Comprehensive update posted live
• 31 May 2012 (me) Review posted live
• 17 June 2011 (jac) Original submission
## References
## Literature Cited
Compartmentalization of the biochemical pathways involved in HHH syndrome as a result of deficiency of the mitochondrial ornithine transporter (ORNT1; encoded by
Reprinted with permission from
|
[] |
31/5/2012
|
13/2/2020
|
10/4/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
hht
|
hht
|
[
"HHT",
"Osler-Weber-Rendu Disease",
"Osler-Weber-Rendu Disease",
"HHT",
"Activin receptor type-1-like",
"Endoglin",
"Mothers against decapentaplegic homolog 4",
"ACVRL1",
"ENG",
"SMAD4",
"Hereditary Hemorrhagic Telangiectasia"
] |
Hereditary Hemorrhagic Telangiectasia
|
Jamie McDonald, David A Stevenson
|
Summary Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years. The diagnosis of HHT is established in a proband with Epistaxis Mucocutaneous telangiectases in characteristic locations Visceral AVMs A first-degree relative diagnosed with HHT on the basis of the preceding criteria Identification of a heterozygous pathogenic variant in HHT is inherited in an autosomal dominant manner with considerable intrafamilial variability. Most individuals have an affected parent. Each child of a proband and the sibs of most probands are at a 50% risk of inheriting the pathogenic variant. Prenatal testing is possible for a pregnancy at increased risk if the pathogenic variant in the family is known.
|
## Diagnosis
According to published consensus clinical diagnostic criteria, the diagnosis of HHT is considered "definite" in an individual with
Hereditary hemorrhagic telangiectasia (HHT)
The clinical diagnosis of HHT can be
Note: (1) The application of clinical diagnostic criteria to children at risk for HHT can fail to identify affected children. Signs and symptoms of HHT generally develop during childhood and adolescence; epistaxis, telangiectases, and symptoms of visceral AVMs are frequently absent in affected children [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Sequence analysis of
Sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Hemorrhagic Telangiectasia
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
To date, one large deletion has been reported in an individual with juvenile polyposis and HHT [
Linkage analysis in one pedigree suggests a 5.4-cm disease gene interval on chromosome 5 (HHT3) [
• Sequence analysis of
• Sequence analysis of
## Suggestive Findings
Hereditary hemorrhagic telangiectasia (HHT)
## Establishing the Diagnosis
The clinical diagnosis of HHT can be
Note: (1) The application of clinical diagnostic criteria to children at risk for HHT can fail to identify affected children. Signs and symptoms of HHT generally develop during childhood and adolescence; epistaxis, telangiectases, and symptoms of visceral AVMs are frequently absent in affected children [
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Sequence analysis of
Sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Hemorrhagic Telangiectasia
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
To date, one large deletion has been reported in an individual with juvenile polyposis and HHT [
Linkage analysis in one pedigree suggests a 5.4-cm disease gene interval on chromosome 5 (HHT3) [
• Sequence analysis of
• Sequence analysis of
## Option 1
Sequence analysis of
Sequence analysis of
For an introduction to multigene panels click
• Sequence analysis of
• Sequence analysis of
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Hemorrhagic Telangiectasia
Genes are listed in alphabetic order.
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
To date, one large deletion has been reported in an individual with juvenile polyposis and HHT [
Linkage analysis in one pedigree suggests a 5.4-cm disease gene interval on chromosome 5 (HHT3) [
## Clinical Characteristics
Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Small AVMs are called telangiectases. The term AVM usually refers to the "large" telangiectases, greater than a few millimeters in diameter and sometimes up to several centimeters in diameter. The most common feature that brings individuals with HHT to medical attention are epistaxis (nosebleeds).
Hereditary Hemorrhagic Telangiectasia: Frequency of Select Features
AVMs = arteriovenous malformations; GI = gastrointestinal
Features of HHT are age-related.
Minor insults to the nasal mucosa (e.g., drying air) result in recurrent bleeding of nasal telangiectases. Epistaxis has an average age of onset of approximately 12 years [
Telangiectases associated with HHT are found primarily on the lips, tongue, face, fingers, buccal and gastrointestinal (GI) mucosa, and nasal mucosa. The average age of onset for non-nasal telangiectases is generally later than epistaxis but may be during childhood; 30% of affected individuals report telangiectases first appearing before age 20 years and two thirds before age 40 years [
Telangiectases are distinguished from petechiae and angiomata by their ability to blanch with pressure, and then immediately but often slowly refill. Because of their thin walls, narrow tortuous paths, and proximity to the surface of the skin or to a mucous membrane, telangiectases can rupture and bleed after only slight trauma. Since the contractile elements in the vessel wall are lacking, given the abnormal arterial connection, bleeding from telangiectases is frequently brisk and difficult to stop. Telangiectases of the skin are significantly less likely to bleed than those of the nasal mucosa.
Telangiectases are common in adulthood throughout the GI mucosa, but the stomach and proximal small intestine (duodenum) are most commonly involved. Approximately one quarter of all individuals with HHT eventually have bleeding from GI telangiectases; GI bleeding is rare before age 50 years [
Epistaxis, or less commonly GI bleeding, can cause mild-to-severe anemia, often requiring iron replacement therapy or (rarely) blood transfusion [
AVMs occur most commonly in the lungs, liver, and brain. While hemorrhage is often the presenting symptom of cerebral AVMs, most lung and liver AVMs present as a consequence of blood shunting through the abnormal vessel and bypassing the capillary bed.
The frequency of
Spinal AVMs appear to be significantly less common but may present with paralysis.
Vascular lesions in the pancreas are found in 18% of individuals with HHT but rarely result in clinical issues [
Pulmonary hypertension is another pulmonary vascular manifestation of HHT, although much less common than pulmonary AVMs. Pulmonary hypertension can either result from systemic arteriovenous shunting in the liver leading to increased cardiac output, or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension [
Pulmonary and cerebral AVMs are more common in individuals with
Pulmonary hypertension in the absence of severe vascular shunting, a rare HHT manifestation, has occurred most commonly in individuals with pathogenic variants in
Pathogenic variants in
Data suggest that no absolute genotype-phenotype correlations exist between clinical phenotypes and specific pathogenic variants [
Penetrance is approximately 95% by late adulthood.
The original description of the syndrome was made by Sutton in 1864. However, Osler in the US, Parkes Weber in the UK, and Rendu in France are typically given credit; hence the eponymous Osler-Weber-Rendu syndrome (or Rendu-Osler-Weber in articles in the French literature). The designation "hereditary hemorrhagic telangiectasia" was suggested in 1912 by one of Osler's residents.
The gene now identified as
The incidence of HHT in North America is estimated at 1:10,000 [
HHT occurs with wide ethnic and geographic distribution. The condition is especially prevalent in the Netherland Antilles because of a founder effect.
## Clinical Description
Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Small AVMs are called telangiectases. The term AVM usually refers to the "large" telangiectases, greater than a few millimeters in diameter and sometimes up to several centimeters in diameter. The most common feature that brings individuals with HHT to medical attention are epistaxis (nosebleeds).
Hereditary Hemorrhagic Telangiectasia: Frequency of Select Features
AVMs = arteriovenous malformations; GI = gastrointestinal
Features of HHT are age-related.
Minor insults to the nasal mucosa (e.g., drying air) result in recurrent bleeding of nasal telangiectases. Epistaxis has an average age of onset of approximately 12 years [
Telangiectases associated with HHT are found primarily on the lips, tongue, face, fingers, buccal and gastrointestinal (GI) mucosa, and nasal mucosa. The average age of onset for non-nasal telangiectases is generally later than epistaxis but may be during childhood; 30% of affected individuals report telangiectases first appearing before age 20 years and two thirds before age 40 years [
Telangiectases are distinguished from petechiae and angiomata by their ability to blanch with pressure, and then immediately but often slowly refill. Because of their thin walls, narrow tortuous paths, and proximity to the surface of the skin or to a mucous membrane, telangiectases can rupture and bleed after only slight trauma. Since the contractile elements in the vessel wall are lacking, given the abnormal arterial connection, bleeding from telangiectases is frequently brisk and difficult to stop. Telangiectases of the skin are significantly less likely to bleed than those of the nasal mucosa.
Telangiectases are common in adulthood throughout the GI mucosa, but the stomach and proximal small intestine (duodenum) are most commonly involved. Approximately one quarter of all individuals with HHT eventually have bleeding from GI telangiectases; GI bleeding is rare before age 50 years [
Epistaxis, or less commonly GI bleeding, can cause mild-to-severe anemia, often requiring iron replacement therapy or (rarely) blood transfusion [
AVMs occur most commonly in the lungs, liver, and brain. While hemorrhage is often the presenting symptom of cerebral AVMs, most lung and liver AVMs present as a consequence of blood shunting through the abnormal vessel and bypassing the capillary bed.
The frequency of
Spinal AVMs appear to be significantly less common but may present with paralysis.
Vascular lesions in the pancreas are found in 18% of individuals with HHT but rarely result in clinical issues [
Pulmonary hypertension is another pulmonary vascular manifestation of HHT, although much less common than pulmonary AVMs. Pulmonary hypertension can either result from systemic arteriovenous shunting in the liver leading to increased cardiac output, or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension [
## Epistaxis (Nosebleeds)
Minor insults to the nasal mucosa (e.g., drying air) result in recurrent bleeding of nasal telangiectases. Epistaxis has an average age of onset of approximately 12 years [
## Telangiectases
Telangiectases associated with HHT are found primarily on the lips, tongue, face, fingers, buccal and gastrointestinal (GI) mucosa, and nasal mucosa. The average age of onset for non-nasal telangiectases is generally later than epistaxis but may be during childhood; 30% of affected individuals report telangiectases first appearing before age 20 years and two thirds before age 40 years [
Telangiectases are distinguished from petechiae and angiomata by their ability to blanch with pressure, and then immediately but often slowly refill. Because of their thin walls, narrow tortuous paths, and proximity to the surface of the skin or to a mucous membrane, telangiectases can rupture and bleed after only slight trauma. Since the contractile elements in the vessel wall are lacking, given the abnormal arterial connection, bleeding from telangiectases is frequently brisk and difficult to stop. Telangiectases of the skin are significantly less likely to bleed than those of the nasal mucosa.
Telangiectases are common in adulthood throughout the GI mucosa, but the stomach and proximal small intestine (duodenum) are most commonly involved. Approximately one quarter of all individuals with HHT eventually have bleeding from GI telangiectases; GI bleeding is rare before age 50 years [
## Anemia
Epistaxis, or less commonly GI bleeding, can cause mild-to-severe anemia, often requiring iron replacement therapy or (rarely) blood transfusion [
## Arteriovenous Malformations (AVMs)
AVMs occur most commonly in the lungs, liver, and brain. While hemorrhage is often the presenting symptom of cerebral AVMs, most lung and liver AVMs present as a consequence of blood shunting through the abnormal vessel and bypassing the capillary bed.
The frequency of
Spinal AVMs appear to be significantly less common but may present with paralysis.
Vascular lesions in the pancreas are found in 18% of individuals with HHT but rarely result in clinical issues [
## Pulmonary Hypertension
Pulmonary hypertension is another pulmonary vascular manifestation of HHT, although much less common than pulmonary AVMs. Pulmonary hypertension can either result from systemic arteriovenous shunting in the liver leading to increased cardiac output, or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension [
## Phenotype Correlations by Gene
Pulmonary and cerebral AVMs are more common in individuals with
Pulmonary hypertension in the absence of severe vascular shunting, a rare HHT manifestation, has occurred most commonly in individuals with pathogenic variants in
Pathogenic variants in
## Genotype-Phenotype Correlations
Data suggest that no absolute genotype-phenotype correlations exist between clinical phenotypes and specific pathogenic variants [
## Penetrance
Penetrance is approximately 95% by late adulthood.
## Nomenclature
The original description of the syndrome was made by Sutton in 1864. However, Osler in the US, Parkes Weber in the UK, and Rendu in France are typically given credit; hence the eponymous Osler-Weber-Rendu syndrome (or Rendu-Osler-Weber in articles in the French literature). The designation "hereditary hemorrhagic telangiectasia" was suggested in 1912 by one of Osler's residents.
The gene now identified as
## Prevalence
The incidence of HHT in North America is estimated at 1:10,000 [
HHT occurs with wide ethnic and geographic distribution. The condition is especially prevalent in the Netherland Antilles because of a founder effect.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Allelic disorders associated with pathogenic variants in
Allelic Disorders
HHT = hereditary hemorrhagic telangiectasia; ID = intellectual disability; JPS = juvenile polyposis syndrome
## Differential Diagnosis
Telangiectases and epistaxis can also be seen in otherwise healthy individuals.
Hereditary disorders of known genetic cause (see
Hereditary disorders of unknown genetic cause:
CRST (
Hereditary benign telangiectasia (OMIM
Pregnancy
Chronic liver disease (However, the telangiectases are almost always of the "spider" class and occur on the face and chest and around the umbilicus.)
Additionally, adults can develop one or a couple of cutaneous telangiectases with age. These often raise concern, especially when the person also has multiple cherry angiomata, which are quite frequent in older individuals and are unrelated to HHT.
Hereditary Disorders of Known Genetic Cause in the Differential Diagnosis of Hereditary Hemorrhagic Telangiectasia
Characterized by multiple, small (1-2 cm in diameter) capillary malformations mostly on face & limbs
May be assoc w/cerebral & spinal AVMs &/or arteriovenous fistulas
Telangiectases reported primarily in those w/
Cutaneous telangiectases are less frequently reported in
PAH is most common feature reported to date [
In a small number of persons,1 or 2 of the following: pulmonary AVM, cerebral AVM, & GI AVM; epistaxis; telangiectases
Neither epistaxis nor characteristic cutaneous telangiectases are consistent features. Telangiectases when reported are atypical for HHT in location (face excluding lips) & appearance (linear or spidery versus punctate).
Several persons w/features overlapping w/HHT reported
AD = autosomal dominant; AR = autosomal recessive; AVM = arteriovenous malformation; CM-AVM = capillary malformation-arteriovenous malformation syndrome; GI = gastrointestinal; MOI = mode of inheritance; PAH = pulmonary arterial hypertension
Fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain
It is uncertain whether
A
• Hereditary disorders of known genetic cause (see
• Hereditary disorders of unknown genetic cause:
• CRST (
• Hereditary benign telangiectasia (OMIM
• CRST (
• Hereditary benign telangiectasia (OMIM
• Pregnancy
• Chronic liver disease (However, the telangiectases are almost always of the "spider" class and occur on the face and chest and around the umbilicus.)
• CRST (
• Hereditary benign telangiectasia (OMIM
• Characterized by multiple, small (1-2 cm in diameter) capillary malformations mostly on face & limbs
• May be assoc w/cerebral & spinal AVMs &/or arteriovenous fistulas
• Telangiectases reported primarily in those w/
• Cutaneous telangiectases are less frequently reported in
• PAH is most common feature reported to date [
• In a small number of persons,1 or 2 of the following: pulmonary AVM, cerebral AVM, & GI AVM; epistaxis; telangiectases
• Neither epistaxis nor characteristic cutaneous telangiectases are consistent features. Telangiectases when reported are atypical for HHT in location (face excluding lips) & appearance (linear or spidery versus punctate).
• Several persons w/features overlapping w/HHT reported
## Management
Guidelines for management of hereditary hemorrhagic telangiectasia (HHT) have been published [
To establish the extent of disease and needs in an individual diagnosed with HHT, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Hemorrhagic Telangiectasia
Assess for history of epistaxis & GI bleeding.
Physical exam for telangiectases
Heart failure secondary to liver AVMs
TIA, stroke, dyspnea, migraines, hemoptysis secondary to pulmonary AVMs
TCE w/agitated saline contrast
Chest radiograph w/pulse oximetry; if chest radiograph is abnormal or oxygen saturation is <96%, proceed w/TCE w/agitated saline contrast.
Clinical screening (e.g., history & physical exam)
Doppler ultrasound (best option when local expertise is available)
Multiphase contrast CT
Contrast abdominal MRI
Hepatic AVMs are not usually symptomatic & when they do become symptomatic, it is not sudden & catastrophic
Treatment options for hepatic AVMs are less satisfactory than those for pulmonary or cerebral AVMs.
As early as possible, preferably in 1st yr of life
In all persons at diagnosis (incl adults)
AVMs = arteriovenous malformations; EGD = esophagogastroduodenoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; MOI = mode of inheritance; TCE = transthoracic contrast echocardiography; TIA = transient ischemic attack
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Hereditary Hemorrhagic Telangiectasia
Humidification
2x-daily topical moisturizing therapy
Hemostatic products (e.g., gauze, sponge, powder products)
Antifibrinolytic therapy (oral tranexamic acid)
Ablation therapies (e.g., laser treatment, radiofrequency ablation, electrosurgery, sclerotherapy)
System antiangiogenic agents (e.g., intravenous bevacizumab)
Septodermoplasty & nasal closure
EGD is 1st-line diagnostic approach for suspected bleeding [
Consider capsule endoscopy if EGD does not identify the source of suspected GI bleeding to help localize the source of bleeding [
Oral iron therapy
IV iron in those intolerant or unresponsive to oral iron therapy
Red blood cell transfusion only in those w/: hemodynamic instability/shock, comorbidities that require a higher hemoglobin target, need to ↑ the hemoglobin acutely (e.g., prior to surgery or pregnancy), or inability to maintain adequate hemoglobin despite frequent iron infusions
Consider occlusion for any pulmonary AVM w/a feeding vessel >1-2 mm in diameter [
Treatment is indicated for dyspnea, exercise intolerance, & hypoxemia, but is most important for prevention of lung hemorrhage & neurologic complications of brain abscess & stroke, even in those w/normal pulmonary function & oxygen saturation.
See Footnote 1.
Occasionally, a small lesion cannot be reached by transcatheter embolotherapy because of its location or the size of the feeding vessel.
Prophylactic antibiotics in accordance w/the American Heart Association protocol for dental cleaning & other procedures w/risk of bacteremia is advised because of the risk of abscess (esp brain abscess) assoc w/right-to-left shunting [
Caution not to introduce air bubbles (to incl air filter if available) is recommended w/IV lines.
Avoid scuba diving in those w/evidence of pulmonary AVMs.
Note: The risk assoc w/these lesions is not for subacute bacterial endocarditis.
Most w/symptomatic hepatic AVMs can be managed w/intensive medical therapy [
Consider intravenous bevacizumab for those w/symptomatic high-output cardiac failure due to hepatic AVMs who have failed to respond to first-line management [
See Footnote 1.
Treatment of symptomatic hepatic AVMs is currently problematic. Embolization of hepatic AVMs (successful for treatment of pulmonary AVMs) has led to lethal hepatic infarctions.
Liver transplantation has been standard treatment for those (usually older) persons whose symptoms of hepatic failure do not respond to medical management [
Liver biopsy should be avoided in persons w/HHT [
AVMs = arteriovenous malformations; EGD = esophagogastroduodenoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; IV = intravenous
Before proceeding with treatment for any visceral AVM, patients and their doctors are encouraged to contact the nearest multidisciplinary HHT clinic, which can be located through the support group
The following surveillance is recommended for all individuals with an established diagnosis of HHT and for all individuals at risk for HHT based on family history in whom HHT has not been ruled out by molecular diagnosis [
Recommended Surveillance for Individuals with Hereditary Hemorrhagic Telangiectasia
Annually
Hematocrit/hemoglobin
Ferritin
In
In
In those w/o previous pulmonary AVM: every 5 yrs
In those w/pulmonary AVM: frequency per vascular specialist
AVM = arteriovenous malformation; EGD = esophagogastroduodenoscopy; HHT = hereditary hemorrhagic telangiectasia; TCE = transthoracic contrast echocardiography
Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. Some individuals with HHT experience increased epistaxis after drinking alcohol.
Anticoagulants including aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. However, HHT is not an absolute contraindication for anticoagulation (prophylactic or therapeutic) or antiplatelet therapy. It is recommended that individuals with HHT receive these therapies when there is an indication, with consideration of their individualized bleeding risks [
When anticoagulation is pursued, unfractionated heparin, low-molecular-weight heparin, and vitamin K antagonists are preferred over direct-acting oral anticoagulants, which are less well tolerated in individuals with HHT [
Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right-to-left shunt.
Liver biopsy should be avoided in individuals with HHT [
It is recommended to evaluate at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from
If the pathogenic variant in the family is known, evaluate with molecular genetic testing.
If the familial pathogenic variant is not known and the diagnosis of HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is established (see
Individuals older than age 40 years should have a targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring.
In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT in addition to an evaluation for brain and pulmonary AVMs should be done initially, as features of HHT may not be identified by medical history and clinical examination in younger individuals.
See
Pregnant women with HHT and untreated pulmonary AVMs are at increased risk for complications related to hemorrhage or embolic events. Women with treated pulmonary AVMs appear to be at no higher risk during pregnancy than those without pulmonary AVMs. For this reason, published management guidelines recommend that pregnant women with HHT who have not been recently screened and/or treated for pulmonary AVM should be managed as follows:
In asymptomatic women, initial screening for pulmonary AVMs should be performed using either transthoracic contrast echocardiography with agitated saline contrast or low-dose noncontrast chest CT, depending on local expertise. Chest CT, when performed, should be done early in the second trimester.
In women with symptoms suggestive of pulmonary AVM, diagnostic testing should be performed using low-dose noncontrast chest CT. This testing can be performed at any gestational age, as clinically indicated.
Pulmonary AVMs should be treated starting in the second trimester unless otherwise clinically indicated.
An unenhanced brain MRI is recommended in pregnant women with symptoms suggestive of cerebral AVM. Women who are asymptomatic do not require routine screening for cerebral AVMs during pregnancy.
Iron replacement is preferred for anemia, but transfusion of packed red blood cells may be necessary for symptomatic anemia refractory to aggressive iron replacement therapy.
Expert consensus is to not withhold an epidural because of a diagnosis of HHT, and that screening for spinal vascular malformations is not required. Two case series showed no evidence of hemorrhagic complications from epidural or spinal anesthesia [
Newer therapies designed to interfere with the development of abnormal vascular connections are being investigated; while numerous case reports and small uncontrolled series indicate promise, results from controlled trials are needed [
Search
• Assess for history of epistaxis & GI bleeding.
• Physical exam for telangiectases
• Heart failure secondary to liver AVMs
• TIA, stroke, dyspnea, migraines, hemoptysis secondary to pulmonary AVMs
• TCE w/agitated saline contrast
• Chest radiograph w/pulse oximetry; if chest radiograph is abnormal or oxygen saturation is <96%, proceed w/TCE w/agitated saline contrast.
• Clinical screening (e.g., history & physical exam)
• Doppler ultrasound (best option when local expertise is available)
• Multiphase contrast CT
• Contrast abdominal MRI
• Hepatic AVMs are not usually symptomatic & when they do become symptomatic, it is not sudden & catastrophic
• Treatment options for hepatic AVMs are less satisfactory than those for pulmonary or cerebral AVMs.
• As early as possible, preferably in 1st yr of life
• In all persons at diagnosis (incl adults)
• Humidification
• 2x-daily topical moisturizing therapy
• Hemostatic products (e.g., gauze, sponge, powder products)
• Antifibrinolytic therapy (oral tranexamic acid)
• Ablation therapies (e.g., laser treatment, radiofrequency ablation, electrosurgery, sclerotherapy)
• System antiangiogenic agents (e.g., intravenous bevacizumab)
• Septodermoplasty & nasal closure
• EGD is 1st-line diagnostic approach for suspected bleeding [
• Consider capsule endoscopy if EGD does not identify the source of suspected GI bleeding to help localize the source of bleeding [
• Oral iron therapy
• IV iron in those intolerant or unresponsive to oral iron therapy
• Red blood cell transfusion only in those w/: hemodynamic instability/shock, comorbidities that require a higher hemoglobin target, need to ↑ the hemoglobin acutely (e.g., prior to surgery or pregnancy), or inability to maintain adequate hemoglobin despite frequent iron infusions
• Consider occlusion for any pulmonary AVM w/a feeding vessel >1-2 mm in diameter [
• Treatment is indicated for dyspnea, exercise intolerance, & hypoxemia, but is most important for prevention of lung hemorrhage & neurologic complications of brain abscess & stroke, even in those w/normal pulmonary function & oxygen saturation.
• See Footnote 1.
• Occasionally, a small lesion cannot be reached by transcatheter embolotherapy because of its location or the size of the feeding vessel.
• Prophylactic antibiotics in accordance w/the American Heart Association protocol for dental cleaning & other procedures w/risk of bacteremia is advised because of the risk of abscess (esp brain abscess) assoc w/right-to-left shunting [
• Caution not to introduce air bubbles (to incl air filter if available) is recommended w/IV lines.
• Avoid scuba diving in those w/evidence of pulmonary AVMs.
• Most w/symptomatic hepatic AVMs can be managed w/intensive medical therapy [
• Consider intravenous bevacizumab for those w/symptomatic high-output cardiac failure due to hepatic AVMs who have failed to respond to first-line management [
• See Footnote 1.
• Treatment of symptomatic hepatic AVMs is currently problematic. Embolization of hepatic AVMs (successful for treatment of pulmonary AVMs) has led to lethal hepatic infarctions.
• Liver transplantation has been standard treatment for those (usually older) persons whose symptoms of hepatic failure do not respond to medical management [
• Liver biopsy should be avoided in persons w/HHT [
• Hematocrit/hemoglobin
• Ferritin
• In
• In
• In those w/o previous pulmonary AVM: every 5 yrs
• In those w/pulmonary AVM: frequency per vascular specialist
• Individuals older than age 40 years should have a targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring.
• In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT in addition to an evaluation for brain and pulmonary AVMs should be done initially, as features of HHT may not be identified by medical history and clinical examination in younger individuals.
• In asymptomatic women, initial screening for pulmonary AVMs should be performed using either transthoracic contrast echocardiography with agitated saline contrast or low-dose noncontrast chest CT, depending on local expertise. Chest CT, when performed, should be done early in the second trimester.
• In women with symptoms suggestive of pulmonary AVM, diagnostic testing should be performed using low-dose noncontrast chest CT. This testing can be performed at any gestational age, as clinically indicated.
• Pulmonary AVMs should be treated starting in the second trimester unless otherwise clinically indicated.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with HHT, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Hemorrhagic Telangiectasia
Assess for history of epistaxis & GI bleeding.
Physical exam for telangiectases
Heart failure secondary to liver AVMs
TIA, stroke, dyspnea, migraines, hemoptysis secondary to pulmonary AVMs
TCE w/agitated saline contrast
Chest radiograph w/pulse oximetry; if chest radiograph is abnormal or oxygen saturation is <96%, proceed w/TCE w/agitated saline contrast.
Clinical screening (e.g., history & physical exam)
Doppler ultrasound (best option when local expertise is available)
Multiphase contrast CT
Contrast abdominal MRI
Hepatic AVMs are not usually symptomatic & when they do become symptomatic, it is not sudden & catastrophic
Treatment options for hepatic AVMs are less satisfactory than those for pulmonary or cerebral AVMs.
As early as possible, preferably in 1st yr of life
In all persons at diagnosis (incl adults)
AVMs = arteriovenous malformations; EGD = esophagogastroduodenoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; MOI = mode of inheritance; TCE = transthoracic contrast echocardiography; TIA = transient ischemic attack
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assess for history of epistaxis & GI bleeding.
• Physical exam for telangiectases
• Heart failure secondary to liver AVMs
• TIA, stroke, dyspnea, migraines, hemoptysis secondary to pulmonary AVMs
• TCE w/agitated saline contrast
• Chest radiograph w/pulse oximetry; if chest radiograph is abnormal or oxygen saturation is <96%, proceed w/TCE w/agitated saline contrast.
• Clinical screening (e.g., history & physical exam)
• Doppler ultrasound (best option when local expertise is available)
• Multiphase contrast CT
• Contrast abdominal MRI
• Hepatic AVMs are not usually symptomatic & when they do become symptomatic, it is not sudden & catastrophic
• Treatment options for hepatic AVMs are less satisfactory than those for pulmonary or cerebral AVMs.
• As early as possible, preferably in 1st yr of life
• In all persons at diagnosis (incl adults)
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Hereditary Hemorrhagic Telangiectasia
Humidification
2x-daily topical moisturizing therapy
Hemostatic products (e.g., gauze, sponge, powder products)
Antifibrinolytic therapy (oral tranexamic acid)
Ablation therapies (e.g., laser treatment, radiofrequency ablation, electrosurgery, sclerotherapy)
System antiangiogenic agents (e.g., intravenous bevacizumab)
Septodermoplasty & nasal closure
EGD is 1st-line diagnostic approach for suspected bleeding [
Consider capsule endoscopy if EGD does not identify the source of suspected GI bleeding to help localize the source of bleeding [
Oral iron therapy
IV iron in those intolerant or unresponsive to oral iron therapy
Red blood cell transfusion only in those w/: hemodynamic instability/shock, comorbidities that require a higher hemoglobin target, need to ↑ the hemoglobin acutely (e.g., prior to surgery or pregnancy), or inability to maintain adequate hemoglobin despite frequent iron infusions
Consider occlusion for any pulmonary AVM w/a feeding vessel >1-2 mm in diameter [
Treatment is indicated for dyspnea, exercise intolerance, & hypoxemia, but is most important for prevention of lung hemorrhage & neurologic complications of brain abscess & stroke, even in those w/normal pulmonary function & oxygen saturation.
See Footnote 1.
Occasionally, a small lesion cannot be reached by transcatheter embolotherapy because of its location or the size of the feeding vessel.
Prophylactic antibiotics in accordance w/the American Heart Association protocol for dental cleaning & other procedures w/risk of bacteremia is advised because of the risk of abscess (esp brain abscess) assoc w/right-to-left shunting [
Caution not to introduce air bubbles (to incl air filter if available) is recommended w/IV lines.
Avoid scuba diving in those w/evidence of pulmonary AVMs.
Note: The risk assoc w/these lesions is not for subacute bacterial endocarditis.
Most w/symptomatic hepatic AVMs can be managed w/intensive medical therapy [
Consider intravenous bevacizumab for those w/symptomatic high-output cardiac failure due to hepatic AVMs who have failed to respond to first-line management [
See Footnote 1.
Treatment of symptomatic hepatic AVMs is currently problematic. Embolization of hepatic AVMs (successful for treatment of pulmonary AVMs) has led to lethal hepatic infarctions.
Liver transplantation has been standard treatment for those (usually older) persons whose symptoms of hepatic failure do not respond to medical management [
Liver biopsy should be avoided in persons w/HHT [
AVMs = arteriovenous malformations; EGD = esophagogastroduodenoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; IV = intravenous
Before proceeding with treatment for any visceral AVM, patients and their doctors are encouraged to contact the nearest multidisciplinary HHT clinic, which can be located through the support group
• Humidification
• 2x-daily topical moisturizing therapy
• Hemostatic products (e.g., gauze, sponge, powder products)
• Antifibrinolytic therapy (oral tranexamic acid)
• Ablation therapies (e.g., laser treatment, radiofrequency ablation, electrosurgery, sclerotherapy)
• System antiangiogenic agents (e.g., intravenous bevacizumab)
• Septodermoplasty & nasal closure
• EGD is 1st-line diagnostic approach for suspected bleeding [
• Consider capsule endoscopy if EGD does not identify the source of suspected GI bleeding to help localize the source of bleeding [
• Oral iron therapy
• IV iron in those intolerant or unresponsive to oral iron therapy
• Red blood cell transfusion only in those w/: hemodynamic instability/shock, comorbidities that require a higher hemoglobin target, need to ↑ the hemoglobin acutely (e.g., prior to surgery or pregnancy), or inability to maintain adequate hemoglobin despite frequent iron infusions
• Consider occlusion for any pulmonary AVM w/a feeding vessel >1-2 mm in diameter [
• Treatment is indicated for dyspnea, exercise intolerance, & hypoxemia, but is most important for prevention of lung hemorrhage & neurologic complications of brain abscess & stroke, even in those w/normal pulmonary function & oxygen saturation.
• See Footnote 1.
• Occasionally, a small lesion cannot be reached by transcatheter embolotherapy because of its location or the size of the feeding vessel.
• Prophylactic antibiotics in accordance w/the American Heart Association protocol for dental cleaning & other procedures w/risk of bacteremia is advised because of the risk of abscess (esp brain abscess) assoc w/right-to-left shunting [
• Caution not to introduce air bubbles (to incl air filter if available) is recommended w/IV lines.
• Avoid scuba diving in those w/evidence of pulmonary AVMs.
• Most w/symptomatic hepatic AVMs can be managed w/intensive medical therapy [
• Consider intravenous bevacizumab for those w/symptomatic high-output cardiac failure due to hepatic AVMs who have failed to respond to first-line management [
• See Footnote 1.
• Treatment of symptomatic hepatic AVMs is currently problematic. Embolization of hepatic AVMs (successful for treatment of pulmonary AVMs) has led to lethal hepatic infarctions.
• Liver transplantation has been standard treatment for those (usually older) persons whose symptoms of hepatic failure do not respond to medical management [
• Liver biopsy should be avoided in persons w/HHT [
## Surveillance
The following surveillance is recommended for all individuals with an established diagnosis of HHT and for all individuals at risk for HHT based on family history in whom HHT has not been ruled out by molecular diagnosis [
Recommended Surveillance for Individuals with Hereditary Hemorrhagic Telangiectasia
Annually
Hematocrit/hemoglobin
Ferritin
In
In
In those w/o previous pulmonary AVM: every 5 yrs
In those w/pulmonary AVM: frequency per vascular specialist
AVM = arteriovenous malformation; EGD = esophagogastroduodenoscopy; HHT = hereditary hemorrhagic telangiectasia; TCE = transthoracic contrast echocardiography
• Hematocrit/hemoglobin
• Ferritin
• In
• In
• In those w/o previous pulmonary AVM: every 5 yrs
• In those w/pulmonary AVM: frequency per vascular specialist
## Agents/Circumstances to Avoid
Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. Some individuals with HHT experience increased epistaxis after drinking alcohol.
Anticoagulants including aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. However, HHT is not an absolute contraindication for anticoagulation (prophylactic or therapeutic) or antiplatelet therapy. It is recommended that individuals with HHT receive these therapies when there is an indication, with consideration of their individualized bleeding risks [
When anticoagulation is pursued, unfractionated heparin, low-molecular-weight heparin, and vitamin K antagonists are preferred over direct-acting oral anticoagulants, which are less well tolerated in individuals with HHT [
Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right-to-left shunt.
Liver biopsy should be avoided in individuals with HHT [
## Evaluation of Relatives at Risk
It is recommended to evaluate at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from
If the pathogenic variant in the family is known, evaluate with molecular genetic testing.
If the familial pathogenic variant is not known and the diagnosis of HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is established (see
Individuals older than age 40 years should have a targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring.
In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT in addition to an evaluation for brain and pulmonary AVMs should be done initially, as features of HHT may not be identified by medical history and clinical examination in younger individuals.
See
• Individuals older than age 40 years should have a targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring.
• In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT in addition to an evaluation for brain and pulmonary AVMs should be done initially, as features of HHT may not be identified by medical history and clinical examination in younger individuals.
## Pregnancy Management
Pregnant women with HHT and untreated pulmonary AVMs are at increased risk for complications related to hemorrhage or embolic events. Women with treated pulmonary AVMs appear to be at no higher risk during pregnancy than those without pulmonary AVMs. For this reason, published management guidelines recommend that pregnant women with HHT who have not been recently screened and/or treated for pulmonary AVM should be managed as follows:
In asymptomatic women, initial screening for pulmonary AVMs should be performed using either transthoracic contrast echocardiography with agitated saline contrast or low-dose noncontrast chest CT, depending on local expertise. Chest CT, when performed, should be done early in the second trimester.
In women with symptoms suggestive of pulmonary AVM, diagnostic testing should be performed using low-dose noncontrast chest CT. This testing can be performed at any gestational age, as clinically indicated.
Pulmonary AVMs should be treated starting in the second trimester unless otherwise clinically indicated.
An unenhanced brain MRI is recommended in pregnant women with symptoms suggestive of cerebral AVM. Women who are asymptomatic do not require routine screening for cerebral AVMs during pregnancy.
Iron replacement is preferred for anemia, but transfusion of packed red blood cells may be necessary for symptomatic anemia refractory to aggressive iron replacement therapy.
Expert consensus is to not withhold an epidural because of a diagnosis of HHT, and that screening for spinal vascular malformations is not required. Two case series showed no evidence of hemorrhagic complications from epidural or spinal anesthesia [
• In asymptomatic women, initial screening for pulmonary AVMs should be performed using either transthoracic contrast echocardiography with agitated saline contrast or low-dose noncontrast chest CT, depending on local expertise. Chest CT, when performed, should be done early in the second trimester.
• In women with symptoms suggestive of pulmonary AVM, diagnostic testing should be performed using low-dose noncontrast chest CT. This testing can be performed at any gestational age, as clinically indicated.
• Pulmonary AVMs should be treated starting in the second trimester unless otherwise clinically indicated.
## Therapies Under Investigation
Newer therapies designed to interfere with the development of abnormal vascular connections are being investigated; while numerous case reports and small uncontrolled series indicate promise, results from controlled trials are needed [
Search
## Genetic Counseling
Hereditary hemorrhagic telangiectasia (HHT) is inherited in an autosomal dominant manner.
Most individuals diagnosed with HHT have an affected parent.
A proband with HHT may rarely have the disorder as the result of
If the proband appears to be the only affected family member (i.e., a simplex case), and:
The HHT-causing pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, allow reliable recurrence risk counseling, and determine if a parent should undergo clinical examination for features of HHT.
The HHT-causing pathogenic variant has not been identified in the proband, recommendations for the evaluation of parents of the proband include physical examination and documentation of medical history targeted at symptoms and manifestations of HHT.
Note: If the familial pathogenic variant is not known and, consequently, HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
If the proband has a known
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with HHT may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless the HHT-causing pathogenic variant has been identified in the proband and molecular genetic testing has established that neither parent is heterozygous for the familial pathogenic variant.
If a parent of the proband is affected and/or is known to have the HHT-causing pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the proband has a known HHT-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, sibs should be considered at risk for HHT and, if the familial pathogenic variant is known, offered molecular genetic testing. If the familial pathogenic variant is not known, sibs should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
See Management:
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Testing of asymptomatic at-risk family members usually involves pre-test consultation to discuss the possible impact of positive and negative test results. Those seeking testing should be counseled regarding possible problems that they may encounter with respect to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Informed consent should be procured, and records kept confidential. Individuals identified to have a pathogenic variant in one of the three HHT-related genes need long-term follow up and evaluations.
Once the HHT-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Most individuals diagnosed with HHT have an affected parent.
• A proband with HHT may rarely have the disorder as the result of
• If the proband appears to be the only affected family member (i.e., a simplex case), and:
• The HHT-causing pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, allow reliable recurrence risk counseling, and determine if a parent should undergo clinical examination for features of HHT.
• The HHT-causing pathogenic variant has not been identified in the proband, recommendations for the evaluation of parents of the proband include physical examination and documentation of medical history targeted at symptoms and manifestations of HHT.
• Note: If the familial pathogenic variant is not known and, consequently, HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
• The HHT-causing pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, allow reliable recurrence risk counseling, and determine if a parent should undergo clinical examination for features of HHT.
• The HHT-causing pathogenic variant has not been identified in the proband, recommendations for the evaluation of parents of the proband include physical examination and documentation of medical history targeted at symptoms and manifestations of HHT.
• Note: If the familial pathogenic variant is not known and, consequently, HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
• If the proband has a known
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with HHT may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless the HHT-causing pathogenic variant has been identified in the proband and molecular genetic testing has established that neither parent is heterozygous for the familial pathogenic variant.
• The HHT-causing pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, allow reliable recurrence risk counseling, and determine if a parent should undergo clinical examination for features of HHT.
• The HHT-causing pathogenic variant has not been identified in the proband, recommendations for the evaluation of parents of the proband include physical examination and documentation of medical history targeted at symptoms and manifestations of HHT.
• Note: If the familial pathogenic variant is not known and, consequently, HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the HHT-causing pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the proband has a known HHT-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, sibs should be considered at risk for HHT and, if the familial pathogenic variant is known, offered molecular genetic testing. If the familial pathogenic variant is not known, sibs should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Mode of Inheritance
Hereditary hemorrhagic telangiectasia (HHT) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with HHT have an affected parent.
A proband with HHT may rarely have the disorder as the result of
If the proband appears to be the only affected family member (i.e., a simplex case), and:
The HHT-causing pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, allow reliable recurrence risk counseling, and determine if a parent should undergo clinical examination for features of HHT.
The HHT-causing pathogenic variant has not been identified in the proband, recommendations for the evaluation of parents of the proband include physical examination and documentation of medical history targeted at symptoms and manifestations of HHT.
Note: If the familial pathogenic variant is not known and, consequently, HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
If the proband has a known
The proband has a
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with HHT may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless the HHT-causing pathogenic variant has been identified in the proband and molecular genetic testing has established that neither parent is heterozygous for the familial pathogenic variant.
If a parent of the proband is affected and/or is known to have the HHT-causing pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the proband has a known HHT-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, sibs should be considered at risk for HHT and, if the familial pathogenic variant is known, offered molecular genetic testing. If the familial pathogenic variant is not known, sibs should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
• Most individuals diagnosed with HHT have an affected parent.
• A proband with HHT may rarely have the disorder as the result of
• If the proband appears to be the only affected family member (i.e., a simplex case), and:
• The HHT-causing pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, allow reliable recurrence risk counseling, and determine if a parent should undergo clinical examination for features of HHT.
• The HHT-causing pathogenic variant has not been identified in the proband, recommendations for the evaluation of parents of the proband include physical examination and documentation of medical history targeted at symptoms and manifestations of HHT.
• Note: If the familial pathogenic variant is not known and, consequently, HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
• The HHT-causing pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, allow reliable recurrence risk counseling, and determine if a parent should undergo clinical examination for features of HHT.
• The HHT-causing pathogenic variant has not been identified in the proband, recommendations for the evaluation of parents of the proband include physical examination and documentation of medical history targeted at symptoms and manifestations of HHT.
• Note: If the familial pathogenic variant is not known and, consequently, HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
• If the proband has a known
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with HHT may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless the HHT-causing pathogenic variant has been identified in the proband and molecular genetic testing has established that neither parent is heterozygous for the familial pathogenic variant.
• The HHT-causing pathogenic variant has been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, allow reliable recurrence risk counseling, and determine if a parent should undergo clinical examination for features of HHT.
• The HHT-causing pathogenic variant has not been identified in the proband, recommendations for the evaluation of parents of the proband include physical examination and documentation of medical history targeted at symptoms and manifestations of HHT.
• Note: If the familial pathogenic variant is not known and, consequently, HHT cannot been ruled out by molecular testing, at-risk family members should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If a parent of the proband is affected and/or is known to have the HHT-causing pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the proband has a known HHT-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, sibs should be considered at risk for HHT and, if the familial pathogenic variant is known, offered molecular genetic testing. If the familial pathogenic variant is not known, sibs should follow the same protocol as is recommended for individuals in whom the diagnosis of HHT is definite (see
## Related Genetic Counseling Issues
See Management:
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Testing of asymptomatic at-risk family members usually involves pre-test consultation to discuss the possible impact of positive and negative test results. Those seeking testing should be counseled regarding possible problems that they may encounter with respect to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Informed consent should be procured, and records kept confidential. Individuals identified to have a pathogenic variant in one of the three HHT-related genes need long-term follow up and evaluations.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the HHT-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
PO Box 329
Monkton MD 21111
•
• PO Box 329
• Monkton MD 21111
•
•
•
## Molecular Genetics
Hereditary Hemorrhagic Telangiectasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hereditary Hemorrhagic Telangiectasia (
Currently, all known genetic defects that cause HHT are in genes that encode proteins within the transforming growth factor beta (TGF-β) signaling pathway.
## Molecular Pathogenesis
Currently, all known genetic defects that cause HHT are in genes that encode proteins within the transforming growth factor beta (TGF-β) signaling pathway.
## Chapter Notes
Jamie has many publications related to HHT, including invited review articles and original research focused particularly on the clinical and molecular diagnosis of HHT. She has served on the Cure HHT Global Research and Medical Advisory Board for many years. She co-chaired the Clinical and Molecular Diagnosis Group at the International HHT Guidelines Conference, which led to publication of the initial consensus guidelines for diagnosis and management in 2011. She was an invited member of the international conference which led to the publication in 2021 of the second consensus guidelines for the diagnosis and management of HHT.
Pinar Bayrak-Toydemir, MD, PhD, Department of Pathology, University of Utah
Alan Guttmacher, MD; National Institutes of Health (2000-2009) Jamie McDonald, MS, CGC (2000-present) Reed E Pyeritz, MD, PhD, FACMG; Perelman School of Medicine, University of Pennsylvania (2009-2021)David Stevenson, MD (2021-present)
24 November 2021 (sw) Comprehensive update posted live
2 February 2017 (sw) Comprehensive update posted live
24 July 2014 (me) Comprehensive update posted live
5 January 2012 (me) Comprehensive update posted live
19 May 2009 (me) Comprehensive update posted live
22 November 2005 (me) Comprehensive update posted live
16 March 2004 (cd) Revision: sequence analysis
26 February 2004 (cd) Revision: quantitative PCR added as a test method
4 August 2003 (cd) Revisions
17 June 2003 (ca) Comprehensive update posted live
26 June 2000 (me) Review posted live
January 2000 (jm) Original submission
• 24 November 2021 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 24 July 2014 (me) Comprehensive update posted live
• 5 January 2012 (me) Comprehensive update posted live
• 19 May 2009 (me) Comprehensive update posted live
• 22 November 2005 (me) Comprehensive update posted live
• 16 March 2004 (cd) Revision: sequence analysis
• 26 February 2004 (cd) Revision: quantitative PCR added as a test method
• 4 August 2003 (cd) Revisions
• 17 June 2003 (ca) Comprehensive update posted live
• 26 June 2000 (me) Review posted live
• January 2000 (jm) Original submission
## Author Notes
Jamie has many publications related to HHT, including invited review articles and original research focused particularly on the clinical and molecular diagnosis of HHT. She has served on the Cure HHT Global Research and Medical Advisory Board for many years. She co-chaired the Clinical and Molecular Diagnosis Group at the International HHT Guidelines Conference, which led to publication of the initial consensus guidelines for diagnosis and management in 2011. She was an invited member of the international conference which led to the publication in 2021 of the second consensus guidelines for the diagnosis and management of HHT.
## Acknowledgments
Pinar Bayrak-Toydemir, MD, PhD, Department of Pathology, University of Utah
## Author History
Alan Guttmacher, MD; National Institutes of Health (2000-2009) Jamie McDonald, MS, CGC (2000-present) Reed E Pyeritz, MD, PhD, FACMG; Perelman School of Medicine, University of Pennsylvania (2009-2021)David Stevenson, MD (2021-present)
## Revision History
24 November 2021 (sw) Comprehensive update posted live
2 February 2017 (sw) Comprehensive update posted live
24 July 2014 (me) Comprehensive update posted live
5 January 2012 (me) Comprehensive update posted live
19 May 2009 (me) Comprehensive update posted live
22 November 2005 (me) Comprehensive update posted live
16 March 2004 (cd) Revision: sequence analysis
26 February 2004 (cd) Revision: quantitative PCR added as a test method
4 August 2003 (cd) Revisions
17 June 2003 (ca) Comprehensive update posted live
26 June 2000 (me) Review posted live
January 2000 (jm) Original submission
• 24 November 2021 (sw) Comprehensive update posted live
• 2 February 2017 (sw) Comprehensive update posted live
• 24 July 2014 (me) Comprehensive update posted live
• 5 January 2012 (me) Comprehensive update posted live
• 19 May 2009 (me) Comprehensive update posted live
• 22 November 2005 (me) Comprehensive update posted live
• 16 March 2004 (cd) Revision: sequence analysis
• 26 February 2004 (cd) Revision: quantitative PCR added as a test method
• 4 August 2003 (cd) Revisions
• 17 June 2003 (ca) Comprehensive update posted live
• 26 June 2000 (me) Review posted live
• January 2000 (jm) Original submission
## References
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|
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"W Brinjikji, VN Iyer, CP Wood, G Lanzino. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis.. J Neurosurg. 2017;127:302-10",
"BT Brinkerhoff, DM Poetker, NW Choong. Long-term therapy with bevacizumab in hereditary hemorrhagic telangiectasia.. N Engl J Med 2011;364:688-9",
"E Buscarini, C Danesino, C Olivieri, G Lupinacci, F De Grazia, L Reduzzi, P Blotta, P Gazzaniga, F Pagella, M Grosso, G Pongiglione, L Buscarini, H Plauchu, A Zambelli. Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia -- results of extensive screening.. Ultraschall Med 2004a;25:348-55",
"E Buscarini, C Danesino, H Plauchu, C de Fazio, C Olivieri, G Brambilla, F Menozzi, L Reduzzi, P Blotta, P Gazzaniga, F Pagella, M Grosso, G Pongiglione, J Cappiello, A Zambelli. High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia.. Ultrasound Med Biol 2004b;30:1089-97",
"E Buscarini, S Gandolfi, S Alicante, C Londoni, G Manfredi. Liver involvement in hereditary hemorrhagic telangiectasia.. Abdom Radiol (NY) 2018;43:1920-30",
"E Buscarini, G Leandro, D Conte, C Danesino, E Daina, G Manfredi, G Lupinacci, G Brambilla, F Menozzi, F De Grazia, P Gazzaniga, G Inama, R Bonardi, P Blotta, P Forner, C Olivieri, A Perna, M Grosso, G Pongiglione, E Boccardi, F Pagella, G Rossi, A Zambelli. Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia.. Dig Dis Sci. 2011;56:2166-78",
"E Buscarini, H Plauchu, G Garcia Tsao, RI White, C Sabbà, F Miller, JC Saurin, JP Pelage, G Lesca, MJ Marion, A Perna, ME Faughnan. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.. Liver Int. 2006;26:1040-6",
"S Circo, JR Gossage. Pulmonary vascular complications of hereditary haemorrhagic telangiectasia.. Curr Opin Pulm Med. 2014;20:421-8",
"SG Cole, ME Begbie, GM Wallace, CL Shovlin. A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5.. J Med Genet 2005;42:577-82",
"V Cottin, S Dupuis-Girod, G Lesca, JF Cordier. Pulmonary vascular manifestations of hereditary hemorrhagic telangiectasia (rendu-osler disease).. Respiration. 2007;74:361-78",
"TM Davidson, SE Olitsky, JL Wei. Hereditary hemorrhagic telangiectasia/avastin.. Laryngoscope 2010;120:432-5",
"EM de Gussem, AY Lausman, AJ Beder, CP Edwards, MH Blanker, KG Terbrugge, JJ Mager, ME Faughnan. Outcomes of pregnancy in women with hereditary hemorrhagic telangiectasia.. Obstet Gynecol. 2014;123:514-20",
"HL Devlin, AE Hosman, CL Shovlin. Antiplatlet and anticoagulant agents in hereditary hemorrhagic telangiectasia.. N Engl J Med. 2013;368:876-8",
"S Dupuis-Girod, V Cottin, CL Shovlin. The lung in hereditary hemorrhagic telangiectasia.. Respiration. 2017;94:315-30",
"S Dupuis-Girod, I Ginon, JC Saurin, D Marion, E Guillot, E Decullier, A Roux, MF Carette, B Gilbert-Dussardier, PY Hatron, P Lacombe, B Lorcerie, S Rivière, R Corre, S Giraud, S Bailly, G Paintaud, D Ternant, PJ Valette, H Plauchu, F Faure. Bevacizumab in patients with HHT and severe hepatic vascular malformations and high cardiac output.. JAMA 2012;307:948-55",
"CP Edwards, N Shehata, ME Faughnan. Hereditary hemorrhagic telangiectasia patients can tolerate anticoagulation.. Ann Hematol. 2012;91:1959-68",
"M El Hajjam, A Mekki, A Palmyre, M Eyries, F Soubrier, I Bourgault Villada, A Ozanne, RY Carlier, T Chinet. RASA1 phenotype overlaps with hereditary haemorrhagic telangiectasia: two case reports.. J Med Genet. 2021;58:645-7",
"A Farhan, F Yuan, E Partan, CR Weiss. Clinical manifestations of patients with GDF2 mutations associated with hereditary hemorrhagic telangiectasia type 5.. Am J Med Genet A. 2021",
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"ME Faughnan, VA Palda, G Garcia-Tsao, UW Geisthoff, J McDonald, DD Proctor, J Spears, DH Brown, E Buscarini, MS Chesnutt, V Cottin, A Ganguly, JR Gossage, AE Guttmacher, RH Hyland, SJ Kennedy, J Korzenik, JJ Mager, AP Ozanne, JF Piccirillo, D Picus, H Plauchu, ME Porteous, RE Pyeritz, DA Ross, C Sabba, K Swanson, P Terry, MC Wallace, CJ Westermann, RI White, LH Young, R Zarrabeitia. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.. J Med Genet. 2011;48:73-87",
"D Flieger, S Hainke, W Fischbach. Dramatic improvement in HHT after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab.. Ann Hematol. 2006;85:631-2",
"P Fodstad, S Dheyauldeen, M Rinde, G. Bachmann-Harildstad. Anti-VEGF with 3-week intervals is effective on anemia in a patient with severe HHT.. Ann Hematol. 2011;90:611-2",
"C Gallione, AS Aylsworth, J Beis, T Berk, B Bernhardt, RD Clark, C Clericuzio, C Danesino, J Drautz, J Fahl, Z Fan, M Faughnan, A Ganguly, J Garvie, K Henderson, U Kini, T Leedom, M Ludman, A Lux, M Maisenbacher, S Maxxucco, C Olivieri, JK Ploos van Amstel, N Prigoda-Lee, RE Pyeritz, W Reardon, K Vandeznade, JD Wladman, RI White, CA Williams, DA Marchuk. Overlapping spectra of SMAD4 mutations in juvenile polyposis and JP-HHT syndrome.. Am J Med Genet 2010;152A:333-9",
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"G. Garcia-Tsao. Liver involvement in hereditary hemorrhagic telangiectasia (HHT).. J Hepatol. 2007;46:499-507",
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"S Gräf, M Haimel, M Bleda, C Hadinnapola, L Southgate, W Li, J Hodgson, B Liu, RM Salmon, M Southwood, RD Machado, JM Martin, CM Treacy, K Yates, LC Daugherty, O Shamardina, D Whitehorn, S Holden, M Aldred, HJ Bogaard, C Church, G Coghlan, R Condliffe, PA Corris, C Danesino, M Eyries, H Gall, S Ghio, HA Ghofrani, JSR Gibbs, B Girerd, AC Houweling, L Howard, M Humbert, DG Kiely, G Kovacs, RV MacKenzie Ross, S Moledina, D Montani, M Newnham, A Olschewski, H Olschewski, AJ Peacock, J Pepke-Zaba, I Prokopenko, CJ Rhodes, L Scelsi, W Seeger, F Soubrier, DF Stein, J Suntharalingam, EM Swietlik, MR Toshner, DA van Heel, A Vonk Noordegraaf, Q Waisfisz, J Wharton, SJ Wort, WH Ouwehand, N Soranzo, A Lawrie, PD Upton, MR Wilkins, RC Trembath, NW Morrell. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.. Nat Commun. 2018;9:1416",
"E Grève, D Moussata, JL Gaudin, MG Lapalus, S Giraud, S Dupuis-Girod, A Calender, H Plauchu, JC Saurin. High diagnostic and clinical impact of small-bowel capsule endoscopy in patients with hereditary hemorrhagic telangiectasia with overt digestive bleeding and/or severe anemia.. Gastrointest Endosc. 2010;71:760-7",
"T Handa, Y Okano, N Nakanishi, T Morisaki, H Morisaki, M. Mishima. BMPR2 gene mutation in pulmonary arteriovenous malformation and pulmonary hypertension: a case report.. Respir Investig. 2014;52:195-8",
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"SW Hetts, DL Cooke, J Nelson, N Gupta, H Fullerton, MR Amans, JA Narvid, P Moftakhar, H McSwain, CF Dowd, RT Higashida, VV Halbach, MT Lawton, H Kim. Influence of patient age on angioarchitecture of brain arteriovenous malformations.. Am J Neuroradiol 2014;35:1376-80",
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"J Hodgson, EM Swietlik, RM Salmon, C Hadinnapola, I Nikolic, J Wharton, J Guo, J Liley, M Haimel, M Bleda, L Southgate, RD Machado, JM Martin, CM Treacy, K Yates, LC Daugherty, O Shamardina, D Whitehorn, S Holden, HJ Bogaard, C Church, G Coghlan, R Condliffe, PA Corris, C Danesino, M Eyries, H Gall, S Ghio, HA Ghofrani, JSR Gibbs, B Girerd, AC Houweling, L Howard, M Humbert, DG Kiely, G Kovacs, A Lawrie, RV MacKenzie Ross, S Moledina, D Montani, A Olschewski, H Olschewski, WH Ouwehand, AJ Peacock, J Pepke-Zaba, I Prokopenko, CJ Rhodes, L Scelsi, W Seeger, F Soubrier, J Suntharalingam, MR Toshner, RC Trembath, A Vonk Noordegraaf, SJ Wort, MR Wilkins, PB Yu, W Li, S Gräf, PD Upton, NW Morrell. Characterization of GDF2 mutations and levels of BMP9 and BMP10 in pulmonary arterial hypertension.. Am J Respir Crit Care Med. 2020;201:575-85",
"AE Hosman, EM de Gussem, WAF Balemans, A Gauthier, CJJ Westermann, RJ Snijder, MC Post, JJ Mager. Screening children for pulmonary arteriovenous malformations: Evaluation of 18 years of experience.. Pediatr Pulmonol. 2017;52:1206-11",
"AA Ianora, M Memeo, C Sabba, A Cirulli, A Rotondo, G Angelelli. Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement.. Radiology 2004;230:250-9",
"VN Iyer, B Saberi, JK Heimbach, JJ Larson, S Raghavaiah, I Ditah, K Swanson, PS Kamath, KD Watt, T Taner, MJ Krowka, MD Leise. Liver transplantation trends and outcomes for hereditary hemorrhagic telangiectasia in the United States.. Transplantation. 2019;103:1418-24",
"RS Kasthuri, M Montifar, J Nelson, H Kim, MT Lawton, ME Faughnan. Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia.. Am J Hematol. 2017",
"AD Kjeldsen, J Kjeldsen. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia.. Am J Gastroenterol 2000;95:415-8",
"AD Kjeldsen, TR Møller, K Brusgaard, P Vase, PE Andersen. Clinical symptoms according to genotype amongst patients with hereditary haemorrhagic telangiectasia.. J Intern Med 2005;258:349-55",
"F Lebrin, S Srun, K Raymond, S Martin, S van den Brink, C Freitas, C Bréant, T Mathivet, B Larrivée, JL Thomas, HM Arthur, CJ Westermann, F Disch, JJ Mager, RJ Snijder, A Eichmann, CL Mummery. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia.. Nat Med. 2010;16:420-8",
"G Lesca, C Olivieri, N Burnichon, F Pagella, MF Carette, B Gilbert-Dussardier, C Goizet, J Roume, M Rabilloud, JC Saurin, V Cottin, J Honnorat, F Coulet, S Giraud, A Calender, C Danesino, E Buscarini, H Plauchu. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network.. Genet Med. 2007;9:14-22",
"TG Letteboer, JJ Mager, RJ Snijder, BP Koeleman, D Lindhout, JK Ploos van Amstel, CJ Westermann. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia.. J Med Genet 2006;43:371-7",
"J Liu, J Yang, X Tang, H Li, Y Shen, W Gu, S. Zhao. Homozygous GDF2-related hereditary hemorrhagic telangiectasia in a Chinese family.. Pediatrics. 2020;146",
"MA Lyle, ER Fenstad, MD McGoon, RP Frantz, MJ Krowka, GC Kane, KL Swanson. Pulmonary hypertension in hereditary hemorrhagic telangiectasia.. Chest. 2016;149:362-371",
"S Majumdar, JP McWilliams. Approach to pulmonary arteriovenous malformations: a comprehensive update.. J Clin Med. 2020;9:1927",
"DA Marchuk, AE Guttmacher, JA Penner, P Ganguly. Report on the workshop on Hereditary Hemorrhagic Telangiectasia, July 10-11, 1997.. Am J Med Genet 1998;76:269-73",
"J McDonald, P Bayrak-Toydemir, D DeMille, W Wooderchak-Donahue, K Whitehead. Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2).. Genet Med 2020;22:1201-5",
"J McDonald, W Wooderchak-Donahue, C VanSant Webb, K Whitehead, DA Stevenson, P Bayrak-Toydemir. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era.. Front Genet. 2015;6:1",
"NM Meier, ML Foster, JT Battaile. Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations: clinical aspects.. Cardiovasc Diagn Ther. 2018;8:316-24",
"A Mitchell, LA Adams, G MacQuillan, J Tibballs. vanden Driesen R, Delriviere L. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia.. Liver Transpl. 2008;14:210-3",
"ER Mohler, V Doriswamy, A Sibley, BA Bernhardt, RE Pyeritz. Transillumination of the fingers for vascular anomalies: a novel method for evaluating hereditary hemorrhagic telangiectasia.. Genet Med 2009;11:356-8",
"M O'Malley, L LaGuardia, MF Kalady, J Parambil, B Heald, C Eng, J Church, CA Burke. The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome.. Dis Colon Rectum. 2012;55:886-92",
"H Plauchu, JP de Chadarévian, A Bideau, JM Robert. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population.. Am J Med Genet 1989;32:291-7",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton, ME Hurles. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33",
"S Revuz, E Decullier, I Ginon, N Lamblin, PY Hatron, P Kaminsky, MF Carette, P Lacombe, AC Simon, S Rivière, JR Harlé, A Fraisse, C Lavigne, V Leguy-Seguin, A Chaouat, C Khouatra, S Dupuis-Girod, E Hachulla. Pulmonary hypertension subtypes associated with hereditary haemorrhagic telangiectasia: haemodynamic profiles and survival probability.. PLoS ONE 2017;12",
"SL Richer, UW Geisthoff, N Livada, PD Ward, L Johnson, A Mainka, KJ Henderson, S Maune, RI White, DA Ross. The Young's procedure for severe epistaxis from HHT.. Am J Rhinol Allergy. 2012;26:401-4",
"CM Rigelsky, C Jennings, R Lehtonen, OA Minai, C Eng, MA Aldred. BMPR2 mutation in a patient with pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia.. Am J Med Genet A 2008;146A:2551-6",
"CL Shovlin, AE Guttmacher, E Buscarini, ME Faughnan, RH Hyland, CJ Westermann, AD Kjeldsen, H Plauchu. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome).. Am J Med Genet 2000;91:66-7",
"CL Shovlin, CM Millar, F Droege, A Kjeldsen, G Manfredi, P Suppressa, S Ugolini, N Coote, AD Fialla, U Geisthoff, GM Lenato, HJ Mager, F Pagella, MC Post, C Sabbà, U Sure, PM Torring, S Dupuis-Girod, E Buscarini. Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia.. Orphanet J Rare Dis. 2019;14:210",
"CL Shovlin, V Sodhi, A McCarthy, P Lasjaunias, JE Jackson, MN Sheppard. Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services.. BJOG 2008;115:1108-15",
"E Soon, M Southwood, K Sheares, J Pepke-Zaba, NW Morrell. Better off blue: BMPR-2 mutation, arteriovenous malformation, and pulmonary arterial hypertension.. Am J Respir Crit Care Med. 2014;189:1435-6",
"F Soubrier, WK Chung, R Machado, E Grünig, M Aldred, M Geraci, JE Loyd, CG Elliott, RC Trembath, JH Newman, M Humbert. Genetics and Genomics of Pulmonary Arterial Hypertension.. J Am Coll Cardiol. 2013;62:D13-21",
"PD Stenson, M Mort, EV Ball, K Evans, M Hayden, S Heywood, M Hussain, AD Phillips, DN Cooper. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.. Hum Genet. 2017;136:665-77",
"P Suppressa, A Liso, C Sabbà. Low dose intravenous bevacizumab for the treatment of anaemia in hereditary haemorrhagic telangiectasia.. Br J Haematol. 2011;152:365",
"KK Topiwala, SD Patel, AM Nouh, MJ Alberts. Novel GDF2 gene mutation associated with pulmonary arteriovenous malformation.. J Stroke Cerebrovasc Dis. 2020;29",
"SO Trerotola, RE Pyeritz. PAVM embolization: an update.. AJR Am J Roentgenol. 2010;195:837-45",
"V Vorselaars, S Velthuis, M van Gent, C Westermann, R Snijder, J Mager, M Post. Pulmonary hypertension in a large cohort with hereditary hemorrhagic telangiectasia.. Respiration 2017;94:242-50",
"VM Vorselaars, S Velthuis, MJ Swaans, JJ Mager, RJ Snijder, BJ Rensing, LV Boersma, MC Post. Percutaneous left atrial appendage closure-An alternative strategy for anticoagulation in atrial fibrillation and hereditary hemorrhagic telangiectasia?. Cardiovasc Diagn Ther. 2015;5:49-53",
"KE Wain, MS Ellingson, J McDonald, A Gammon, M Roberts, P Pichurin, I Winship, DL Riegert-Johnson, JN Weitzel, NM Lindor. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review.. Genet Med. 2014;16:588-93",
"CL Welle, BT Welch, W Brinjikji, EC Ehman, SK Venkatesh, MP Johnson, VN Iyer, MD Leise, CP Wood. Abdominal manifestations of hereditary hemorrhagic telangiectasia: a series of 333 patients over 15 years.. Abdom Radiol (NY) 2019;44:2384-91",
"KJ Whitehead, NB Sautter, JP McWilliams, MM Chakinala, CA Merlo, MH Johnson, M James, EM Everett, MS Clancy, ME Faughnan, SP Oh, SE Olitsky, RE Pyeritz, JR Gossage. Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia: a randomized clinical trial.. JAMA 2016;316:943-51",
"WL Wooderchak-Donahue, G Akay, K Whitehead, E Briggs, DA Stevenson, B O'Fallon, M Velinder, A Farrell, W Shen, E Bedoukian, CM Skrabann, RJ Antaya, K Henderson, J Pollak, J Treat, R Day, JE Jacher, M Hannibal, K Bontempo, G Marth, P Bayrak-Toydemir, J McDonald. Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)?. Genet Med 2019;21:2007-14",
"WL Wooderchak-Donahue, J McDonald, B O'Fallon, PD Upton, W Li, BL Roman, S Young, P Plant, GT Fülöp, C Langa, NW Morrell, LM Botella, C Bernabeu, DA Stevenson, JR Runo, P Bayrak-Toydemir. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia.. Am J Hum Genet. 2013;93:530-7"
] |
26/6/2000
|
24/11/2021
|
16/3/2004
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
hi
|
hi
|
[
"Congenital Hyperinsulinism (CHI)",
"Familial Hyperinsulinism",
"Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI)",
"Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI)",
"Congenital Hyperinsulinism (CHI)",
"Familial Hyperinsulinism",
"ATP-binding cassette sub-family C member 8",
"ATP-sensitive inward rectifier potassium channel 11",
"Dicarboxylate carrier SLC25A8",
"Glutamate dehydrogenase 1, mitochondrial",
"Hepatocyte nuclear factor 1-alpha",
"Hepatocyte nuclear factor 4-alpha",
"Hexokinase-1",
"Hexokinase-4",
"Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial",
"Insulin receptor",
"Monocarboxylate transporter 1",
"Phosphomannomutase 2",
"ABCC8",
"GCK",
"GLUD1",
"HADH",
"HK1",
"HNF1A",
"HNF4A",
"INSR",
"KCNJ11",
"PMM2",
"SLC16A1",
"UCP2",
"Nonsyndromic Genetic Hyperinsulinism",
"Overview"
] |
Nonsyndromic Genetic Hyperinsulinism Overview
|
David Gillis
|
Summary The purpose of this overview is to: Describe the Review the Provide an Inform (when possible) Inform
|
## Clinical Characteristics of Nonsyndromic Genetic Hyperinsulinism
Nonsyndromic genetic hyperinsulinism (HI) is characterized by hypoglycemia that ranges from severe neonatal onset to childhood onset with mild symptoms. Neonatal-onset disease manifests within hours to days after birth. In the newborn period, presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea. Childhood-onset disease manifests in the first months or years of life. Children can present with an unprovoked seizure and/or hypoglycemia at the time of acute illness during which nutritional intake is reduced. Some individuals may be asymptomatic. Even within the same family, disease manifestations can range from mild to severe and clinical onset can range from immediately after birth to late in childhood.
In most individuals, HI can be definitively and rapidly diagnosed if the appropriate laboratory tests are done on blood and urine samples during an episode of spontaneous hypoglycemia or during monitored fasting (glucose <50 mg/dL) (see
Hyperinsulinism: Diagnostic Tests
TSH = thyroid-stimulating hormone
Reprinted from
Note: (1) "Inappropriately elevated plasma insulin concentration" is difficult to define, largely because of marked differences in specificity and sensitivity of commercial insulin assays. The concentrations mentioned here and in the literature must not be interpreted as definitive. (2) The plasma glucose concentration that signifies symptomatic hypoglycemia is controversial, but measurement of plasma insulin should be done when plasma glucose is <50 mg/dL.
Inappropriate hypoketonemia (plasma-free fatty acid concentration <1.5 mmol/L)
Note: In the newborn period ketone production is impaired and the presence of low ketones should be considered together with the rest of the clinical and laboratory picture.
A positive glucagon stimulation test (See
A markedly elevated glucose requirement to prevent hypoglycemia (i.e., exogenous glucose requirements that may exceed 15 mg/kg/min [normal neonate: 5-8 mg/kg/min])
Fluorodopa F 18 positron emission tomography (
Pancreatic beta cells (comprising <2% of all pancreatic cells) synthesize, store, and secrete insulin. Beta cells are located within the islets of Langerhans. Two major pancreatic histologic types ("diffuse" and "focal") have been described in individuals with nonsyndromic genetic HI. A third histologic form ("atypical" or "mosaic") has also been described.
Note: With the current availability of imaging and molecular genetic testing, diagnosis and management decisions do not require histology. Biopsy is not part of the initial evaluation, and the pancreatic histology is only known if surgical management is warranted.
If medical treatment can be safely maintained, glycemic control usually becomes easier with time, and most individuals treated medically enter clinical remission after several months or years of treatment [
• Inappropriate hypoketonemia (plasma-free fatty acid concentration <1.5 mmol/L)
• Note: In the newborn period ketone production is impaired and the presence of low ketones should be considered together with the rest of the clinical and laboratory picture.
• A positive glucagon stimulation test (See
• A markedly elevated glucose requirement to prevent hypoglycemia (i.e., exogenous glucose requirements that may exceed 15 mg/kg/min [normal neonate: 5-8 mg/kg/min])
## Clinical Manifestations
Nonsyndromic genetic hyperinsulinism (HI) is characterized by hypoglycemia that ranges from severe neonatal onset to childhood onset with mild symptoms. Neonatal-onset disease manifests within hours to days after birth. In the newborn period, presenting symptoms may be nonspecific, including seizures, hypotonia, poor feeding, and apnea. Childhood-onset disease manifests in the first months or years of life. Children can present with an unprovoked seizure and/or hypoglycemia at the time of acute illness during which nutritional intake is reduced. Some individuals may be asymptomatic. Even within the same family, disease manifestations can range from mild to severe and clinical onset can range from immediately after birth to late in childhood.
## Laboratory Features
In most individuals, HI can be definitively and rapidly diagnosed if the appropriate laboratory tests are done on blood and urine samples during an episode of spontaneous hypoglycemia or during monitored fasting (glucose <50 mg/dL) (see
Hyperinsulinism: Diagnostic Tests
TSH = thyroid-stimulating hormone
Reprinted from
Note: (1) "Inappropriately elevated plasma insulin concentration" is difficult to define, largely because of marked differences in specificity and sensitivity of commercial insulin assays. The concentrations mentioned here and in the literature must not be interpreted as definitive. (2) The plasma glucose concentration that signifies symptomatic hypoglycemia is controversial, but measurement of plasma insulin should be done when plasma glucose is <50 mg/dL.
Inappropriate hypoketonemia (plasma-free fatty acid concentration <1.5 mmol/L)
Note: In the newborn period ketone production is impaired and the presence of low ketones should be considered together with the rest of the clinical and laboratory picture.
A positive glucagon stimulation test (See
A markedly elevated glucose requirement to prevent hypoglycemia (i.e., exogenous glucose requirements that may exceed 15 mg/kg/min [normal neonate: 5-8 mg/kg/min])
• Inappropriate hypoketonemia (plasma-free fatty acid concentration <1.5 mmol/L)
• Note: In the newborn period ketone production is impaired and the presence of low ketones should be considered together with the rest of the clinical and laboratory picture.
• A positive glucagon stimulation test (See
• A markedly elevated glucose requirement to prevent hypoglycemia (i.e., exogenous glucose requirements that may exceed 15 mg/kg/min [normal neonate: 5-8 mg/kg/min])
## Imaging
Fluorodopa F 18 positron emission tomography (
## Histology
Pancreatic beta cells (comprising <2% of all pancreatic cells) synthesize, store, and secrete insulin. Beta cells are located within the islets of Langerhans. Two major pancreatic histologic types ("diffuse" and "focal") have been described in individuals with nonsyndromic genetic HI. A third histologic form ("atypical" or "mosaic") has also been described.
Note: With the current availability of imaging and molecular genetic testing, diagnosis and management decisions do not require histology. Biopsy is not part of the initial evaluation, and the pancreatic histology is only known if surgical management is warranted.
## Prognosis
If medical treatment can be safely maintained, glycemic control usually becomes easier with time, and most individuals treated medically enter clinical remission after several months or years of treatment [
## Causes of Nonsyndromic Genetic Hyperinsulinism
Nonsyndromic genetic hyperinsulinism (HI) is the most common cause of persistent neonatal hypoglycemia and should be considered in every infant presenting with unexplained hypoglycemia. Pathogenic variants in many genes have been associated with nonsyndromic genetic HI; the precise number is difficult to report with accuracy because of overlap with syndromic HI [
Nonsyndromic Genetic Hyperinsulinism: Genes and Distinguishing Clinical Features
Large for gestational age
Severe refractory hypoglycemia in the 1st 48 hrs of life
Respond only partially to diet or diazoxide & may require pancreatic resection
40% have focal form
Diabetes may develop later in life
Founder variants in Ashkenazi Jewish & Finnish populations
Normal growth parameters at birth
Present at age ~1 yr (range: 2 days-30 yrs)
Respond to diet & diazoxide therapy; exceptions reported
Variable penetrance
Ranges from mild diazoxide-responsive hypoglycemia to severe, diazoxide-unresponsive hypoglycemia
Insulin secretion in response to elevation & suppression of glucose levels is qualitatively normal, but the glucose set-point at which insulin secretion is turned off is abnormally low.
Mild-to-moderate hyperammonemia (1.5-4x upper limit of normal)
Ammonia levels are not related to ambient glucose levels or to duration of fasting & appear to be benign.
Mild hypoglycemia usually presents after neonatal period.
May be assoc w/exquisite sensitivity to leucine challenge
Most respond well to diazoxide; rarely, surgery is required to prevent recurrent hypoglycemia.
↑ urine 3-hydroxyglutaric acid & serum 3-hydroxybutyryl-carnitine
Severe hypoglycemia after leucine administration
Mild diazoxide-responsive hypoglycemia; severe hypoglycemia has been reported.
Normal urinary 3-hydoxyglutaric acid & normal plasma acylcarnitine profile does not exclude the diagnosis.
Present before age 1 yr
40% present w/seizure
Diazoxide responsive
Failure to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting
Not leucine sensitive
Large for gestational age
Mild diazoxide-sensitive hypoglycemia
Hypoglycemia usually resolves in childhood.
Large for gestational age
Mild diazoxide-sensitive hypoglycemia
Hypoglycemia in neonatal & early infantile period
Insulinopenic diabetes mellitus during adolescence
Postprandial hypoglycemia may be exacerbated by exercise.
Variable age at onset & typical elevated insulin:C peptide ratio
Large for gestational age
Severe refractory hypoglycemia in 1st 48 hrs of life
Affected infants usually respond only partially to diet or diazoxide therapy; may require pancreatic resection.
40% have focal form
Normal growth parameters at birth
Present at age ~1 yr (range: 2 days-30 yrs)
Respond to diet & diazoxide therapy; exceptions reported
Variable penetrance
Can present in infancy w/diazoxide-responsive HI w/o other apparent features
Additional features of CDG type Ia become apparent over time, incl polycystic kidney disease, liver disease, liver cysts, & neurologic dysfunction
Hypoglycemia occurs during childhood or later.
Severe hypoglycemia after exercise
Mild diazoxide-responsive hypoglycemia
Children reported w/hypoglycemia 4 hrs after glucose intake
Role as monogenic cause of hypoglycemia has been questioned
NA
AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorders of glycosylation; HI = hyperinsulinism; MOI = mode of inheritance; NA = not applicable
Genes are listed alphabetically.
Appears to be a rare cause of nonsyndromic genetic HI (3/153 in a Finnish series) [
Variable phenotype by age is reported, with children developing post-glucose-challenge hypoglycemia [
Syndromes Associated with Hyperinsulinism
AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; MOI = mode of inheritance; XL = X-linked
Beckwith-Wiedemann syndrome (BWS) is associated with abnormal expression of imprinted genes in the BWS critical region. Abnormal expression of imprinted genes can be caused by a constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5 known to be associated with BWS; a 11p15.5 copy number variant; or a heterozygous maternally inherited
Infants of diabetic mothers (hypoglycemia typically resolves within days to weeks after birth but may require dietary glucose therapy with or without drug therapy with diazoxide);
Transient hyperinsulinemic hypoglycemia of infancy, which typically responds well to diazoxide therapy and may occur after history of perinatal stress or asphyxia;
Infants born to mothers taking certain drugs [
• Large for gestational age
• Severe refractory hypoglycemia in the 1st 48 hrs of life
• Respond only partially to diet or diazoxide & may require pancreatic resection
• 40% have focal form
• Diabetes may develop later in life
• Founder variants in Ashkenazi Jewish & Finnish populations
• Normal growth parameters at birth
• Present at age ~1 yr (range: 2 days-30 yrs)
• Respond to diet & diazoxide therapy; exceptions reported
• Variable penetrance
• Ranges from mild diazoxide-responsive hypoglycemia to severe, diazoxide-unresponsive hypoglycemia
• Insulin secretion in response to elevation & suppression of glucose levels is qualitatively normal, but the glucose set-point at which insulin secretion is turned off is abnormally low.
• Mild-to-moderate hyperammonemia (1.5-4x upper limit of normal)
• Ammonia levels are not related to ambient glucose levels or to duration of fasting & appear to be benign.
• Mild hypoglycemia usually presents after neonatal period.
• May be assoc w/exquisite sensitivity to leucine challenge
• Most respond well to diazoxide; rarely, surgery is required to prevent recurrent hypoglycemia.
• ↑ urine 3-hydroxyglutaric acid & serum 3-hydroxybutyryl-carnitine
• Severe hypoglycemia after leucine administration
• Mild diazoxide-responsive hypoglycemia; severe hypoglycemia has been reported.
• Normal urinary 3-hydoxyglutaric acid & normal plasma acylcarnitine profile does not exclude the diagnosis.
• Present before age 1 yr
• 40% present w/seizure
• Diazoxide responsive
• Failure to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting
• Not leucine sensitive
• Large for gestational age
• Mild diazoxide-sensitive hypoglycemia
• Hypoglycemia usually resolves in childhood.
• Large for gestational age
• Mild diazoxide-sensitive hypoglycemia
• Hypoglycemia in neonatal & early infantile period
• Insulinopenic diabetes mellitus during adolescence
• Postprandial hypoglycemia may be exacerbated by exercise.
• Variable age at onset & typical elevated insulin:C peptide ratio
• Large for gestational age
• Severe refractory hypoglycemia in 1st 48 hrs of life
• Affected infants usually respond only partially to diet or diazoxide therapy; may require pancreatic resection.
• 40% have focal form
• Normal growth parameters at birth
• Present at age ~1 yr (range: 2 days-30 yrs)
• Respond to diet & diazoxide therapy; exceptions reported
• Variable penetrance
• Can present in infancy w/diazoxide-responsive HI w/o other apparent features
• Additional features of CDG type Ia become apparent over time, incl polycystic kidney disease, liver disease, liver cysts, & neurologic dysfunction
• Hypoglycemia occurs during childhood or later.
• Severe hypoglycemia after exercise
• Mild diazoxide-responsive hypoglycemia
• Children reported w/hypoglycemia 4 hrs after glucose intake
• Role as monogenic cause of hypoglycemia has been questioned
• Infants of diabetic mothers (hypoglycemia typically resolves within days to weeks after birth but may require dietary glucose therapy with or without drug therapy with diazoxide);
• Transient hyperinsulinemic hypoglycemia of infancy, which typically responds well to diazoxide therapy and may occur after history of perinatal stress or asphyxia;
• Infants born to mothers taking certain drugs [
## Differential Diagnosis of Nonsyndromic Genetic HI
Syndromes Associated with Hyperinsulinism
AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; MOI = mode of inheritance; XL = X-linked
Beckwith-Wiedemann syndrome (BWS) is associated with abnormal expression of imprinted genes in the BWS critical region. Abnormal expression of imprinted genes can be caused by a constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5 known to be associated with BWS; a 11p15.5 copy number variant; or a heterozygous maternally inherited
Infants of diabetic mothers (hypoglycemia typically resolves within days to weeks after birth but may require dietary glucose therapy with or without drug therapy with diazoxide);
Transient hyperinsulinemic hypoglycemia of infancy, which typically responds well to diazoxide therapy and may occur after history of perinatal stress or asphyxia;
Infants born to mothers taking certain drugs [
• Infants of diabetic mothers (hypoglycemia typically resolves within days to weeks after birth but may require dietary glucose therapy with or without drug therapy with diazoxide);
• Transient hyperinsulinemic hypoglycemia of infancy, which typically responds well to diazoxide therapy and may occur after history of perinatal stress or asphyxia;
• Infants born to mothers taking certain drugs [
## Evaluation Strategies to Identify the Genetic Cause of Nonsyndromic Genetic Hyperinsulinism in a Proband
Establishing a specific genetic cause of nonsyndromic genetic hyperinsulinism (HI):
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical history, family history, and molecular genetic testing.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a medical history, family history, and molecular genetic testing.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
## Medical Management of Nonsyndromic Genetic Hyperinsulinism Based on Genetic Cause
Once initial diagnostic blood samples are obtained, the hypoglycemia must be corrected immediately using intravenous glucose at a dose sufficient to prevent further hypoglycemia and irreversible brain damage. The rate of glucose infusion may be high, often greater than 15 mg/kg/min, and frequently requires central venous access. The definition of adequate glucose control has been the subject of discussion. A Pediatric Endocrine Society guideline recommends maintaining plasma glucose levels above 70 mg/dL (3.9 mmol/L) [
Emergency treatment options for hypoglycemia must be available at all times in case of an unexpected hypoglycemic episode. During initial treatment, a second intravenous line should preferably be kept open in case of blockage of the first line in order to avoid a long wait while a new line is being prepared. If not already being infused, glucagon should also be ready and can be given rapidly by either intramuscular or subcutaneous injection or intranasal application.
During the next phase of treatment, the aim is to eliminate parenteral glucose requirements and involves a combination of medical therapies as described in
Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer
Nighttime continuous gastric drip containing glucose or glucose polymer
Background continuous glucose in gastric drip with intermittent supplementary feeds
In some individuals with severe HI, even the most aggressive medical management fails to consistently maintain plasma glucose concentration above 60-70 mg/dL. In such individuals, surgery must be considered. Prior to surgical intervention,
Identification of biallelic pathogenic variants (associated with autosomal recessive HI) or a heterozygous dominant-acting pathogenic variant (associated with autosomal dominant HI) is diagnostic of diffuse disease.
Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the maternal allele suggests diffuse disease; it is assumed that the other pathogenic variant on the paternal allele was missed because of technical limitations of the molecular genetic testing.
Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the paternal allele is consistent with and highly suggestive of focal disease, although it cannot be considered diagnostic, as molecular genetic testing methods could have failed to detect a pathogenic variant on the maternal allele. In such individuals, further testing to diagnose and localize focal disease is indicated.
Currently, long-term medical therapy is the recommended treatment for individuals with diffuse disease. When long-term medical therapy fails, extensive (80%-95%) pancreatic resection may be considered. This is only considered in exceptional, unresponsive cases, as such children remain at risk for persistent hypoglycemia postoperatively and have a high likelihood of developing insulin-requiring diabetes mellitus later in childhood [
In persons with clinically mild disease, episodes of subtle, undiagnosed hypoglycemia can cause permanent brain damage. Therefore, close monitoring and treatment is just as critical in those with mild HI as it is in severe HI. Furthermore, in persons with mild disease and in those with severe disease in clinical remission, severe hypoglycemia may be precipitated by intercurrent viral illness. Thus, it is imperative that parents monitor glucose concentrations closely especially during intercurrent illness, even in the absence of symptomatic hypoglycemia. Identification of the genetic cause of nonsyndromic HI can help guide the frequency of blood glucose testing. Individuals who are diazoxide responsive and take their medication regularly will need less frequent glucose monitoring than non-diazoxide-responsive individuals. In the first few years of life, use of continuous glucose monitoring is recommended for children with very unstable glucose levels regardless of the genetic cause [
Prolonged fasting of any sort should be avoided.
Affected individuals who previously underwent near-total or subtotal pancreatectomy typically have insulin-requiring diabetes by the time they become pregnant. In these women treatment is the same as for individuals with preexisting diabetes of any cause. There is little published experience with pregnancy in individuals who were treated conservatively or who underwent limited pancreatectomy for focal nonsyndromic genetic HI. In this situation, close monitoring of glucose to detect both recurrent hypoglycemia and hyperglycemia is warranted. If hyperglycemia is documented, treatment should be instituted as for any woman with gestational diabetes.
A fetus at risk for nonsyndromic genetic HI should be monitored for size and weight. Excessive fetal weight gain during the last trimester of pregnancy increases the risk of obstetric complications and of cesarean delivery. In pregnant women with a history of nonsyndromic genetic HI and gestational hyperglycemia due to prior surgical treatment, the fetus should be monitored as for any case of preexisting type 1, preexisting type 2, or gestational diabetes.
See
• Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer
• Nighttime continuous gastric drip containing glucose or glucose polymer
• Background continuous glucose in gastric drip with intermittent supplementary feeds
• Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer
• Nighttime continuous gastric drip containing glucose or glucose polymer
• Background continuous glucose in gastric drip with intermittent supplementary feeds
• Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer
• Nighttime continuous gastric drip containing glucose or glucose polymer
• Background continuous glucose in gastric drip with intermittent supplementary feeds
• Identification of biallelic pathogenic variants (associated with autosomal recessive HI) or a heterozygous dominant-acting pathogenic variant (associated with autosomal dominant HI) is diagnostic of diffuse disease.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the maternal allele suggests diffuse disease; it is assumed that the other pathogenic variant on the paternal allele was missed because of technical limitations of the molecular genetic testing.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the paternal allele is consistent with and highly suggestive of focal disease, although it cannot be considered diagnostic, as molecular genetic testing methods could have failed to detect a pathogenic variant on the maternal allele. In such individuals, further testing to diagnose and localize focal disease is indicated.
• Identification of biallelic pathogenic variants (associated with autosomal recessive HI) or a heterozygous dominant-acting pathogenic variant (associated with autosomal dominant HI) is diagnostic of diffuse disease.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the maternal allele suggests diffuse disease; it is assumed that the other pathogenic variant on the paternal allele was missed because of technical limitations of the molecular genetic testing.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the paternal allele is consistent with and highly suggestive of focal disease, although it cannot be considered diagnostic, as molecular genetic testing methods could have failed to detect a pathogenic variant on the maternal allele. In such individuals, further testing to diagnose and localize focal disease is indicated.
• Identification of biallelic pathogenic variants (associated with autosomal recessive HI) or a heterozygous dominant-acting pathogenic variant (associated with autosomal dominant HI) is diagnostic of diffuse disease.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the maternal allele suggests diffuse disease; it is assumed that the other pathogenic variant on the paternal allele was missed because of technical limitations of the molecular genetic testing.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the paternal allele is consistent with and highly suggestive of focal disease, although it cannot be considered diagnostic, as molecular genetic testing methods could have failed to detect a pathogenic variant on the maternal allele. In such individuals, further testing to diagnose and localize focal disease is indicated.
## Initial Treatment
Once initial diagnostic blood samples are obtained, the hypoglycemia must be corrected immediately using intravenous glucose at a dose sufficient to prevent further hypoglycemia and irreversible brain damage. The rate of glucose infusion may be high, often greater than 15 mg/kg/min, and frequently requires central venous access. The definition of adequate glucose control has been the subject of discussion. A Pediatric Endocrine Society guideline recommends maintaining plasma glucose levels above 70 mg/dL (3.9 mmol/L) [
Emergency treatment options for hypoglycemia must be available at all times in case of an unexpected hypoglycemic episode. During initial treatment, a second intravenous line should preferably be kept open in case of blockage of the first line in order to avoid a long wait while a new line is being prepared. If not already being infused, glucagon should also be ready and can be given rapidly by either intramuscular or subcutaneous injection or intranasal application.
## Long-Term Medical Management
During the next phase of treatment, the aim is to eliminate parenteral glucose requirements and involves a combination of medical therapies as described in
Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer
Nighttime continuous gastric drip containing glucose or glucose polymer
Background continuous glucose in gastric drip with intermittent supplementary feeds
• Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer
• Nighttime continuous gastric drip containing glucose or glucose polymer
• Background continuous glucose in gastric drip with intermittent supplementary feeds
• Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer
• Nighttime continuous gastric drip containing glucose or glucose polymer
• Background continuous glucose in gastric drip with intermittent supplementary feeds
• Frequent high-carbohydrate feedings, including formula supplemented with glucose polymer
• Nighttime continuous gastric drip containing glucose or glucose polymer
• Background continuous glucose in gastric drip with intermittent supplementary feeds
## Surgical Management
In some individuals with severe HI, even the most aggressive medical management fails to consistently maintain plasma glucose concentration above 60-70 mg/dL. In such individuals, surgery must be considered. Prior to surgical intervention,
Identification of biallelic pathogenic variants (associated with autosomal recessive HI) or a heterozygous dominant-acting pathogenic variant (associated with autosomal dominant HI) is diagnostic of diffuse disease.
Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the maternal allele suggests diffuse disease; it is assumed that the other pathogenic variant on the paternal allele was missed because of technical limitations of the molecular genetic testing.
Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the paternal allele is consistent with and highly suggestive of focal disease, although it cannot be considered diagnostic, as molecular genetic testing methods could have failed to detect a pathogenic variant on the maternal allele. In such individuals, further testing to diagnose and localize focal disease is indicated.
Currently, long-term medical therapy is the recommended treatment for individuals with diffuse disease. When long-term medical therapy fails, extensive (80%-95%) pancreatic resection may be considered. This is only considered in exceptional, unresponsive cases, as such children remain at risk for persistent hypoglycemia postoperatively and have a high likelihood of developing insulin-requiring diabetes mellitus later in childhood [
• Identification of biallelic pathogenic variants (associated with autosomal recessive HI) or a heterozygous dominant-acting pathogenic variant (associated with autosomal dominant HI) is diagnostic of diffuse disease.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the maternal allele suggests diffuse disease; it is assumed that the other pathogenic variant on the paternal allele was missed because of technical limitations of the molecular genetic testing.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the paternal allele is consistent with and highly suggestive of focal disease, although it cannot be considered diagnostic, as molecular genetic testing methods could have failed to detect a pathogenic variant on the maternal allele. In such individuals, further testing to diagnose and localize focal disease is indicated.
• Identification of biallelic pathogenic variants (associated with autosomal recessive HI) or a heterozygous dominant-acting pathogenic variant (associated with autosomal dominant HI) is diagnostic of diffuse disease.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the maternal allele suggests diffuse disease; it is assumed that the other pathogenic variant on the paternal allele was missed because of technical limitations of the molecular genetic testing.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the paternal allele is consistent with and highly suggestive of focal disease, although it cannot be considered diagnostic, as molecular genetic testing methods could have failed to detect a pathogenic variant on the maternal allele. In such individuals, further testing to diagnose and localize focal disease is indicated.
• Identification of biallelic pathogenic variants (associated with autosomal recessive HI) or a heterozygous dominant-acting pathogenic variant (associated with autosomal dominant HI) is diagnostic of diffuse disease.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the maternal allele suggests diffuse disease; it is assumed that the other pathogenic variant on the paternal allele was missed because of technical limitations of the molecular genetic testing.
• Identification of a heterozygous pathogenic variant (associated with autosomal recessive HI) on the paternal allele is consistent with and highly suggestive of focal disease, although it cannot be considered diagnostic, as molecular genetic testing methods could have failed to detect a pathogenic variant on the maternal allele. In such individuals, further testing to diagnose and localize focal disease is indicated.
## Surveillance
In persons with clinically mild disease, episodes of subtle, undiagnosed hypoglycemia can cause permanent brain damage. Therefore, close monitoring and treatment is just as critical in those with mild HI as it is in severe HI. Furthermore, in persons with mild disease and in those with severe disease in clinical remission, severe hypoglycemia may be precipitated by intercurrent viral illness. Thus, it is imperative that parents monitor glucose concentrations closely especially during intercurrent illness, even in the absence of symptomatic hypoglycemia. Identification of the genetic cause of nonsyndromic HI can help guide the frequency of blood glucose testing. Individuals who are diazoxide responsive and take their medication regularly will need less frequent glucose monitoring than non-diazoxide-responsive individuals. In the first few years of life, use of continuous glucose monitoring is recommended for children with very unstable glucose levels regardless of the genetic cause [
## Agents/Circumstances to Avoid
Prolonged fasting of any sort should be avoided.
## Pregnancy Management
Affected individuals who previously underwent near-total or subtotal pancreatectomy typically have insulin-requiring diabetes by the time they become pregnant. In these women treatment is the same as for individuals with preexisting diabetes of any cause. There is little published experience with pregnancy in individuals who were treated conservatively or who underwent limited pancreatectomy for focal nonsyndromic genetic HI. In this situation, close monitoring of glucose to detect both recurrent hypoglycemia and hyperglycemia is warranted. If hyperglycemia is documented, treatment should be instituted as for any woman with gestational diabetes.
A fetus at risk for nonsyndromic genetic HI should be monitored for size and weight. Excessive fetal weight gain during the last trimester of pregnancy increases the risk of obstetric complications and of cesarean delivery. In pregnant women with a history of nonsyndromic genetic HI and gestational hyperglycemia due to prior surgical treatment, the fetus should be monitored as for any case of preexisting type 1, preexisting type 2, or gestational diabetes.
See
## Risk Assessment and Surveillance of At-Risk Relatives for Early Detection and Treatment of Nonsyndromic Genetic Hyperinsulinism
Recurrence risk assessment for family members of an individual with nonsyndromic genetic hyperinsulinism (HI) requires identification of the genetic cause of HI in the proband (see
Nonsyndromic Genetic Hyperinsulinism: Mode of Inheritance
HI = hyperinsulinism
Severe HI caused by autosomal recessive pathogenic variants in
Both parents of an affected child are presumed to be heterozygous for an autosomal recessive HI-related pathogenic variant.
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an autosomal recessive HI-related pathogenic variant and allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a child with autosomal recessive diffuse HI are typically asymptomatic.
If both parents are known to be heterozygous for an autosomal recessive HI-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial pathogenic variants.
Sibs who inherit:
Biallelic pathogenic variants will be affected; however, manifestations may range from mild to severe in sibs with HI, and clinical presentation may range from immediately after birth to late in childhood.
An autosomal recessive HI-related
A normal allele from the father and an autosomal recessive HI-related
An
Unless an affected individual's reproductive partner also has autosomal recessive HI or is heterozygous, offspring will be obligate heterozygotes for a pathogenic variant. The carrier frequency in the general population is approximately 1% or less; however, populations with founder variants and higher carrier frequencies have been reported.
Heterozygous offspring of a male proband with
Some individuals with autosomal dominant diffuse HI inherited a causative pathogenic variant from an affected heterozygous parent.
More typically, an individual with autosomal dominant diffuse HI has the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for surveillance. If a parent is found to have the autosomal dominant HI-related pathogenic variant, clinical testing for fasting and postprandial hypoglycemia is recommended (see Management,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for autosomal dominant diffuse HI because of the possibility of reduced penetrance in a parent or the possibility of parental gonadal mosaicism.
Focal HI is caused by a paternally inherited
Although no instances of focal HI caused by a
Molecular genetic testing is recommended for the father of the proband to confirm that the father is heterozygous for the pathogenic variant identified in the proband and to inform recurrence risk assessment.
Sibs of a proband with focal HI have a 50% chance of inheriting the germline
Because focal HI manifests only when the inherited pathogenic variant is on the paternally derived allele and a separate, independent somatic event results in the loss of the maternal allele (loss of heterozygosity), the risk for focal HI in a sib with an inherited pathogenic variant is estimated to be 1:540 [
Each child of a male proband with focal HI is at risk of developing focal HI. To develop focal HI, the individual must inherit the pathogenic variant from the father (50% chance) and a second somatic event must occur, the latter being quite uncommon. The estimated risk for focal HI to the offspring of a male proband with focal HI is 1:540 [
The risk of diffuse HI in offspring depends on the genetic status of the proband’s reproductive partner: offspring will have diffuse HI only if they inherit a pathogenic variant from both parents (see
The presence of focal HI in one sib does not rule out possible diffuse disease in another sib. Such an occurrence was reported in a consanguineous family in which both the mother and the father were heterozygous for an
To date, all individuals with histologically proven mosaic HI [
It is appropriate to clarify the clinical/genetic status of sibs of an individual with focal or diffuse HI so that appropriate evaluation and treatment can be initiated before hypoglycemia occurs. Because of the severe neurologic consequences of delayed diagnosis and treatment, it is imperative that at-risk newborns be followed closely from birth and a definitive diagnosis made as rapidly as possible. Evaluations can include the following:
Molecular genetic testing if the pathogenic variant(s) in the family are known. Note: If the causative pathogenic variant(s) have been identified in a proband, it is prudent to test all at-risk relatives; depending on the findings, more extensive family investigations may be warranted.
If the pathogenic variant(s) in the family are not known, careful glucose monitoring of newborns thought to be at risk based on the inheritance pattern should be undertaken (see
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with genetic HI, particularly if both partners are of the same ancestry.
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for a pregnancy at increased risk for diffuse HI (involvement of beta cells throughout the pancreas) are possible. Parents who elect to continue a pregnancy in which the fetus has been determined to be affected have the advantage of initiating treatment immediately following birth, thus preventing early, severe hypoglycemia.
In families of individuals with focal HI (pancreatic adenomatous hyperplasia that involves a limited region of the pancreas), prenatal testing is not informative: while the paternal pathogenic variant can be identified in the DNA of an at-risk fetus, no testing can identify which fetuses will also have a somatic event leading to loss of the maternal allele.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• Both parents of an affected child are presumed to be heterozygous for an autosomal recessive HI-related pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an autosomal recessive HI-related pathogenic variant and allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a child with autosomal recessive diffuse HI are typically asymptomatic.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an autosomal recessive HI-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Sibs who inherit:
• Biallelic pathogenic variants will be affected; however, manifestations may range from mild to severe in sibs with HI, and clinical presentation may range from immediately after birth to late in childhood.
• An autosomal recessive HI-related
• A normal allele from the father and an autosomal recessive HI-related
• An
• Biallelic pathogenic variants will be affected; however, manifestations may range from mild to severe in sibs with HI, and clinical presentation may range from immediately after birth to late in childhood.
• An autosomal recessive HI-related
• A normal allele from the father and an autosomal recessive HI-related
• An
• Biallelic pathogenic variants will be affected; however, manifestations may range from mild to severe in sibs with HI, and clinical presentation may range from immediately after birth to late in childhood.
• An autosomal recessive HI-related
• A normal allele from the father and an autosomal recessive HI-related
• An
• Unless an affected individual's reproductive partner also has autosomal recessive HI or is heterozygous, offspring will be obligate heterozygotes for a pathogenic variant. The carrier frequency in the general population is approximately 1% or less; however, populations with founder variants and higher carrier frequencies have been reported.
• Heterozygous offspring of a male proband with
• Some individuals with autosomal dominant diffuse HI inherited a causative pathogenic variant from an affected heterozygous parent.
• More typically, an individual with autosomal dominant diffuse HI has the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for surveillance. If a parent is found to have the autosomal dominant HI-related pathogenic variant, clinical testing for fasting and postprandial hypoglycemia is recommended (see Management,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for autosomal dominant diffuse HI because of the possibility of reduced penetrance in a parent or the possibility of parental gonadal mosaicism.
• Focal HI is caused by a paternally inherited
• Although no instances of focal HI caused by a
• Molecular genetic testing is recommended for the father of the proband to confirm that the father is heterozygous for the pathogenic variant identified in the proband and to inform recurrence risk assessment.
• Sibs of a proband with focal HI have a 50% chance of inheriting the germline
• Because focal HI manifests only when the inherited pathogenic variant is on the paternally derived allele and a separate, independent somatic event results in the loss of the maternal allele (loss of heterozygosity), the risk for focal HI in a sib with an inherited pathogenic variant is estimated to be 1:540 [
• Each child of a male proband with focal HI is at risk of developing focal HI. To develop focal HI, the individual must inherit the pathogenic variant from the father (50% chance) and a second somatic event must occur, the latter being quite uncommon. The estimated risk for focal HI to the offspring of a male proband with focal HI is 1:540 [
• The risk of diffuse HI in offspring depends on the genetic status of the proband’s reproductive partner: offspring will have diffuse HI only if they inherit a pathogenic variant from both parents (see
• The presence of focal HI in one sib does not rule out possible diffuse disease in another sib. Such an occurrence was reported in a consanguineous family in which both the mother and the father were heterozygous for an
• Molecular genetic testing if the pathogenic variant(s) in the family are known. Note: If the causative pathogenic variant(s) have been identified in a proband, it is prudent to test all at-risk relatives; depending on the findings, more extensive family investigations may be warranted.
• If the pathogenic variant(s) in the family are not known, careful glucose monitoring of newborns thought to be at risk based on the inheritance pattern should be undertaken (see
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with genetic HI, particularly if both partners are of the same ancestry.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Genetic Risk Assessment
Recurrence risk assessment for family members of an individual with nonsyndromic genetic hyperinsulinism (HI) requires identification of the genetic cause of HI in the proband (see
Nonsyndromic Genetic Hyperinsulinism: Mode of Inheritance
HI = hyperinsulinism
Severe HI caused by autosomal recessive pathogenic variants in
## Autosomal Recessive Inheritance of Diffuse HI – Risk to Family Members
Both parents of an affected child are presumed to be heterozygous for an autosomal recessive HI-related pathogenic variant.
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an autosomal recessive HI-related pathogenic variant and allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
The heterozygous parents of a child with autosomal recessive diffuse HI are typically asymptomatic.
If both parents are known to be heterozygous for an autosomal recessive HI-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial pathogenic variants.
Sibs who inherit:
Biallelic pathogenic variants will be affected; however, manifestations may range from mild to severe in sibs with HI, and clinical presentation may range from immediately after birth to late in childhood.
An autosomal recessive HI-related
A normal allele from the father and an autosomal recessive HI-related
An
Unless an affected individual's reproductive partner also has autosomal recessive HI or is heterozygous, offspring will be obligate heterozygotes for a pathogenic variant. The carrier frequency in the general population is approximately 1% or less; however, populations with founder variants and higher carrier frequencies have been reported.
Heterozygous offspring of a male proband with
• Both parents of an affected child are presumed to be heterozygous for an autosomal recessive HI-related pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an autosomal recessive HI-related pathogenic variant and allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a child with autosomal recessive diffuse HI are typically asymptomatic.
• A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
• Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for an autosomal recessive HI-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Sibs who inherit:
• Biallelic pathogenic variants will be affected; however, manifestations may range from mild to severe in sibs with HI, and clinical presentation may range from immediately after birth to late in childhood.
• An autosomal recessive HI-related
• A normal allele from the father and an autosomal recessive HI-related
• An
• Biallelic pathogenic variants will be affected; however, manifestations may range from mild to severe in sibs with HI, and clinical presentation may range from immediately after birth to late in childhood.
• An autosomal recessive HI-related
• A normal allele from the father and an autosomal recessive HI-related
• An
• Biallelic pathogenic variants will be affected; however, manifestations may range from mild to severe in sibs with HI, and clinical presentation may range from immediately after birth to late in childhood.
• An autosomal recessive HI-related
• A normal allele from the father and an autosomal recessive HI-related
• An
• Unless an affected individual's reproductive partner also has autosomal recessive HI or is heterozygous, offspring will be obligate heterozygotes for a pathogenic variant. The carrier frequency in the general population is approximately 1% or less; however, populations with founder variants and higher carrier frequencies have been reported.
• Heterozygous offspring of a male proband with
## Autosomal Dominant Inheritance of Diffuse HI – Risk to Family Members
Some individuals with autosomal dominant diffuse HI inherited a causative pathogenic variant from an affected heterozygous parent.
More typically, an individual with autosomal dominant diffuse HI has the disorder as the result of a
If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for surveillance. If a parent is found to have the autosomal dominant HI-related pathogenic variant, clinical testing for fasting and postprandial hypoglycemia is recommended (see Management,
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for autosomal dominant diffuse HI because of the possibility of reduced penetrance in a parent or the possibility of parental gonadal mosaicism.
• Some individuals with autosomal dominant diffuse HI inherited a causative pathogenic variant from an affected heterozygous parent.
• More typically, an individual with autosomal dominant diffuse HI has the disorder as the result of a
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for surveillance. If a parent is found to have the autosomal dominant HI-related pathogenic variant, clinical testing for fasting and postprandial hypoglycemia is recommended (see Management,
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for autosomal dominant diffuse HI because of the possibility of reduced penetrance in a parent or the possibility of parental gonadal mosaicism.
## Focal HI – Risk to Family Members
Focal HI is caused by a paternally inherited
Although no instances of focal HI caused by a
Molecular genetic testing is recommended for the father of the proband to confirm that the father is heterozygous for the pathogenic variant identified in the proband and to inform recurrence risk assessment.
Sibs of a proband with focal HI have a 50% chance of inheriting the germline
Because focal HI manifests only when the inherited pathogenic variant is on the paternally derived allele and a separate, independent somatic event results in the loss of the maternal allele (loss of heterozygosity), the risk for focal HI in a sib with an inherited pathogenic variant is estimated to be 1:540 [
Each child of a male proband with focal HI is at risk of developing focal HI. To develop focal HI, the individual must inherit the pathogenic variant from the father (50% chance) and a second somatic event must occur, the latter being quite uncommon. The estimated risk for focal HI to the offspring of a male proband with focal HI is 1:540 [
The risk of diffuse HI in offspring depends on the genetic status of the proband’s reproductive partner: offspring will have diffuse HI only if they inherit a pathogenic variant from both parents (see
The presence of focal HI in one sib does not rule out possible diffuse disease in another sib. Such an occurrence was reported in a consanguineous family in which both the mother and the father were heterozygous for an
• Focal HI is caused by a paternally inherited
• Although no instances of focal HI caused by a
• Molecular genetic testing is recommended for the father of the proband to confirm that the father is heterozygous for the pathogenic variant identified in the proband and to inform recurrence risk assessment.
• Sibs of a proband with focal HI have a 50% chance of inheriting the germline
• Because focal HI manifests only when the inherited pathogenic variant is on the paternally derived allele and a separate, independent somatic event results in the loss of the maternal allele (loss of heterozygosity), the risk for focal HI in a sib with an inherited pathogenic variant is estimated to be 1:540 [
• Each child of a male proband with focal HI is at risk of developing focal HI. To develop focal HI, the individual must inherit the pathogenic variant from the father (50% chance) and a second somatic event must occur, the latter being quite uncommon. The estimated risk for focal HI to the offspring of a male proband with focal HI is 1:540 [
• The risk of diffuse HI in offspring depends on the genetic status of the proband’s reproductive partner: offspring will have diffuse HI only if they inherit a pathogenic variant from both parents (see
• The presence of focal HI in one sib does not rule out possible diffuse disease in another sib. Such an occurrence was reported in a consanguineous family in which both the mother and the father were heterozygous for an
## Mosaic HI – Risk to Family Members
To date, all individuals with histologically proven mosaic HI [
## Evaluation of Relatives at Risk
It is appropriate to clarify the clinical/genetic status of sibs of an individual with focal or diffuse HI so that appropriate evaluation and treatment can be initiated before hypoglycemia occurs. Because of the severe neurologic consequences of delayed diagnosis and treatment, it is imperative that at-risk newborns be followed closely from birth and a definitive diagnosis made as rapidly as possible. Evaluations can include the following:
Molecular genetic testing if the pathogenic variant(s) in the family are known. Note: If the causative pathogenic variant(s) have been identified in a proband, it is prudent to test all at-risk relatives; depending on the findings, more extensive family investigations may be warranted.
If the pathogenic variant(s) in the family are not known, careful glucose monitoring of newborns thought to be at risk based on the inheritance pattern should be undertaken (see
• Molecular genetic testing if the pathogenic variant(s) in the family are known. Note: If the causative pathogenic variant(s) have been identified in a proband, it is prudent to test all at-risk relatives; depending on the findings, more extensive family investigations may be warranted.
• If the pathogenic variant(s) in the family are not known, careful glucose monitoring of newborns thought to be at risk based on the inheritance pattern should be undertaken (see
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with genetic HI, particularly if both partners are of the same ancestry.
The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with genetic HI, particularly if both partners are of the same ancestry.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for a pregnancy at increased risk for diffuse HI (involvement of beta cells throughout the pancreas) are possible. Parents who elect to continue a pregnancy in which the fetus has been determined to be affected have the advantage of initiating treatment immediately following birth, thus preventing early, severe hypoglycemia.
In families of individuals with focal HI (pancreatic adenomatous hyperplasia that involves a limited region of the pancreas), prenatal testing is not informative: while the paternal pathogenic variant can be identified in the DNA of an at-risk fetus, no testing can identify which fetuses will also have a somatic event leading to loss of the maternal allele.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
## Chapter Notes
Dr David Gillis is active in treating children with hyperinsulinism and has been involved in clinical research, particularly focused on long-term outcomes of children with this disease. He would be happy to communicate with persons who have any questions regarding diagnosis and therapy of nonsyndromic or syndromic congenital hyperinsulinism. Email:
David Gillis, MD (2019-present)Benjamin Glaser, MD; Hadassah-Hebrew University Medical Center (2003-2019)
31 October 2024 (sw) Comprehensive update posted live
21 March 2019 (sw) Comprehensive update posted live; format changed to overview
24 January 2013 (me) Comprehensive update posted live
23 February 2010 (me) Comprehensive update posted live
19 August 2003 (me) Review posted live
12 May 2003 (bg) Original submission
• 31 October 2024 (sw) Comprehensive update posted live
• 21 March 2019 (sw) Comprehensive update posted live; format changed to overview
• 24 January 2013 (me) Comprehensive update posted live
• 23 February 2010 (me) Comprehensive update posted live
• 19 August 2003 (me) Review posted live
• 12 May 2003 (bg) Original submission
## Author Notes
Dr David Gillis is active in treating children with hyperinsulinism and has been involved in clinical research, particularly focused on long-term outcomes of children with this disease. He would be happy to communicate with persons who have any questions regarding diagnosis and therapy of nonsyndromic or syndromic congenital hyperinsulinism. Email:
## Author History
David Gillis, MD (2019-present)Benjamin Glaser, MD; Hadassah-Hebrew University Medical Center (2003-2019)
## Revision History
31 October 2024 (sw) Comprehensive update posted live
21 March 2019 (sw) Comprehensive update posted live; format changed to overview
24 January 2013 (me) Comprehensive update posted live
23 February 2010 (me) Comprehensive update posted live
19 August 2003 (me) Review posted live
12 May 2003 (bg) Original submission
• 31 October 2024 (sw) Comprehensive update posted live
• 21 March 2019 (sw) Comprehensive update posted live; format changed to overview
• 24 January 2013 (me) Comprehensive update posted live
• 23 February 2010 (me) Comprehensive update posted live
• 19 August 2003 (me) Review posted live
• 12 May 2003 (bg) Original submission
## References
## Literature Cited
|
[] |
19/8/2003
|
31/10/2024
|
15/6/2010
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
higes
|
higes
|
[
"Job Syndrome",
"STAT3-Deficient Hyper-IgE Syndrome",
"STAT3 Deficiency",
"STAT3-HIES",
"STAT3 Loss-of-Function Hyper-IgE Syndrome (STAT3 LOF HIES)",
"Job Syndrome",
"STAT3 Deficiency",
"STAT3-Deficient Hyper-IgE Syndrome (STAT3-HIES)",
"STAT3 Loss-of-Function Hyper-IgE Syndrome (STAT3 LOF HIES)",
"Signal transducer and activator of transcription 3",
"STAT3",
"STAT3 Hyper IgE Syndrome"
] |
Amy P Hsu, Joie Davis, Jennifer M Puck, Steven M Holland, Alexandra F Freeman
|
Summary The diagnosis of
|
## Diagnosis
Newborn rash and typically eczematous rash at least through childhood
Recurrent skin boils (often "cold," manifesting little inflammatory reaction)
Cyst-forming pneumonias
Mucocutaneous candidiasis
Nonimmune features such as three or more retained primary teeth, scoliosis, bone fractures following minimal trauma, hyperextensibility of joints, characteristic facial appearance, increased nasal width, high palate
Laboratory test results showing:
Elevations of serum concentration of immunoglobulin E (IgE) to levels above 2000 IU/mL (normal <100 IU/mL in adults);
Eosinophilia (>700/μL);
Diminished circulating memory T and B cells and near absence of IL-17-producing Th17 cells.
Note: Not all features need to be present to suspect
A clinical scoring system was devised by the NIH group who recognized
However, molecular genetic testing for
The diagnosis of
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
An in-frame deletion of exons 22 and 23 has been reported [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Newborn rash and typically eczematous rash at least through childhood
• Recurrent skin boils (often "cold," manifesting little inflammatory reaction)
• Cyst-forming pneumonias
• Mucocutaneous candidiasis
• Nonimmune features such as three or more retained primary teeth, scoliosis, bone fractures following minimal trauma, hyperextensibility of joints, characteristic facial appearance, increased nasal width, high palate
• Laboratory test results showing:
• Elevations of serum concentration of immunoglobulin E (IgE) to levels above 2000 IU/mL (normal <100 IU/mL in adults);
• Eosinophilia (>700/μL);
• Diminished circulating memory T and B cells and near absence of IL-17-producing Th17 cells.
• Elevations of serum concentration of immunoglobulin E (IgE) to levels above 2000 IU/mL (normal <100 IU/mL in adults);
• Eosinophilia (>700/μL);
• Diminished circulating memory T and B cells and near absence of IL-17-producing Th17 cells.
• Elevations of serum concentration of immunoglobulin E (IgE) to levels above 2000 IU/mL (normal <100 IU/mL in adults);
• Eosinophilia (>700/μL);
• Diminished circulating memory T and B cells and near absence of IL-17-producing Th17 cells.
• For an introduction to multigene panels click
## Suggestive Findings
Newborn rash and typically eczematous rash at least through childhood
Recurrent skin boils (often "cold," manifesting little inflammatory reaction)
Cyst-forming pneumonias
Mucocutaneous candidiasis
Nonimmune features such as three or more retained primary teeth, scoliosis, bone fractures following minimal trauma, hyperextensibility of joints, characteristic facial appearance, increased nasal width, high palate
Laboratory test results showing:
Elevations of serum concentration of immunoglobulin E (IgE) to levels above 2000 IU/mL (normal <100 IU/mL in adults);
Eosinophilia (>700/μL);
Diminished circulating memory T and B cells and near absence of IL-17-producing Th17 cells.
Note: Not all features need to be present to suspect
A clinical scoring system was devised by the NIH group who recognized
However, molecular genetic testing for
• Newborn rash and typically eczematous rash at least through childhood
• Recurrent skin boils (often "cold," manifesting little inflammatory reaction)
• Cyst-forming pneumonias
• Mucocutaneous candidiasis
• Nonimmune features such as three or more retained primary teeth, scoliosis, bone fractures following minimal trauma, hyperextensibility of joints, characteristic facial appearance, increased nasal width, high palate
• Laboratory test results showing:
• Elevations of serum concentration of immunoglobulin E (IgE) to levels above 2000 IU/mL (normal <100 IU/mL in adults);
• Eosinophilia (>700/μL);
• Diminished circulating memory T and B cells and near absence of IL-17-producing Th17 cells.
• Elevations of serum concentration of immunoglobulin E (IgE) to levels above 2000 IU/mL (normal <100 IU/mL in adults);
• Eosinophilia (>700/μL);
• Diminished circulating memory T and B cells and near absence of IL-17-producing Th17 cells.
• Elevations of serum concentration of immunoglobulin E (IgE) to levels above 2000 IU/mL (normal <100 IU/mL in adults);
• Eosinophilia (>700/μL);
• Diminished circulating memory T and B cells and near absence of IL-17-producing Th17 cells.
## Establishing the Diagnosis
The diagnosis of
Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Molecular genetic testing approaches can include a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
An in-frame deletion of exons 22 and 23 has been reported [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
An in-frame deletion of exons 22 and 23 has been reported [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
Individuals with
Recurrent skin and sinopulmonary infections are noted in early childhood.
Recurrent staphylococcal boils usually manifest in the first few years of life, and may be "cold," lacking the cardinal features of inflammation, warmth, redness, and pain.
Recurrent pneumonias begin as well in the first few years, with the most common bacterial isolates being
Staphylococcal infections outside of the skin and lung, such as osteomyelitis or liver abscess, occur but much less frequently.
Mucocutaneous candidiasis affecting the oropharynx, vagina, fingernails, and toenails is common.
Opportunistic infections including
Decreased central memory T-cells may lead to increased incidence of varicella zoster virus (VZV) reactivation and modestly increased levels of circulating Epstein-Barr virus [
Individuals with
Osteoporosis and minimal trauma fractures start in early childhood.
Scoliosis typically develops through childhood and adolescence, and may require surgical correction.
Joint hyperextensibility is common, and adults may have degenerative joint disease.
Varying degrees of craniosynostosis can be seen, although surgical correction is rarely required. Skull radiographs often have a "beaten copper" appearance. Mild craniosynostosis is frequently noted in skull imaging.
The focal hyperintensities are usually localized to the white matter and tend to increase in number with age.
Both the Chiari 1 malformations and the hyperintensities are usually asymptomatic [
The combination of tortuosity and dilatation is found in approximately 50% of affected individuals; either abnormality is present in approximately 70%.
Clinical sequelae have been rare but include myocardial infarction.
Cerebral artery aneurysm has also been described and is infrequently associated with subarachnoid hemorrhage.
Symptoms of esophageal dysmotility are present in more than 50% of individuals and manifest as gastrointestinal reflux and dysphagia.
Upper endoscopy frequently shows eosinophilic esophagitis.
Diverticula can occur at a relatively young age and may be associated with bowel perforation [
Spontaneous intestinal perforations have also been described.
Significant gastrointestinal bleeds can occur from aneurysms and Dieulafoy lesions (abnormally large artery in the lining of the gastrointestinal system).
Survival is typically into adulthood, but a shortened life span was typical in the past. Most individuals are now living into or past the sixth decade.
Most deaths of individuals with
Myocardial infarction may be related to coronary artery aneurysms and subarachnoid hemorrhage may be related to intracranial aneurysms [
Lymphomas occur at an increased frequency; treatment with standard chemotherapy has been successful.
No genotype-phenotype correlations for
Intrafamilial variability is minimal and penetrance appears to be complete.
Dominant-negative pathogenic variants in
The prevalence of
• Recurrent staphylococcal boils usually manifest in the first few years of life, and may be "cold," lacking the cardinal features of inflammation, warmth, redness, and pain.
• Recurrent pneumonias begin as well in the first few years, with the most common bacterial isolates being
• Staphylococcal infections outside of the skin and lung, such as osteomyelitis or liver abscess, occur but much less frequently.
• Mucocutaneous candidiasis affecting the oropharynx, vagina, fingernails, and toenails is common.
• Opportunistic infections including
• Decreased central memory T-cells may lead to increased incidence of varicella zoster virus (VZV) reactivation and modestly increased levels of circulating Epstein-Barr virus [
• Osteoporosis and minimal trauma fractures start in early childhood.
• Scoliosis typically develops through childhood and adolescence, and may require surgical correction.
• Joint hyperextensibility is common, and adults may have degenerative joint disease.
• Varying degrees of craniosynostosis can be seen, although surgical correction is rarely required. Skull radiographs often have a "beaten copper" appearance. Mild craniosynostosis is frequently noted in skull imaging.
• The focal hyperintensities are usually localized to the white matter and tend to increase in number with age.
• Both the Chiari 1 malformations and the hyperintensities are usually asymptomatic [
• The combination of tortuosity and dilatation is found in approximately 50% of affected individuals; either abnormality is present in approximately 70%.
• Clinical sequelae have been rare but include myocardial infarction.
• Symptoms of esophageal dysmotility are present in more than 50% of individuals and manifest as gastrointestinal reflux and dysphagia.
• Upper endoscopy frequently shows eosinophilic esophagitis.
• Diverticula can occur at a relatively young age and may be associated with bowel perforation [
• Spontaneous intestinal perforations have also been described.
• Significant gastrointestinal bleeds can occur from aneurysms and Dieulafoy lesions (abnormally large artery in the lining of the gastrointestinal system).
• Most deaths of individuals with
• Myocardial infarction may be related to coronary artery aneurysms and subarachnoid hemorrhage may be related to intracranial aneurysms [
• Lymphomas occur at an increased frequency; treatment with standard chemotherapy has been successful.
## Clinical Description
Individuals with
Recurrent skin and sinopulmonary infections are noted in early childhood.
Recurrent staphylococcal boils usually manifest in the first few years of life, and may be "cold," lacking the cardinal features of inflammation, warmth, redness, and pain.
Recurrent pneumonias begin as well in the first few years, with the most common bacterial isolates being
Staphylococcal infections outside of the skin and lung, such as osteomyelitis or liver abscess, occur but much less frequently.
Mucocutaneous candidiasis affecting the oropharynx, vagina, fingernails, and toenails is common.
Opportunistic infections including
Decreased central memory T-cells may lead to increased incidence of varicella zoster virus (VZV) reactivation and modestly increased levels of circulating Epstein-Barr virus [
Individuals with
Osteoporosis and minimal trauma fractures start in early childhood.
Scoliosis typically develops through childhood and adolescence, and may require surgical correction.
Joint hyperextensibility is common, and adults may have degenerative joint disease.
Varying degrees of craniosynostosis can be seen, although surgical correction is rarely required. Skull radiographs often have a "beaten copper" appearance. Mild craniosynostosis is frequently noted in skull imaging.
The focal hyperintensities are usually localized to the white matter and tend to increase in number with age.
Both the Chiari 1 malformations and the hyperintensities are usually asymptomatic [
The combination of tortuosity and dilatation is found in approximately 50% of affected individuals; either abnormality is present in approximately 70%.
Clinical sequelae have been rare but include myocardial infarction.
Cerebral artery aneurysm has also been described and is infrequently associated with subarachnoid hemorrhage.
Symptoms of esophageal dysmotility are present in more than 50% of individuals and manifest as gastrointestinal reflux and dysphagia.
Upper endoscopy frequently shows eosinophilic esophagitis.
Diverticula can occur at a relatively young age and may be associated with bowel perforation [
Spontaneous intestinal perforations have also been described.
Significant gastrointestinal bleeds can occur from aneurysms and Dieulafoy lesions (abnormally large artery in the lining of the gastrointestinal system).
Survival is typically into adulthood, but a shortened life span was typical in the past. Most individuals are now living into or past the sixth decade.
Most deaths of individuals with
Myocardial infarction may be related to coronary artery aneurysms and subarachnoid hemorrhage may be related to intracranial aneurysms [
Lymphomas occur at an increased frequency; treatment with standard chemotherapy has been successful.
• Recurrent staphylococcal boils usually manifest in the first few years of life, and may be "cold," lacking the cardinal features of inflammation, warmth, redness, and pain.
• Recurrent pneumonias begin as well in the first few years, with the most common bacterial isolates being
• Staphylococcal infections outside of the skin and lung, such as osteomyelitis or liver abscess, occur but much less frequently.
• Mucocutaneous candidiasis affecting the oropharynx, vagina, fingernails, and toenails is common.
• Opportunistic infections including
• Decreased central memory T-cells may lead to increased incidence of varicella zoster virus (VZV) reactivation and modestly increased levels of circulating Epstein-Barr virus [
• Osteoporosis and minimal trauma fractures start in early childhood.
• Scoliosis typically develops through childhood and adolescence, and may require surgical correction.
• Joint hyperextensibility is common, and adults may have degenerative joint disease.
• Varying degrees of craniosynostosis can be seen, although surgical correction is rarely required. Skull radiographs often have a "beaten copper" appearance. Mild craniosynostosis is frequently noted in skull imaging.
• The focal hyperintensities are usually localized to the white matter and tend to increase in number with age.
• Both the Chiari 1 malformations and the hyperintensities are usually asymptomatic [
• The combination of tortuosity and dilatation is found in approximately 50% of affected individuals; either abnormality is present in approximately 70%.
• Clinical sequelae have been rare but include myocardial infarction.
• Symptoms of esophageal dysmotility are present in more than 50% of individuals and manifest as gastrointestinal reflux and dysphagia.
• Upper endoscopy frequently shows eosinophilic esophagitis.
• Diverticula can occur at a relatively young age and may be associated with bowel perforation [
• Spontaneous intestinal perforations have also been described.
• Significant gastrointestinal bleeds can occur from aneurysms and Dieulafoy lesions (abnormally large artery in the lining of the gastrointestinal system).
• Most deaths of individuals with
• Myocardial infarction may be related to coronary artery aneurysms and subarachnoid hemorrhage may be related to intracranial aneurysms [
• Lymphomas occur at an increased frequency; treatment with standard chemotherapy has been successful.
## Presentation
Individuals with
## Immunologic Characteristics
Recurrent skin and sinopulmonary infections are noted in early childhood.
Recurrent staphylococcal boils usually manifest in the first few years of life, and may be "cold," lacking the cardinal features of inflammation, warmth, redness, and pain.
Recurrent pneumonias begin as well in the first few years, with the most common bacterial isolates being
Staphylococcal infections outside of the skin and lung, such as osteomyelitis or liver abscess, occur but much less frequently.
Mucocutaneous candidiasis affecting the oropharynx, vagina, fingernails, and toenails is common.
Opportunistic infections including
Decreased central memory T-cells may lead to increased incidence of varicella zoster virus (VZV) reactivation and modestly increased levels of circulating Epstein-Barr virus [
• Recurrent staphylococcal boils usually manifest in the first few years of life, and may be "cold," lacking the cardinal features of inflammation, warmth, redness, and pain.
• Recurrent pneumonias begin as well in the first few years, with the most common bacterial isolates being
• Staphylococcal infections outside of the skin and lung, such as osteomyelitis or liver abscess, occur but much less frequently.
• Mucocutaneous candidiasis affecting the oropharynx, vagina, fingernails, and toenails is common.
• Opportunistic infections including
• Decreased central memory T-cells may lead to increased incidence of varicella zoster virus (VZV) reactivation and modestly increased levels of circulating Epstein-Barr virus [
## Nonimmunologic Characteristics
Individuals with
Osteoporosis and minimal trauma fractures start in early childhood.
Scoliosis typically develops through childhood and adolescence, and may require surgical correction.
Joint hyperextensibility is common, and adults may have degenerative joint disease.
Varying degrees of craniosynostosis can be seen, although surgical correction is rarely required. Skull radiographs often have a "beaten copper" appearance. Mild craniosynostosis is frequently noted in skull imaging.
The focal hyperintensities are usually localized to the white matter and tend to increase in number with age.
Both the Chiari 1 malformations and the hyperintensities are usually asymptomatic [
The combination of tortuosity and dilatation is found in approximately 50% of affected individuals; either abnormality is present in approximately 70%.
Clinical sequelae have been rare but include myocardial infarction.
Cerebral artery aneurysm has also been described and is infrequently associated with subarachnoid hemorrhage.
Symptoms of esophageal dysmotility are present in more than 50% of individuals and manifest as gastrointestinal reflux and dysphagia.
Upper endoscopy frequently shows eosinophilic esophagitis.
Diverticula can occur at a relatively young age and may be associated with bowel perforation [
Spontaneous intestinal perforations have also been described.
Significant gastrointestinal bleeds can occur from aneurysms and Dieulafoy lesions (abnormally large artery in the lining of the gastrointestinal system).
• Osteoporosis and minimal trauma fractures start in early childhood.
• Scoliosis typically develops through childhood and adolescence, and may require surgical correction.
• Joint hyperextensibility is common, and adults may have degenerative joint disease.
• Varying degrees of craniosynostosis can be seen, although surgical correction is rarely required. Skull radiographs often have a "beaten copper" appearance. Mild craniosynostosis is frequently noted in skull imaging.
• The focal hyperintensities are usually localized to the white matter and tend to increase in number with age.
• Both the Chiari 1 malformations and the hyperintensities are usually asymptomatic [
• The combination of tortuosity and dilatation is found in approximately 50% of affected individuals; either abnormality is present in approximately 70%.
• Clinical sequelae have been rare but include myocardial infarction.
• Symptoms of esophageal dysmotility are present in more than 50% of individuals and manifest as gastrointestinal reflux and dysphagia.
• Upper endoscopy frequently shows eosinophilic esophagitis.
• Diverticula can occur at a relatively young age and may be associated with bowel perforation [
• Spontaneous intestinal perforations have also been described.
• Significant gastrointestinal bleeds can occur from aneurysms and Dieulafoy lesions (abnormally large artery in the lining of the gastrointestinal system).
## Major Causes of Morbidity and Mortality
Survival is typically into adulthood, but a shortened life span was typical in the past. Most individuals are now living into or past the sixth decade.
Most deaths of individuals with
Myocardial infarction may be related to coronary artery aneurysms and subarachnoid hemorrhage may be related to intracranial aneurysms [
Lymphomas occur at an increased frequency; treatment with standard chemotherapy has been successful.
• Most deaths of individuals with
• Myocardial infarction may be related to coronary artery aneurysms and subarachnoid hemorrhage may be related to intracranial aneurysms [
• Lymphomas occur at an increased frequency; treatment with standard chemotherapy has been successful.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
## Penetrance
Intrafamilial variability is minimal and penetrance appears to be complete.
## Nomenclature
Dominant-negative pathogenic variants in
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
Germline gain-of-function
There have been three individuals with heterozygous null variants, all of whom lacked the hallmark features of
Somatic
## Differential Diagnosis
Disorders with Elevated Serum Concentration of IgE to Consider in the Differential Diagnosis of
Absence (typically) of other features of AD-HIES
Individuals w/severe atopic dermatitis often have more (& more severe) allergies (e.g., environmental, food that may lead to anaphylaxis) than those w/AD-HIES.
Affected infants are usually sicker than those w/HIES.
Lymphadenopathy, hepatosplenomegaly, opportunistic infections
Eczema
Recurrent skin & lung infections
↑ occurrence of viral skin infections (e.g.,
Absence of nonimmunologic findings of
Recurrent skin & lung infections
Craniosynostosis & scoliosis
Developmental delays (common)
Cytopenias w/lymphopenia & neutropenia
Rash typically more ichthyotic in appearance w/assoc trichorrhexis invaginata (bamboo hair)
Enteropathy w/failure to thrive frequently present
Thrombocytopenia w/small platelets; high incidence of autoimmune disease & lymphoma in later childhood & adulthood; typically more opportunistic infections than in HIES
Typically seen in males (isolated cases of affected females w/skewed X-inactivation resulting in disease phenotype reported)
AD = autosomal dominant; AR = autosomal recessive; HIES = hyper IgE syndrome; MOI = mode of inheritance; XL = X-linked
OMIM
Atopic dermatitis has many causes (many of which are unknown);
Atopic dermatitis caused by
Omenn syndrome is a form of SCID (severe combined immunodeficiency) that can result from pathogenic variants in
Most individuals initially described as having autosomal recessive hyper IgE were found to have biallelic pathogenic variants in
Note: A single report of human TYK2 deficiency described moderately high serum concentration of IgE in conjunction with disseminated bacillus Calmette-Guérin infection and susceptibility to viral and other infections [
• Absence (typically) of other features of AD-HIES
• Individuals w/severe atopic dermatitis often have more (& more severe) allergies (e.g., environmental, food that may lead to anaphylaxis) than those w/AD-HIES.
• Affected infants are usually sicker than those w/HIES.
• Lymphadenopathy, hepatosplenomegaly, opportunistic infections
• Eczema
• Recurrent skin & lung infections
• ↑ occurrence of viral skin infections (e.g.,
• Absence of nonimmunologic findings of
• Recurrent skin & lung infections
• Craniosynostosis & scoliosis
• Developmental delays (common)
• Cytopenias w/lymphopenia & neutropenia
• Rash typically more ichthyotic in appearance w/assoc trichorrhexis invaginata (bamboo hair)
• Enteropathy w/failure to thrive frequently present
• Thrombocytopenia w/small platelets; high incidence of autoimmune disease & lymphoma in later childhood & adulthood; typically more opportunistic infections than in HIES
• Typically seen in males (isolated cases of affected females w/skewed X-inactivation resulting in disease phenotype reported)
## Management
To establish the extent of disease in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Scoliosis typically progresses through adolescence.
Osteoporosis can be present in children & adults; DXA screening recommended.
Aneurysms much more common in adults than in children
Screening by brain MRA & heart CTA or coronary artery MRA every 3 yrs recommended for adolescents & adults
DXA = dual-energy x-ray absorptiometry
Currently, there is no complete cure or targeted treatment for
There is no known treatment or prevention for the nonimmunologic characteristics.
The role of hematopoietic cell transplantation (HSCT) in
Treatment of Manifestations in Individuals with
If structural damage to the lungs (e.g., bronchiectasis &/or pneumatoceles) has occurred, the breadth of antimicrobial coverage may need to be extended, incl antifungals, as these structural abnormalities become secondarily infected w/gram-negative bacteria (e.g.,
In the setting of bronchiectasis, consideration of azithromycin to prevent exacerbations if no mycobacterial infection present
TMP/SMX = trimethoprim/sulfamethoxazole
1/2-1 cup bleach per bathtub of water for 15 minutes three times weekly
Recommended Surveillance for Individuals with
Brain MRA for cerebral aneurysm
CTA or MRA for coronary artery aneurysm
Molecular genetic testing of at-risk relatives of a proband with a known
See
Cessation of prophylactic antimicrobials is often advised during pregnancy. This may increase the risk of infection and should be taken into consideration. There have been pregnancies without complication, but also instances in which lung disease has worsened after pregnancy, potentially from limited antimicrobial use, delayed radiographic diagnosis, and impaired pulmonary clearance.
Risks associated with pregnancy should be discussed with affected females who have pulmonary compromise, severe scoliosis, or other complications of
Search
Parents have reported that because of the severe eczema of their child, there have been occasions when the health care providers have alerted Child Protective Services reporting that the child is not being kept clean. While skin hygiene is very important, in spite of the best efforts of caregivers, sometimes the skin flares are severe. Questions about parental neglect/abuse have also arisen when a toddler or young child appears with evidence of repeated fractures. Health care providers who are attuned to these possibilities can serve as important advocates for the parents and family.
• Scoliosis typically progresses through adolescence.
• Osteoporosis can be present in children & adults; DXA screening recommended.
• Aneurysms much more common in adults than in children
• Screening by brain MRA & heart CTA or coronary artery MRA every 3 yrs recommended for adolescents & adults
• If structural damage to the lungs (e.g., bronchiectasis &/or pneumatoceles) has occurred, the breadth of antimicrobial coverage may need to be extended, incl antifungals, as these structural abnormalities become secondarily infected w/gram-negative bacteria (e.g.,
• In the setting of bronchiectasis, consideration of azithromycin to prevent exacerbations if no mycobacterial infection present
• Brain MRA for cerebral aneurysm
• CTA or MRA for coronary artery aneurysm
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Scoliosis typically progresses through adolescence.
Osteoporosis can be present in children & adults; DXA screening recommended.
Aneurysms much more common in adults than in children
Screening by brain MRA & heart CTA or coronary artery MRA every 3 yrs recommended for adolescents & adults
DXA = dual-energy x-ray absorptiometry
• Scoliosis typically progresses through adolescence.
• Osteoporosis can be present in children & adults; DXA screening recommended.
• Aneurysms much more common in adults than in children
• Screening by brain MRA & heart CTA or coronary artery MRA every 3 yrs recommended for adolescents & adults
## Treatment of Manifestations
Currently, there is no complete cure or targeted treatment for
There is no known treatment or prevention for the nonimmunologic characteristics.
The role of hematopoietic cell transplantation (HSCT) in
Treatment of Manifestations in Individuals with
If structural damage to the lungs (e.g., bronchiectasis &/or pneumatoceles) has occurred, the breadth of antimicrobial coverage may need to be extended, incl antifungals, as these structural abnormalities become secondarily infected w/gram-negative bacteria (e.g.,
In the setting of bronchiectasis, consideration of azithromycin to prevent exacerbations if no mycobacterial infection present
TMP/SMX = trimethoprim/sulfamethoxazole
1/2-1 cup bleach per bathtub of water for 15 minutes three times weekly
• If structural damage to the lungs (e.g., bronchiectasis &/or pneumatoceles) has occurred, the breadth of antimicrobial coverage may need to be extended, incl antifungals, as these structural abnormalities become secondarily infected w/gram-negative bacteria (e.g.,
• In the setting of bronchiectasis, consideration of azithromycin to prevent exacerbations if no mycobacterial infection present
## Surveillance
Recommended Surveillance for Individuals with
Brain MRA for cerebral aneurysm
CTA or MRA for coronary artery aneurysm
• Brain MRA for cerebral aneurysm
• CTA or MRA for coronary artery aneurysm
## Evaluation of Relatives at Risk
Molecular genetic testing of at-risk relatives of a proband with a known
See
## Pregnancy Management
Cessation of prophylactic antimicrobials is often advised during pregnancy. This may increase the risk of infection and should be taken into consideration. There have been pregnancies without complication, but also instances in which lung disease has worsened after pregnancy, potentially from limited antimicrobial use, delayed radiographic diagnosis, and impaired pulmonary clearance.
Risks associated with pregnancy should be discussed with affected females who have pulmonary compromise, severe scoliosis, or other complications of
## Therapies Under Investigation
Search
## Other
Parents have reported that because of the severe eczema of their child, there have been occasions when the health care providers have alerted Child Protective Services reporting that the child is not being kept clean. While skin hygiene is very important, in spite of the best efforts of caregivers, sometimes the skin flares are severe. Questions about parental neglect/abuse have also arisen when a toddler or young child appears with evidence of repeated fractures. Health care providers who are attuned to these possibilities can serve as important advocates for the parents and family.
## Genetic Counseling
The majority of individuals with
Some individuals diagnosed with
Recommendations for the evaluation of parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly affected [
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• The majority of individuals with
• Some individuals diagnosed with
• Recommendations for the evaluation of parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly affected [
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Mode of Inheritance
## Risk to Family Members
The majority of individuals with
Some individuals diagnosed with
Recommendations for the evaluation of parents of a proband with an apparent
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly affected [
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known
• The majority of individuals with
• Some individuals diagnosed with
• Recommendations for the evaluation of parents of a proband with an apparent
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly affected [
• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known
## Related Genetic Counseling Issues
See Management,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
459 Columbus Avenue
Suite 509
New York NY 10024
Canada
United Kingdom
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• 459 Columbus Avenue
• Suite 509
• New York NY 10024
•
•
• Canada
•
•
• United Kingdom
•
•
•
•
•
•
•
## Molecular Genetics
STAT3 Hyper IgE Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for STAT3 Hyper IgE Syndrome (
Expression of an abnormal gene product with a dominant-negative effect is associated with
Null alleles have not been detected, consistent with the dominant-negative mechanism. Homozygous
Notable
Variants listed in the table have been provided by the authors.
Somatic variants in
## Molecular Pathogenesis
Expression of an abnormal gene product with a dominant-negative effect is associated with
Null alleles have not been detected, consistent with the dominant-negative mechanism. Homozygous
Notable
Variants listed in the table have been provided by the authors.
## Cancer and Benign Tumors
Somatic variants in
## References
## Literature Cited
## Chapter Notes
26 March 2020 (ha) Comprehensive update posted live
7 June 2012 (me) Comprehensive update posted live
23 February 2010 (me) Review posted live
16 July 2009 (jp) Original submission
• 26 March 2020 (ha) Comprehensive update posted live
• 7 June 2012 (me) Comprehensive update posted live
• 23 February 2010 (me) Review posted live
• 16 July 2009 (jp) Original submission
## Revision History
26 March 2020 (ha) Comprehensive update posted live
7 June 2012 (me) Comprehensive update posted live
23 February 2010 (me) Review posted live
16 July 2009 (jp) Original submission
• 26 March 2020 (ha) Comprehensive update posted live
• 7 June 2012 (me) Comprehensive update posted live
• 23 February 2010 (me) Review posted live
• 16 July 2009 (jp) Original submission
|
[
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"WG Borges, T Hensley, JC Carey, BA Petrak, HR Hill. The face of Job.. J Pediatr. 1998;133:303-5",
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"HL Koskela, S Eldfors, P Ellonen, AJ van Adrichem, H Kuusanmäki, EI Andersson, S Lagström, MJ Clemente, T Olson, SE Jalkanen, MM Majumder, H Almusa, H Edgren, M Lepistö, P Mattila, K Guinta, P Koistinen, T Kuittinen, K Penttinen, A Parsons, J Knowles, J Saarela, K Wennerberg, O Kallioniemi, K Porkka, TP Loughran, CA Heckman, JP Maciejewski, S Mustjoki. Somatic STAT3 mutations in large granular lymphocytic leukemia.. N Engl J Med. 2012;366:1905-13",
"AY Kreins, MJ Ciancanelli, S Okada, XF Kong, N Ramírez-Alejo, SS Kilic, J El Baghdadi, S Nonoyama, SA Mahdaviana, F Ailal, A Bousfiha, D Mansouri, E Nievas, CS Ma, G Rao, A Bernasconi, H Sun Kuehn, J Niemela, J Stoddard, P Deveau, A Cobat, S El Azbaoui, A Sabri, CK Lim, M Sundin, DT Avery, R Halwani, AV Grant, B Boisson, D Bogunovic, Y Itan, M Moncada-Velez, R Martinez-Barricarte, M Migaud, C Deswarte, L Alsina, D Kotlarz, C Klein, I Muller-Fleckenstein, B Fleckenstein, V Cormier-Daire, S Rose-John, C Picard, L Hammarstrom, A Puel, S Al-Muhsen, L Abel, D Chaussabel, SD Rosenzweig, Y Minegishi, SG Tangye, J Bustamante, JL Casanova, S Boisson-Dupuis. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome.. J Exp Med. 2015;212:1641-62",
"JC Ling, AF Freeman, AM Gharib, AE Arai, RJ Lederman, DR Rosing, SM Holland. Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome.. Clin Immunol. 2007;122:255-8",
"JD Milner, TP Vogel, L Forbes, CA Ma, A Stray-Pederson, JE Niemela, JJ Lyons, KR Engelhardt, Y Zhang, N Topcagic, ED Roberson, H Matthews, JW Verbsky, T Dasu, A Vargas-Hernandez, N Varghese, KL McClain, LB Karam, K Nahmod, G Makedonas, EM Mace, HS Sorte, G Perminow, VK Rao, MP O'Connell, S Price, HC Su, M Butrick, J McElwee, JD Hughes, J Willet, D Swan, Y Xu, M Santibanez-Koref, V Slowik, DL Dinwiddie, CE Ciaccio, CJ Saunders, S Septer, SF Kingsmore, AJ White, AJ Cant, S Hambleton, MA Cooper. Early onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function STAT3 mutations.. Blood. 2015;125:591-9",
"Y Minegishi, M Saito, T Morio, K Watanabe, K Agematsu, S Tsuchiya, H Takada, T Hara, N Kawamura, T Ariga, H Kaneko, N Kondo, I Tsuge, A Yachie, Y Sakiyama, T Iwata, F Bessho, T Ohishi, K Joh, K Imai, K Kogawa, M Shinohara, M Fujieda, H Wakiguchi, S Pasic, M Abinun, HD Ochs, ED Renner, A Jansson, BH Belohradsky, A Metin, N Shimizu, S Mizutani, T Miyawaki, S Nonoyama, H Karasuyama. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity.. Immunity. 2006;25:745-55",
"M Natarajan, AP Hsu, MA Weinreich, Y Zhang, JE Niemela, JA Butman, S Pittaluga, J Sugui, AL Collar, JK Lim, T Zangeneh, T Carr, AJ Oler, M Similuk, LB Rosen, JV Desai, AF Freeman, SM Holland, KJ Kwon-Chung, JD Milner, MS Lionakis. Aspergillosis, eosinophilic esophagitis, and allergic rhinitis in signal transducer and activator of transcription 3 haploinsufficiency.. J Allergy Clin Immunol. 2018;142:993-997",
"CD Odio, KL Milligan, K McGowan, AK Rudman Spergel, R Bishop, L Boris, A Urban, P Welch, T Heller, D Kleiner, MA Jackson, SM Holland, AF Freeman. Endemic mycoses in patients with STAT3- mutated hyper-IgE (Job) syndrome.. J Allergy Clin Immunol. 2015;136:1411-3",
"NC Patel, JL Gallagher, TR Torgerson, AL Gilman. Successful haploidentical donor hematopoietic stem cell transplant and restoration of STAT3 function in an adolescent with autosomal dominant hyper-IgE syndrome.. J Clin Immunol. 2015;35:479-85",
"A Peled, O Sarig, G Sun, L Samuelov, CA Ma, Y Zhang, T DiMaggio, CG Nelson, KD Stone, AF Freeman, L Malki, LS Vidal, LM Chamarthy, V Briskin, J Mohamad, M Pavlovsky, JE Walter, JD Milner, E Sprecher. Loss-of-function mutations in caspase recruitment domain containing protein 14 (CARD14) are associated with a severe variant of atopic dermatitis.. J Allergy Clin Immunol. 2019;143:173-81",
"ED Renner, JM Puck, SM Holland, M Schmitt, M Weiss, M Frosch, M Bergmann, J Davis, BH Belohradsky, B Grimbacher. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity.. J Pediatr. 2004;144:93-9",
"LF Schimke, J Sawalle-Belohradsky, J Roesler, A Wollenberg, A Rack, M Borte, N Rieber, R Cremer, E Maass, R Dopfer, J Reichenbach, V Wahn, M Hoenig, AF Jansson, A Roesen-Wolff, B Schaub, R Seger, HR Hill, HD Ochs, TR Torgerson, BH Belohradsky, ED Renner. Diagnostic approach to the hyper-IgE syndromes: immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis.. J Allergy Clin Immunol. 2010;126:611-7.e1",
"T Schwerd, SRF Twigg, D Aschenbrenner, S Manrique, KA Miller, IB Taylor, M Capitani, SJ McGowan, E Sweeney, A Weber, L Chen, P Bowness, A Riordan, A Cant, AF Freeman, JD Milner, SM Holland, N Frede, M Müller, D Schmidt-Arras, B Grimbacher, SA Wall, EY Jones, AOM Wilkie, HH Uhlig. A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis.. J Exp Med. 2017;214:2547-62",
"N Shahmarvand, A Nagy, J Ahahryani, RS Ohgami. Mutations of the signal transducer and activator of transcription family of genes in cancer.. Cancer Sci. 2018;109:926-33",
"AM Siegel, J Heimall, AF Freeman, AP Hsu, E Brittain, JM Brenchley, DC Douek, GH Fahle, JI Cohen, SM Holland, JD Milner. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory.. Immunity. 2011;35:806-18",
"KJ Sowerwine, PA Shaw, W Gu, JC Ling, MT Collins, DN Darnell, VL Anderson, J Davis, A Hsu, P Welch, JM Puck, SM Holland, AF Freeman. Bone density and fractures in autosomal dominant hyper IgE syndrome.. J Clin Immunol. 2014;34:260-4",
"PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207",
"DG Stover, AF Freeman, PW Wright, DS Hummell, RM Ness. Diverticulitis in a young man with hyper-IgE syndrome.. South Med J. 2010;103:1261-3",
"A Stray-Pedersen, PH Backe, HS Sorte, L Mørkrid, NY Chokshi, HC Erichsen, T Gambin, KB Elgstøen, M Bjørås, MW Wlodarski, M Krüger, SN Jhangiani, DM Muzny, A Patel, KM Raymond, GS Sasa, RA Krance, CA Martinez, SM Abraham, C Speckmann, S Ehl, P Hall, LR Forbes, E Merckoll, J Westvik, G Nishimura, CF Rustad, TG Abrahamsen, A Rønnestad, LT Osnes, T Egeland, OK Rødningen, CR Beck, EA Boerwinkle, RA Gibbs, JR Lupski, JS Orange, E Lausch, IC Hanson. PGM3 mutations cause a congenital disorder of glycosylation with severe immunodeficiency and skeletal dysplasia.. Am J Hum Genet. 2014;95:96-107",
"K Takeda, K Noguchi, W Shi, T Tanaka, M Matsumoto, N Yoshida, T Kishimoto, S Akira. Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality.. Proc Natl Acad Sci USA. 1997;94:3801-4",
"C Woellner, EM Gertz, AA Schäffer, M Lagos, M Perro, EO Glocker, MC Pietrogrande, F Cossu, JL Franco, N Matamoros, B Pietrucha, E Heropolitańska-Pliszka, M Yeganeh, M Moin, T Español, S Ehl, AR Gennery, M Abinun, A Breborowicz, T Niehues, SS Kilic, A Junker, SE Turvey, A Plebani, B Sánchez, BZ Garty, C Pignata, C Cancrini, J Litzman, O Sanal, U Baumann, R Bacchetta, AP Hsu, JN Davis, L Hammarström, EG Davies, E Eren, PD Arkwright, JS Moilanen, D Viemann, S Khan, L Maródi, AJ Cant, AF Freeman, JM Puck, SM Holland, B Grimbacher. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.. J Allergy Clin Immunol. 2010;125:424-432.e8",
"M Yanagimachi, T Ohya, T Yokosuka, R Kajiwara, F Tanaka, H Goto, T Takashima, T Morio, S Yokota. The potential and limits of hematopoietic stem cell therapy for the treatment of autosomal dominant hyper IgE syndrome.. J Clin Immunol. 2016;36:511-6",
"Q Zhang, JC Davis, IT Lamborn, AF Freeman, H Jing, AJ Favreau, HF Matthews, J Davis, ML Turner, G Uzel, SM Holland, HC Su. Combined immunodeficiency associated with DOCK8 mutations.. N Engl J Med. 2009;361:2046-55",
"Y Zhang, X Yu, M Ichikawa, JJ Lyons, S Datta, IT Lamborn, H Jing, ES Kim, M Biancalana, LA Wolfe, T DiMaggio, HF Matthews, SM Kranick, KD Stone, SM Holland, DS Reich, JD Hughes, H Mehmet, J McElwee, AF Freeman, HH Freeze, HC Su, JD Milner. Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity and neurocognitive impairment.. J Allergy Clin Immunol. 2014;133:1400-9"
] |
23/2/2010
|
26/3/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
hirschsprung-ov
|
hirschsprung-ov
|
[
"Aganglionic Megacolon",
"HSCR",
"Aganglionic Megacolon",
"HSCR",
"7-dehydrocholesterol reductase",
"Brain-derived neurotrophic factor",
"Elongator complex protein 1",
"Endothelin receptor type B",
"Endothelin-3",
"Endothelin-converting enzyme 1",
"Glial cell line-derived neurotrophic factor",
"KIF-binding protein",
"Neural cell adhesion molecule L1",
"Neurofibromin",
"Neurturin",
"Not applicable",
"Paired mesoderm homeobox protein 2B",
"Proto-oncogene tyrosine-protein kinase receptor ret",
"Transcription factor 4",
"Transcription factor SOX-10",
"Zinc finger E-box-binding homeobox 2",
"BDNF",
"DHCR7",
"ECE1",
"EDN3",
"EDNRB",
"ELP1",
"GDNF",
"KIFBP",
"L1CAM",
"NF1",
"NRTN",
"PHOX2B",
"RET",
"RMRP",
"SOX10",
"TCF4",
"ZEB2",
"Hirschsprung Disease",
"Overview"
] |
Hirschsprung Disease Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Melissa A Parisi
|
Summary Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. The aganglionic segment includes the distal rectum and a variable length of contiguous proximal intestine. In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon (short-segment disease); in 15%-20%, aganglionosis extends proximal to the sigmoid colon (long-segment disease); in about 5%, aganglionosis affects the entire large intestine (total colonic aganglionosis). Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis). HSCR is considered a neurocristopathy, a disorder of cells and tissues derived from the neural crest, and may occur as an isolated finding or as part of a multisystem disorder. Affected infants frequently present in the first two months of life with symptoms of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life, constipation, emesis, abdominal pain or distention, and occasionally diarrhea. However, because the initial diagnosis of HSCR may be delayed until late childhood or adulthood, HSCR should be considered in anyone with lifelong severe constipation. Individuals with HSCR are at risk for enterocolitis and/or potentially lethal intestinal perforation. The diagnosis of HSCR requires histopathologic demonstration of absence of enteric ganglion cells in the distal rectum. Suction biopsies of rectal mucosa and submucosa are the preferred diagnostic test in most centers because they can be performed safely without general anesthesia. Syndromes associated with HSCR are diagnosed by clinical findings, cytogenetic analysis, or in some cases, by specific molecular or biochemical tests. Isolated HSCR (i.e., HSCR in the absence of related systemic findings) is a disorder associated with pathogenic variants in a number of genes. Recurrence risk depends on the underlying cause.
|
## Definition
Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. The aganglionic segment includes the distal rectum and a variable length of contiguous proximal intestine.
In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon ("short-segment disease").
In approximately 15%-20%, the aganglionosis extends proximal to the sigmoid colon (long-segment disease).
In approximately 5% of individuals, aganglionosis affects the entire large intestine (total colonic aganglionosis).
Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis) [
Affected infants frequently present in the first two months of life with symptoms of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life (50%-90% of newborns with HSCR), constipation, emesis, abdominal pain or distention, and occasionally diarrhea. However, initial diagnosis of HSCR later in childhood or in adulthood occurs frequently enough that HSCR should be considered if an individual reports lifelong severe constipation.
Individuals with HSCR are at risk for enterocolitis and/or potentially lethal intestinal perforation.
The incidence of short-segment disease (80% of HSCR) is four times greater in males than in females; equal numbers of males and females present with long-segment HSCR [
The diagnosis of HSCR requires histopathologic demonstration of absence of enteric ganglion cells in the distal rectum. Suction biopsies of rectal mucosa and submucosa are the preferred diagnostic test in most centers because they can be performed safely without general anesthesia. Absence of ganglion cells in the submucosa of 50-75 sections examined from a biopsy establishes the diagnosis. Accessory findings include hypertrophic submucosal nerves and/or an abnormal acetylcholinesterase enzyme staining pattern [
The diagnosis may be supported by anorectal manometry, abdominal radiographs that show a dilated proximal colon with empty rectum, or barium enema studies that demonstrate delayed emptying time and a funnel-like transition zone between proximal dilated and distal constricted bowel [
Although radiographic studies may be helpful in delineating the proximal extent of aganglionosis, intraoperative intestinal rectal biopsy is used to establish the precise boundary during surgical resection.
The following disorders should be readily distinguished from HSCR on the basis of other clinical signs, specific tests for those disorders, and a suction biopsy that does not show evidence of aganglionosis.
In newborns with evidence of intestinal obstruction, other possible causes include the following:
Gastrointestinal malformations such as atresia, malrotation, or duplication
Meconium ileus secondary to cystic fibrosis (see
Conditions that cause ganglioneuromatosis, such as MEN 2B [
Conditions associated with abnormalities of the enteric nervous system or musculature, termed chronic intestinal pseudoobstruction (including intestinal neuronal dysplasia [IND]) [
Acquired forms of severe constipation/obstruction may be caused by maternal factors such as infection, alcohol ingestion, or congenital hypothyroidism [
The incidence of HSCR is approximately one in 5,000 live births [
Persons of northern European origin: 1.5 in 10,000 live births
African Americans: 2.1 in 10,000
Asians: 2.8 in 10,000
Within the Mennonite population of Pennsylvania, a founder variant in
• In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon ("short-segment disease").
• In approximately 15%-20%, the aganglionosis extends proximal to the sigmoid colon (long-segment disease).
• In approximately 5% of individuals, aganglionosis affects the entire large intestine (total colonic aganglionosis).
• Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis) [
• Gastrointestinal malformations such as atresia, malrotation, or duplication
• Meconium ileus secondary to cystic fibrosis (see
• Conditions that cause ganglioneuromatosis, such as MEN 2B [
• Conditions associated with abnormalities of the enteric nervous system or musculature, termed chronic intestinal pseudoobstruction (including intestinal neuronal dysplasia [IND]) [
• Persons of northern European origin: 1.5 in 10,000 live births
• African Americans: 2.1 in 10,000
• Asians: 2.8 in 10,000
## Clinical Manifestations
Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract. The aganglionic segment includes the distal rectum and a variable length of contiguous proximal intestine.
In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon ("short-segment disease").
In approximately 15%-20%, the aganglionosis extends proximal to the sigmoid colon (long-segment disease).
In approximately 5% of individuals, aganglionosis affects the entire large intestine (total colonic aganglionosis).
Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis) [
Affected infants frequently present in the first two months of life with symptoms of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life (50%-90% of newborns with HSCR), constipation, emesis, abdominal pain or distention, and occasionally diarrhea. However, initial diagnosis of HSCR later in childhood or in adulthood occurs frequently enough that HSCR should be considered if an individual reports lifelong severe constipation.
Individuals with HSCR are at risk for enterocolitis and/or potentially lethal intestinal perforation.
The incidence of short-segment disease (80% of HSCR) is four times greater in males than in females; equal numbers of males and females present with long-segment HSCR [
• In 80% of individuals, aganglionosis is restricted to the rectosigmoid colon ("short-segment disease").
• In approximately 15%-20%, the aganglionosis extends proximal to the sigmoid colon (long-segment disease).
• In approximately 5% of individuals, aganglionosis affects the entire large intestine (total colonic aganglionosis).
• Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis) [
## Establishing the Diagnosis
The diagnosis of HSCR requires histopathologic demonstration of absence of enteric ganglion cells in the distal rectum. Suction biopsies of rectal mucosa and submucosa are the preferred diagnostic test in most centers because they can be performed safely without general anesthesia. Absence of ganglion cells in the submucosa of 50-75 sections examined from a biopsy establishes the diagnosis. Accessory findings include hypertrophic submucosal nerves and/or an abnormal acetylcholinesterase enzyme staining pattern [
The diagnosis may be supported by anorectal manometry, abdominal radiographs that show a dilated proximal colon with empty rectum, or barium enema studies that demonstrate delayed emptying time and a funnel-like transition zone between proximal dilated and distal constricted bowel [
Although radiographic studies may be helpful in delineating the proximal extent of aganglionosis, intraoperative intestinal rectal biopsy is used to establish the precise boundary during surgical resection.
## Differential Diagnosis
The following disorders should be readily distinguished from HSCR on the basis of other clinical signs, specific tests for those disorders, and a suction biopsy that does not show evidence of aganglionosis.
In newborns with evidence of intestinal obstruction, other possible causes include the following:
Gastrointestinal malformations such as atresia, malrotation, or duplication
Meconium ileus secondary to cystic fibrosis (see
Conditions that cause ganglioneuromatosis, such as MEN 2B [
Conditions associated with abnormalities of the enteric nervous system or musculature, termed chronic intestinal pseudoobstruction (including intestinal neuronal dysplasia [IND]) [
Acquired forms of severe constipation/obstruction may be caused by maternal factors such as infection, alcohol ingestion, or congenital hypothyroidism [
• Gastrointestinal malformations such as atresia, malrotation, or duplication
• Meconium ileus secondary to cystic fibrosis (see
• Conditions that cause ganglioneuromatosis, such as MEN 2B [
• Conditions associated with abnormalities of the enteric nervous system or musculature, termed chronic intestinal pseudoobstruction (including intestinal neuronal dysplasia [IND]) [
## Prevalence
The incidence of HSCR is approximately one in 5,000 live births [
Persons of northern European origin: 1.5 in 10,000 live births
African Americans: 2.1 in 10,000
Asians: 2.8 in 10,000
Within the Mennonite population of Pennsylvania, a founder variant in
• Persons of northern European origin: 1.5 in 10,000 live births
• African Americans: 2.1 in 10,000
• Asians: 2.8 in 10,000
## Causes
A chromosome abnormality is present in approximately 12% of individuals with HSCR (
The most common chromosome abnormality associated with HSCR is Down syndrome (trisomy 21), which occurs in 2%-10% of all individuals with HSCR [
Some chromosome aberrations include deletions that encompass HSCR-associated genes:
del13q22 (
del10q11.2 (
del10q23.1 (
del2q22 (
del 4p12 (
Identification of individuals with HSCR and such deletions aided in discovery of several of these genes, and reinforces the haploinsufficiency model of HSCR pathogenesis in individuals with a deletion of one of the genes.
Other chromosome anomalies (del 17q21/dup 17q21-q23 [
Chromosome Abnormalities Associated with HSCR
CHD = congenital heart disease; ID = intellectual disability
Monogenic disorders are those caused by mutation of a single gene and inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Both syndromic and nonsyndromic causes of HSCR are recognized.
Syndromes associated with HSCR are listed in alphabetic order; the prevalence of HSCR in each syndrome varies widely and is estimated in
Inheritance is autosomal recessive. The involved gene,
Note: Goldberg-Shprintzen syndrome is distinct from the
While most individuals with MEN 2A do not have aganglionosis, and vice versa, in some series an estimated 2.5%-5% of individuals with HSCR have a MEN 2A-associated
No evidence for
In general, WS4 results from homozygosity for
In contrast, all the pathogenic
Monogenic Syndromic Forms of HSCR
ACC = agenesis of the corpus callosum; AD = autosomal dominant; AR = autosomal recessive;
Chromosome locus from
Limited data are available.
In FMTC, affected individuals do not have pheochromocytoma or hyperparathyroidism.
Nonsyndromic HSCR (in which HSCR occurs without other anomalies) has been associated with pathogenic variants in a number of genes [
Genes Associated with Nonsyndromic HSCR
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Chromosome locus from
Pathogenic variants in the gene have also been reported with syndromic forms of HSCR (see
In addition to clearly pathogenic
Homozygous pathogenic variants have been associated with total colonic aganglionosis in some cases.
A variant in this gene is insufficient by itself to cause disease in most cases Click
Limited data are available.
The syndromic form is usually associated with homozygous pathogenic variants in this gene.
Although rare coding pathogenic variants in
Most pathogenic variants are associated with nonsyndromic forms of HSCR; however, because a few individuals are reported to have other anomalies this form of HSCR may also be syndromic.
Copy number variants (mostly deletions) in this gene have also been implicated in HSCR. Most reported deletions have been intragenic rather than large copy number variants [
One individual had a rectocutaneous fistula.
Variants in
Approximately 18% of individuals with HSCR have at least one other congenital anomaly [
Some of the most frequent anomalies include congenital heart defects (≤5% of individuals with HSCR, excluding those with Down syndrome), gastrointestinal malformations (including Meckel diverticulum, malrotation, and imperforate anus, with an incidence of ≤4% of individuals with HSCR), central nervous system abnormalities (a broad spectrum of disorders, in ≤4%), and genitourinary abnormalities (including cryptorchidism, hypospadias, and renal malformations, in ≤7%). Craniofacial abnormalities and spina bifida have also been seen in association with HSCR [
HSCR with Congenital Anomalies of Unknown Cause
ASD = atrial septal defect; ID = intellectual disability; PDA = patent ductus arteriosus; VSD= ventricular septal defect
Incidence figures are derived from
• del13q22 (
• del10q11.2 (
• del10q23.1 (
• del2q22 (
• del 4p12 (
• While most individuals with MEN 2A do not have aganglionosis, and vice versa, in some series an estimated 2.5%-5% of individuals with HSCR have a MEN 2A-associated
## Chromosomal Causes
A chromosome abnormality is present in approximately 12% of individuals with HSCR (
The most common chromosome abnormality associated with HSCR is Down syndrome (trisomy 21), which occurs in 2%-10% of all individuals with HSCR [
Some chromosome aberrations include deletions that encompass HSCR-associated genes:
del13q22 (
del10q11.2 (
del10q23.1 (
del2q22 (
del 4p12 (
Identification of individuals with HSCR and such deletions aided in discovery of several of these genes, and reinforces the haploinsufficiency model of HSCR pathogenesis in individuals with a deletion of one of the genes.
Other chromosome anomalies (del 17q21/dup 17q21-q23 [
Chromosome Abnormalities Associated with HSCR
CHD = congenital heart disease; ID = intellectual disability
• del13q22 (
• del10q11.2 (
• del10q23.1 (
• del2q22 (
• del 4p12 (
## Single-Gene Causes
Monogenic disorders are those caused by mutation of a single gene and inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Both syndromic and nonsyndromic causes of HSCR are recognized.
Syndromes associated with HSCR are listed in alphabetic order; the prevalence of HSCR in each syndrome varies widely and is estimated in
Inheritance is autosomal recessive. The involved gene,
Note: Goldberg-Shprintzen syndrome is distinct from the
While most individuals with MEN 2A do not have aganglionosis, and vice versa, in some series an estimated 2.5%-5% of individuals with HSCR have a MEN 2A-associated
No evidence for
In general, WS4 results from homozygosity for
In contrast, all the pathogenic
Monogenic Syndromic Forms of HSCR
ACC = agenesis of the corpus callosum; AD = autosomal dominant; AR = autosomal recessive;
Chromosome locus from
Limited data are available.
In FMTC, affected individuals do not have pheochromocytoma or hyperparathyroidism.
Nonsyndromic HSCR (in which HSCR occurs without other anomalies) has been associated with pathogenic variants in a number of genes [
Genes Associated with Nonsyndromic HSCR
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Chromosome locus from
Pathogenic variants in the gene have also been reported with syndromic forms of HSCR (see
In addition to clearly pathogenic
Homozygous pathogenic variants have been associated with total colonic aganglionosis in some cases.
A variant in this gene is insufficient by itself to cause disease in most cases Click
Limited data are available.
The syndromic form is usually associated with homozygous pathogenic variants in this gene.
Although rare coding pathogenic variants in
Most pathogenic variants are associated with nonsyndromic forms of HSCR; however, because a few individuals are reported to have other anomalies this form of HSCR may also be syndromic.
Copy number variants (mostly deletions) in this gene have also been implicated in HSCR. Most reported deletions have been intragenic rather than large copy number variants [
One individual had a rectocutaneous fistula.
Variants in
• While most individuals with MEN 2A do not have aganglionosis, and vice versa, in some series an estimated 2.5%-5% of individuals with HSCR have a MEN 2A-associated
## Syndromic HSCR
Syndromes associated with HSCR are listed in alphabetic order; the prevalence of HSCR in each syndrome varies widely and is estimated in
Inheritance is autosomal recessive. The involved gene,
Note: Goldberg-Shprintzen syndrome is distinct from the
While most individuals with MEN 2A do not have aganglionosis, and vice versa, in some series an estimated 2.5%-5% of individuals with HSCR have a MEN 2A-associated
No evidence for
In general, WS4 results from homozygosity for
In contrast, all the pathogenic
Monogenic Syndromic Forms of HSCR
ACC = agenesis of the corpus callosum; AD = autosomal dominant; AR = autosomal recessive;
Chromosome locus from
Limited data are available.
In FMTC, affected individuals do not have pheochromocytoma or hyperparathyroidism.
• While most individuals with MEN 2A do not have aganglionosis, and vice versa, in some series an estimated 2.5%-5% of individuals with HSCR have a MEN 2A-associated
## Nonsyndromic HSCR
Nonsyndromic HSCR (in which HSCR occurs without other anomalies) has been associated with pathogenic variants in a number of genes [
Genes Associated with Nonsyndromic HSCR
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Chromosome locus from
Pathogenic variants in the gene have also been reported with syndromic forms of HSCR (see
In addition to clearly pathogenic
Homozygous pathogenic variants have been associated with total colonic aganglionosis in some cases.
A variant in this gene is insufficient by itself to cause disease in most cases Click
Limited data are available.
The syndromic form is usually associated with homozygous pathogenic variants in this gene.
Although rare coding pathogenic variants in
Most pathogenic variants are associated with nonsyndromic forms of HSCR; however, because a few individuals are reported to have other anomalies this form of HSCR may also be syndromic.
Copy number variants (mostly deletions) in this gene have also been implicated in HSCR. Most reported deletions have been intragenic rather than large copy number variants [
One individual had a rectocutaneous fistula.
Variants in
## Unknown Cause
Approximately 18% of individuals with HSCR have at least one other congenital anomaly [
Some of the most frequent anomalies include congenital heart defects (≤5% of individuals with HSCR, excluding those with Down syndrome), gastrointestinal malformations (including Meckel diverticulum, malrotation, and imperforate anus, with an incidence of ≤4% of individuals with HSCR), central nervous system abnormalities (a broad spectrum of disorders, in ≤4%), and genitourinary abnormalities (including cryptorchidism, hypospadias, and renal malformations, in ≤7%). Craniofacial abnormalities and spina bifida have also been seen in association with HSCR [
HSCR with Congenital Anomalies of Unknown Cause
ASD = atrial septal defect; ID = intellectual disability; PDA = patent ductus arteriosus; VSD= ventricular septal defect
Incidence figures are derived from
## Evaluation Strategy
Identification of the cause of Hirschsprung disease (HSCR) aids in establishing prognosis and mode of inheritance for genetic counseling.
To help establish the cause of HSCR, the workup for an individual with HSCR includes the following:
Establish the diagnosis of monogenic syndromic HSCR (
Suggest monogenic nonsyndromic HSCR (
For monogenic nonsyndromic HSCR, molecular genetic testing of
Some groups recommend testing for
If a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Establish the diagnosis of monogenic syndromic HSCR (
• Suggest monogenic nonsyndromic HSCR (
• Establish the diagnosis of monogenic syndromic HSCR (
• Suggest monogenic nonsyndromic HSCR (
• For monogenic nonsyndromic HSCR, molecular genetic testing of
• Some groups recommend testing for
• If a
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• For monogenic nonsyndromic HSCR, molecular genetic testing of
• Some groups recommend testing for
• If a
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• Establish the diagnosis of monogenic syndromic HSCR (
• Suggest monogenic nonsyndromic HSCR (
• For monogenic nonsyndromic HSCR, molecular genetic testing of
• Some groups recommend testing for
• If a
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Genetic Counseling
If a proband has an inherited or
In probands with nonsyndromic HSCR without a clear etiology, HSCR is considered to be a polygenic disorder with reduced penetrance, variable expressivity, and a 4:1 predominance in males.
Nonsyndromic autosomal dominant HSCR
A significant proportion of affected individuals have inherited a pathogenic variant from an unaffected parent, a finding that presumably can be attributed to reduced penetrance and variable expressivity.
In a few documented cases, affected individuals inherited two (likely pathogenic) variants in different HSCR-related genes, one variant from each parent (presumably representing digenic inheritance) [
A proband with nonsyndromic autosomal dominant HSCR may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Nonsyndromic HSCR of unknown etiology: empiric risks
The parents of a proband with nonsyndromic HSCR of unknown etiology are likely to be unaffected.
Nonsyndromic autosomal dominant HSCR
The risk to the sibs of the proband with nonsyndromic autosomal dominant HSCR depends on the genetic status of the proband's parents.
If a parent of the proband is affected and/or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit a pathogenic variant may not develop manifestations of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
Nonsyndromic HSCR of unknown etiology: empiric risks
The overall risk to sibs of a proband is 4% (vs 0.02%, the incidence of HSCR in the general population) [
The risk is higher to sibs of probands with long-segment disease and depends on the sex of the proband and sib (
The risk to sibs of probands with short-segment disease is lower and more consistent with the risks associated with a recessive or multifactorial pattern of inheritance (
Recurrence Risk for HSCR in Sibs Based on Length of Involved Segment
Based on
Nonsyndromic autosomal dominant HSCR
Each child of an individual with nonsyndromic autosomal dominant HSCR has a 50% chance of inheriting the pathogenic variant.
Because of reduced penetrance, the offspring who inherits a pathogenic variant may not develop symptoms of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
Nonsyndromic HSCR of unknown etiology: empiric risks
Offspring of a proband with nonsyndromic HSCR of unknown etiology are at increased risk of having HSCR; however, precise estimates are not available.
The risk to other family members depends on the genetic status of the proband's parents.
If a parent is affected, his or her family members may be at risk.
Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for nonsyndromic autosomal dominant HSCR are possible.
Requests for prenatal testing for conditions such as nonsyndromic HSCR are not common since a fetus identified as having a potential pathogenic variant may never develop manifestations of HSCR. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
• Nonsyndromic autosomal dominant HSCR
• A significant proportion of affected individuals have inherited a pathogenic variant from an unaffected parent, a finding that presumably can be attributed to reduced penetrance and variable expressivity.
• In a few documented cases, affected individuals inherited two (likely pathogenic) variants in different HSCR-related genes, one variant from each parent (presumably representing digenic inheritance) [
• A proband with nonsyndromic autosomal dominant HSCR may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• A significant proportion of affected individuals have inherited a pathogenic variant from an unaffected parent, a finding that presumably can be attributed to reduced penetrance and variable expressivity.
• In a few documented cases, affected individuals inherited two (likely pathogenic) variants in different HSCR-related genes, one variant from each parent (presumably representing digenic inheritance) [
• A proband with nonsyndromic autosomal dominant HSCR may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Nonsyndromic HSCR of unknown etiology: empiric risks
• The parents of a proband with nonsyndromic HSCR of unknown etiology are likely to be unaffected.
• The parents of a proband with nonsyndromic HSCR of unknown etiology are likely to be unaffected.
• A significant proportion of affected individuals have inherited a pathogenic variant from an unaffected parent, a finding that presumably can be attributed to reduced penetrance and variable expressivity.
• In a few documented cases, affected individuals inherited two (likely pathogenic) variants in different HSCR-related genes, one variant from each parent (presumably representing digenic inheritance) [
• A proband with nonsyndromic autosomal dominant HSCR may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• The parents of a proband with nonsyndromic HSCR of unknown etiology are likely to be unaffected.
• Nonsyndromic autosomal dominant HSCR
• The risk to the sibs of the proband with nonsyndromic autosomal dominant HSCR depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit a pathogenic variant may not develop manifestations of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• The risk to the sibs of the proband with nonsyndromic autosomal dominant HSCR depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit a pathogenic variant may not develop manifestations of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• Nonsyndromic HSCR of unknown etiology: empiric risks
• The overall risk to sibs of a proband is 4% (vs 0.02%, the incidence of HSCR in the general population) [
• The risk is higher to sibs of probands with long-segment disease and depends on the sex of the proband and sib (
• The risk to sibs of probands with short-segment disease is lower and more consistent with the risks associated with a recessive or multifactorial pattern of inheritance (
• The overall risk to sibs of a proband is 4% (vs 0.02%, the incidence of HSCR in the general population) [
• The risk is higher to sibs of probands with long-segment disease and depends on the sex of the proband and sib (
• The risk to sibs of probands with short-segment disease is lower and more consistent with the risks associated with a recessive or multifactorial pattern of inheritance (
• The risk to the sibs of the proband with nonsyndromic autosomal dominant HSCR depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit a pathogenic variant may not develop manifestations of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• The overall risk to sibs of a proband is 4% (vs 0.02%, the incidence of HSCR in the general population) [
• The risk is higher to sibs of probands with long-segment disease and depends on the sex of the proband and sib (
• The risk to sibs of probands with short-segment disease is lower and more consistent with the risks associated with a recessive or multifactorial pattern of inheritance (
• Nonsyndromic autosomal dominant HSCR
• Each child of an individual with nonsyndromic autosomal dominant HSCR has a 50% chance of inheriting the pathogenic variant.
• Because of reduced penetrance, the offspring who inherits a pathogenic variant may not develop symptoms of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• Each child of an individual with nonsyndromic autosomal dominant HSCR has a 50% chance of inheriting the pathogenic variant.
• Because of reduced penetrance, the offspring who inherits a pathogenic variant may not develop symptoms of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• Nonsyndromic HSCR of unknown etiology: empiric risks
• Offspring of a proband with nonsyndromic HSCR of unknown etiology are at increased risk of having HSCR; however, precise estimates are not available.
• Offspring of a proband with nonsyndromic HSCR of unknown etiology are at increased risk of having HSCR; however, precise estimates are not available.
• Each child of an individual with nonsyndromic autosomal dominant HSCR has a 50% chance of inheriting the pathogenic variant.
• Because of reduced penetrance, the offspring who inherits a pathogenic variant may not develop symptoms of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• Offspring of a proband with nonsyndromic HSCR of unknown etiology are at increased risk of having HSCR; however, precise estimates are not available.
• The risk to other family members depends on the genetic status of the proband's parents.
• If a parent is affected, his or her family members may be at risk.
## Mode of Inheritance
If a proband has an inherited or
In probands with nonsyndromic HSCR without a clear etiology, HSCR is considered to be a polygenic disorder with reduced penetrance, variable expressivity, and a 4:1 predominance in males.
## Risk to Family Members – Nonsyndromic HSCR
Nonsyndromic autosomal dominant HSCR
A significant proportion of affected individuals have inherited a pathogenic variant from an unaffected parent, a finding that presumably can be attributed to reduced penetrance and variable expressivity.
In a few documented cases, affected individuals inherited two (likely pathogenic) variants in different HSCR-related genes, one variant from each parent (presumably representing digenic inheritance) [
A proband with nonsyndromic autosomal dominant HSCR may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Nonsyndromic HSCR of unknown etiology: empiric risks
The parents of a proband with nonsyndromic HSCR of unknown etiology are likely to be unaffected.
Nonsyndromic autosomal dominant HSCR
The risk to the sibs of the proband with nonsyndromic autosomal dominant HSCR depends on the genetic status of the proband's parents.
If a parent of the proband is affected and/or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit a pathogenic variant may not develop manifestations of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
Nonsyndromic HSCR of unknown etiology: empiric risks
The overall risk to sibs of a proband is 4% (vs 0.02%, the incidence of HSCR in the general population) [
The risk is higher to sibs of probands with long-segment disease and depends on the sex of the proband and sib (
The risk to sibs of probands with short-segment disease is lower and more consistent with the risks associated with a recessive or multifactorial pattern of inheritance (
Recurrence Risk for HSCR in Sibs Based on Length of Involved Segment
Based on
Nonsyndromic autosomal dominant HSCR
Each child of an individual with nonsyndromic autosomal dominant HSCR has a 50% chance of inheriting the pathogenic variant.
Because of reduced penetrance, the offspring who inherits a pathogenic variant may not develop symptoms of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
Nonsyndromic HSCR of unknown etiology: empiric risks
Offspring of a proband with nonsyndromic HSCR of unknown etiology are at increased risk of having HSCR; however, precise estimates are not available.
The risk to other family members depends on the genetic status of the proband's parents.
If a parent is affected, his or her family members may be at risk.
• Nonsyndromic autosomal dominant HSCR
• A significant proportion of affected individuals have inherited a pathogenic variant from an unaffected parent, a finding that presumably can be attributed to reduced penetrance and variable expressivity.
• In a few documented cases, affected individuals inherited two (likely pathogenic) variants in different HSCR-related genes, one variant from each parent (presumably representing digenic inheritance) [
• A proband with nonsyndromic autosomal dominant HSCR may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• A significant proportion of affected individuals have inherited a pathogenic variant from an unaffected parent, a finding that presumably can be attributed to reduced penetrance and variable expressivity.
• In a few documented cases, affected individuals inherited two (likely pathogenic) variants in different HSCR-related genes, one variant from each parent (presumably representing digenic inheritance) [
• A proband with nonsyndromic autosomal dominant HSCR may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Nonsyndromic HSCR of unknown etiology: empiric risks
• The parents of a proband with nonsyndromic HSCR of unknown etiology are likely to be unaffected.
• The parents of a proband with nonsyndromic HSCR of unknown etiology are likely to be unaffected.
• A significant proportion of affected individuals have inherited a pathogenic variant from an unaffected parent, a finding that presumably can be attributed to reduced penetrance and variable expressivity.
• In a few documented cases, affected individuals inherited two (likely pathogenic) variants in different HSCR-related genes, one variant from each parent (presumably representing digenic inheritance) [
• A proband with nonsyndromic autosomal dominant HSCR may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• The parents of a proband with nonsyndromic HSCR of unknown etiology are likely to be unaffected.
• Nonsyndromic autosomal dominant HSCR
• The risk to the sibs of the proband with nonsyndromic autosomal dominant HSCR depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit a pathogenic variant may not develop manifestations of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• The risk to the sibs of the proband with nonsyndromic autosomal dominant HSCR depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit a pathogenic variant may not develop manifestations of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• Nonsyndromic HSCR of unknown etiology: empiric risks
• The overall risk to sibs of a proband is 4% (vs 0.02%, the incidence of HSCR in the general population) [
• The risk is higher to sibs of probands with long-segment disease and depends on the sex of the proband and sib (
• The risk to sibs of probands with short-segment disease is lower and more consistent with the risks associated with a recessive or multifactorial pattern of inheritance (
• The overall risk to sibs of a proband is 4% (vs 0.02%, the incidence of HSCR in the general population) [
• The risk is higher to sibs of probands with long-segment disease and depends on the sex of the proband and sib (
• The risk to sibs of probands with short-segment disease is lower and more consistent with the risks associated with a recessive or multifactorial pattern of inheritance (
• The risk to the sibs of the proband with nonsyndromic autosomal dominant HSCR depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or has the pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit a pathogenic variant may not develop manifestations of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• The overall risk to sibs of a proband is 4% (vs 0.02%, the incidence of HSCR in the general population) [
• The risk is higher to sibs of probands with long-segment disease and depends on the sex of the proband and sib (
• The risk to sibs of probands with short-segment disease is lower and more consistent with the risks associated with a recessive or multifactorial pattern of inheritance (
• Nonsyndromic autosomal dominant HSCR
• Each child of an individual with nonsyndromic autosomal dominant HSCR has a 50% chance of inheriting the pathogenic variant.
• Because of reduced penetrance, the offspring who inherits a pathogenic variant may not develop symptoms of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• Each child of an individual with nonsyndromic autosomal dominant HSCR has a 50% chance of inheriting the pathogenic variant.
• Because of reduced penetrance, the offspring who inherits a pathogenic variant may not develop symptoms of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• Nonsyndromic HSCR of unknown etiology: empiric risks
• Offspring of a proband with nonsyndromic HSCR of unknown etiology are at increased risk of having HSCR; however, precise estimates are not available.
• Offspring of a proband with nonsyndromic HSCR of unknown etiology are at increased risk of having HSCR; however, precise estimates are not available.
• Each child of an individual with nonsyndromic autosomal dominant HSCR has a 50% chance of inheriting the pathogenic variant.
• Because of reduced penetrance, the offspring who inherits a pathogenic variant may not develop symptoms of HSCR, and for those who do develop HSCR, the degree of severity cannot be predicted.
• Offspring of a proband with nonsyndromic HSCR of unknown etiology are at increased risk of having HSCR; however, precise estimates are not available.
• The risk to other family members depends on the genetic status of the proband's parents.
• If a parent is affected, his or her family members may be at risk.
## Related Genetic Counseling Issues
## Prenatal Testing and Preimplantation Genetic Testing – Nonsyndromic Autosomal Dominant HSCR
Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for nonsyndromic autosomal dominant HSCR are possible.
Requests for prenatal testing for conditions such as nonsyndromic HSCR are not common since a fetus identified as having a potential pathogenic variant may never develop manifestations of HSCR. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
## Resources
United Kingdom
PO Box 170864
Milwaukee WI 53217-8076
PO Box 170864
Milwaukee WI 53217-8076
2312 Savoy Street
Hoover AL 35226-1528
•
• United Kingdom
•
•
•
•
• PO Box 170864
• Milwaukee WI 53217-8076
•
•
• PO Box 170864
• Milwaukee WI 53217-8076
•
•
• 2312 Savoy Street
• Hoover AL 35226-1528
•
## Management
Resection of the aganglionic segment and anastomosis of proximal bowel to the anus ("pull-through") is the standard treatment for HSCR and can be performed as a single procedure or in stages. A variety of surgical anastomoses have been developed with the general goal of eliminating obstruction while preserving continence.
An effort is generally made to resect a variable length of gut just proximal to the aganglionic zone since this transitional area may have altered pathologic properties (e.g., hypoganglionosis) and physiologic properties that are not conducive to normal intestinal motility [
Individuals with extensive intestinal aganglionosis who develop irreversible intestinal failure may be candidates for intestinal transplantation [
## Treatment of Manifestations
Resection of the aganglionic segment and anastomosis of proximal bowel to the anus ("pull-through") is the standard treatment for HSCR and can be performed as a single procedure or in stages. A variety of surgical anastomoses have been developed with the general goal of eliminating obstruction while preserving continence.
An effort is generally made to resect a variable length of gut just proximal to the aganglionic zone since this transitional area may have altered pathologic properties (e.g., hypoganglionosis) and physiologic properties that are not conducive to normal intestinal motility [
Individuals with extensive intestinal aganglionosis who develop irreversible intestinal failure may be candidates for intestinal transplantation [
## References
## Literature Cited
## Chapter Notes
Raj Paul Kapur, MD, PhD; University of Washington (2002-2004) Melissa Parisi, MD, PhD (2002-present)
5 March 2020 (ma) Retired chapter: Phenotype is too broad.
1 October 2015 (me) Comprehensive update posted live
10 November 2011 (cd) Revision: sequence analysis and prenatal testing available for mutations in
26 December 2006 (me) Comprehensive update posted live
28 July 2004 (me) Comprehensive update posted live
12 July 2002 (me) Overview posted live
23 February 2002 (mp) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 5 March 2020 (ma) Retired chapter: Phenotype is too broad.
• 1 October 2015 (me) Comprehensive update posted live
• 10 November 2011 (cd) Revision: sequence analysis and prenatal testing available for mutations in
• 26 December 2006 (me) Comprehensive update posted live
• 28 July 2004 (me) Comprehensive update posted live
• 12 July 2002 (me) Overview posted live
• 23 February 2002 (mp) Original submission
## Author History
Raj Paul Kapur, MD, PhD; University of Washington (2002-2004) Melissa Parisi, MD, PhD (2002-present)
## Revision History
5 March 2020 (ma) Retired chapter: Phenotype is too broad.
1 October 2015 (me) Comprehensive update posted live
10 November 2011 (cd) Revision: sequence analysis and prenatal testing available for mutations in
26 December 2006 (me) Comprehensive update posted live
28 July 2004 (me) Comprehensive update posted live
12 July 2002 (me) Overview posted live
23 February 2002 (mp) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 5 March 2020 (ma) Retired chapter: Phenotype is too broad.
• 1 October 2015 (me) Comprehensive update posted live
• 10 November 2011 (cd) Revision: sequence analysis and prenatal testing available for mutations in
• 26 December 2006 (me) Comprehensive update posted live
• 28 July 2004 (me) Comprehensive update posted live
• 12 July 2002 (me) Overview posted live
• 23 February 2002 (mp) Original submission
|
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] |
12/7/2002
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1/10/2015
|
10/11/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
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